Advances in Experimental Medicine and Biology 862

Breast Cancer Research Foundation

Patricia A. Ganz
Editor

Improving
Outcomes for
Breast Cancer
Survivors
Perspectives on Research Challenges
and Opportunities
Advances in Experimental Medicine and Biology

The Breast Cancer Research Foundation

Larry Norton, MD
Medical Director, Evelyn H. Lauder Breast Center
Memorial Sloan Kettering Cancer Center
Professor of Medicine, Weill Cornell Medical College
Scientific Director, Breast Cancer Research Foundation

Clifford Hudis, MD
Chief, Breast Medicine Service
Memorial Sloan Kettering Cancer Center
Professor of Medicine, Weill Cornell Medical College
Chairman, Scientific Advisory Board, Breast Cancer Research Foundation

Volume 862

Editorial Board:

IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel

ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA
JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA
RODOLFO PAOLETTI, University of Milan, Milan, Italy

More information about this series at http://www.springer.com/series/5584

Patricia A. Ganz
Editor

Improving Outcomes for

Breast Cancer Survivors
Perspectives on Research Challenges
and Opportunities
Editor
Patricia A. Ganz
Distinguished Professor of Health Policy & Management and Medicine
UCLA Fielding School of Public Health
David Geffen School of Medicine at UCLA
Director, Cancer Prevention & Control Research
Jonsson Comprehensive Cancer Center
Los Angeles, CA, USA

ISSN 0065-2598 ISSN 2214-8019 (electronic)

Advances in Experimental Medicine and Biology
ISBN 978-3-319-16365-9 ISBN 978-3-319-16366-6 (eBook)
DOI 10.1007/978-3-319-16366-6

Library of Congress Control Number: 2015938588

Springer Cham Heidelberg New York Dordrecht London

© Breast Cancer Research Foundation 2015
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About the Breast Cancer Research Foundation

The Breast Cancer Research Foundation (BCRF) advances the world’s most
promising research to eradicate breast cancer. Founded by Evelyn H. Lauder in
1993, BCRF has raised more than $550 million to fuel discoveries in tumor biology,
genetics, prevention, treatment, survivorship, and metastasis, making it one of the
largest nongovernmental funders of breast cancer research in the world. In 2014,
BCRF invested $58.6 million in research, including $11.6 million to the interna-
tional Evelyn H. Lauder Founder’s Fund focused on metastasis, to support more
than 220 researchers at leading medical institutions across six continents. By spend-
ing 91 cents of every dollar on research and public awareness programs, BCRF
remains one of the nation's most fiscally responsible nonprofits. BCRF is the only
breast cancer organization with an “A+” from CharityWatch and has been awarded
Charity Navigator’s highest rating of four stars 13 times since 2002. For more infor-
mation, please visit: www.bcrfcure.org.

v
Series Editors

Larry Norton, M.D.

Deputy Physician-in-Chief for Breast Cancer Programs; Medical Director,
Evelyn H. Lauder Breast Center; Norna S. Sarofim Chair in Clinical Oncology,
Memorial Sloan Kettering Cancer Center

Dr. Norton is a board-certified medical oncologist with broad interests in cancer

prevention, diagnosis, and treatment. In his clinical practice, he cares for women
with breast cancer and is now Deputy Physician-in-Chief for Breast Cancer
Programs at Memorial Sloan Kettering and Medical Director of the Evelyn H.
Lauder Breast Center.
His research concerns the basic biology of cancer; the mathematics of tumor
causation and growth; and the development of approaches to better diagnosis, pre-
vention, and drug treatment of the disease. He is involved in many areas of research,
including identifying the genes that predispose people to cancer or that cause cancer
and developing new drugs, monoclonal antibodies that target growth factor recep-
tors, and vaccines. A major milestone in his research career was the development of

vii
viii Series Editors

an approach to therapy called “dose density” or “sequential dose density,” which

maximizes the killing of cancer cells while minimizing toxicity.
Dr. Norton is currently the principal investigator of a program project grant from
the National Cancer Institute (NCI) that is aimed at better understanding breast
cancer in the laboratory and in bringing these advances into clinical practice. On a
national level, he was formerly the Chair of the Breast Committee of the NCI’s
Cancer and Leukemia Group B. He was President of the American Society of
Clinical Oncology (ASCO) from 2001 to 2002 and was appointed by President
Clinton to serve on the National Cancer Advisory Board (the board of directors of
The NCI). He has served as Scientific Director of the Breast Cancer Research
Foundation since its inception in 1993.
Among many awards over the course of my career, he was honored to receive
ASCO’s David A. Karnofsky Award and The McGuire Lectureship at the San
Antonio Breast Cancer Symposium. He is an author of more than 350 articles and
many book chapters; has served as a visiting professor throughout USA, Canada,
South America, Europe, Israel, and Asia; and has also trained many cancer doctors
and researchers.

Clifford A. Hudis, M.D.

Chief, Breast Medicine Service
Memorial Sloan Kettering Cancer Center

Dr. Hudis is Chief of the Breast Medicine Service and Attending Physician at
Memorial Sloan Kettering Cancer Center (MSKCC) in New York City, where he is
co-Leader of the Breast Disease Management Team and a Professor of Medicine at
the Weill Cornell Medical College. He is the immediate Past President of the
American Society of Clinical Oncology (ASCO), Chairman of BCRF Scientific
Advisory Board, co-Chair of the Breast Committee of the Alliance (formerly the
CALGB), and a member of the Steering Committee of the Translational Breast
Cancer Research Consortium (TBCRC).
Series Editors ix

A 1983 graduate of the Medical College of Pennsylvania (a combined 6-year

BA/MD program with Lehigh University), Dr. Hudis trained in Internal Medicine in
Philadelphia before completing his fellowship in Medical Oncology at MSKCC. He
joined the faculty in 1991.
Dr. Hudis’s research includes the development of a wide range of novel drugs
and the study of relevant correlative science endpoints in breast cancer. With his
collaborators both at MSKCC and elsewhere, his personal research is focused on
understanding the mechanisms that link diet, obesity, inflammation, and breast can-
cer risk and outcomes. Building on their discoveries of low-grade inflammation in
association with overweight and obesity, Dr. Hudis and his colleagues are studying
interventions that may reduce the risk, and return, of breast cancer. Across his ser-
vice at MSKCC, his team conducts studies of novel-targeted therapies in advanced
disease, of new strategies in the adjuvant and neo-adjuvant settings, and of risk
reduction.
Preface

Breast cancer is a heterogeneous disease. There are multiple biological subtypes of

breast cancer that dictate diverse therapies whose application results in prolonged
survival for the vast majority of patients. The women (and men) who are diagnosed
with breast cancer are also heterogeneous. They experience the disease in individual
ways that are often dependent on their age, socioeconomic and partnership status,
residence in an urban or rural environment, access to care and receipt of appropriate
treatment, and receipt of adequate psychosocial support during and after treatment.
Breast cancer treatments extend over many months of primary treatment, followed
by prolonged endocrine treatments for the majority of women. A segment of the
breast cancer population lives with metastatic disease while receiving continuous
serial treatments during which time physical, psychosocial, and financial concerns
are substantial. Nearly three million US breast cancer survivors must adjust to “the
new normal.”
In this volume, we focus on the patient-centered outcomes of breast cancer, high-
lighting specific patient populations, their unique needs and experiences, as well as
more general outcomes (symptoms, quality of life, psychosocial concerns) and
chronic health risks that are consequences of breast cancer and its treatments. We
also focus on opportunities for health and wellness promotion that are essential to
facilitating recovery after breast cancer treatment. It was a privilege for me to serve
as the editor for this first volume in a series that is a collaboration between the
Breast Cancer Research Foundation (BCRF) and Springer. The content of this vol-
ume reflects the commitment of both organizations to this area of breast cancer
research, as well as the depth of the BCRF research portfolio in this domain. The 16
contributing authors are all funded BCRF investigators and their research reveals
the breadth of scientific research on breast cancer outcomes.
We are extremely grateful to Dr. Larry Norton, whose visionary scientific leader-
ship of the BCRF has created a community of investigators dedicated to conducting
research along the entire continuum of scientific inquiry—from cells to society. In
conceiving of this book series and our work on this volume, Dr. Norton encouraged

xi
xii Preface

us to “share our viewpoints, interpretations, and ‘gut feelings’ about where we are,
where we are going, and how we think we should get there. We don’t always agree,
but creative thought feeds off our opinions, as long as they are evidence based and
insightful. This project is an attempt to recapture that spirited conversation. This is
your chance to get your ideas, criticisms, questions, predictions, and concepts for
how we can make progress faster out there for discussion, maybe debate, and—I
would hope—action.” Larry, I hope we have delivered on your request!
Finally, as we worked hard during a 12-month period to produce this volume,
we were inspired by the memory of the late Evelyn Lauder, as well as the dedi-
cated BCRF staff—Myra Biblowit, Margaret (Peg) Mastrianni, and many others.
They have made it possible for this group of investigators to pursue the most inno-
vative and exciting research they can imagine, focused on improving outcomes for
patients with breast cancer. We extend our sincere appreciation to the BCRF and
its supporters.

Los Angeles, CA Patricia A. Ganz

March 2015
Contents

1 Breast Cancer Survivorship: Where Are We Today? .......................... 1

Patricia A. Ganz and Pamela J. Goodwin
2 Special Issues in Younger Women with Breast Cancer ....................... 9
Patricia A. Ganz, Julienne E. Bower, and Annette L. Stanton
3 Special Issues in Older Women with Breast Cancer ............................ 23
Arti Hurria and Hy Muss
4 Breast Cancer Among Special Populations: Disparities
in Care Across the Cancer Control Continuum ................................... 39
Electra D. Paskett
5 Symptoms: Fatigue and Cognitive Dysfunction ................................... 53
Julienne E. Bower and Patricia A. Ganz
6 Symptoms: Chemotherapy-Induced Peripheral Neuropathy ............. 77
Bryan P. Schneider, Dawn L. Hershman, and Charles Loprinzi
7 Symptoms: Aromatase Inhibitor Induced Arthralgias ....................... 89
Dawn L. Hershman, Charles Loprinzi, and Bryan P. Schneider
8 Symptoms: Lymphedema ....................................................................... 101
Electra D. Paskett
9 Symptoms: Menopause, Infertility, and Sexual Health ....................... 115
Debra L. Barton and Patricia A. Ganz
10 Host Factors and Risk of Breast Cancer Recurrence:
Genetic, Epigenetic and Biologic Factors and Breast
Cancer Outcomes .................................................................................... 143
Christine B. Ambrosone, Chi-Chen Hong, and Pamela J. Goodwin

xiii
xiv Contents

11 Comorbidities and Their Management: Potential Impact

on Breast Cancer Outcomes ................................................................... 155
Chi-Chen Hong, Christine B. Ambrosone, and Pamela J. Goodwin
12 Modifiable Lifestyle Factors and Breast Cancer Outcomes:
Current Controversies and Research Recommendations ................... 177
Pamela J. Goodwin, Christine B. Ambrosone, and Chi-Chen Hong
13 Risk Reduction from Weight Management and Physical
Activity Interventions ............................................................................. 193
Melinda L. Irwin, Carol Fabian, and Anne McTiernan
14 Prevention and Treatment of Cardiac Dysfunction
in Breast Cancer Survivors .................................................................... 213
Carol Fabian
15 Psychological Adjustment in Breast Cancer Survivors ....................... 231
Annette L. Stanton and Julienne E. Bower
16 Living with Metastatic Breast Cancer .................................................. 243
Patricia A. Ganz and Annette L. Stanton
17 Quality of Care, Including Survivorship Care Plans ........................... 255
Dawn L. Hershman and Patricia A. Ganz

Index ................................................................................................................. 271

About the Editor

Patricia A. Ganz M.D. currently holds an American Cancer Society Clinical

Research Professorship and is a Professor in the UCLA Schools of Medicine and
Public Health. For over 30 years, Dr. Ganz has been doing systematic research on
the health-related quality of life impact of cancer and its treatment. Through her
research, she has contributed to the understanding of how women adjust to the diag-
nosis of breast cancer, including its effects on their physical, emotional, social, and
sexual well-being. Her current research focuses on understanding the biological
mechanisms associated with the development of posttreatment fatigue and cogni-
tive dysfunction, along with the development and testing of interventions to miti-
gate these symptoms in breast cancer patients and survivors. Dr. Ganz is a founding
member of the National Coalition for Cancer Survivorship (NCCS) and was previ-
ously awarded the Breast Cancer Research Foundation’s Jill Rose Award and the
Susan G. Komen Professor of Survivorship. Dr. Ganz is the first recipient of the
ASCO Professorship in Breast Cancer Comparative Effectiveness Research. Dr.
Ganz serves as a Deputy Editor for the Journal of the National Cancer Institute and
Associate Editor of CA-A Journal for Clinicians. She has also been actively involved
in measurement of quality of life endpoints in clinical trials, with leadership roles in
the Southwest Oncology Group (SWOG), the National Surgical Adjuvant Breast
and Bowel Project (NSABP), and now NRG Oncology. She has published over 390
scientific papers and countless book chapters, and she has also edited three books
with Springer. She has received over 23,000 citations in her career.

xv
Chapter 1
Breast Cancer Survivorship:
Where Are We Today?

Patricia A. Ganz and Pamela J. Goodwin

Abstract Breast cancer is the most common cancer in women, and survivors with
this diagnosis account for almost one fourth of the over 14 million cancer survivors
in the US. After several decades of basic and clinical trials research, we have learned
much about the heterogeneity of breast cancer and have evolved a complex and
multidisciplinary treatment approach to the disease. Increasingly, we are paying
attention to the long term and late effects of breast cancer treatment, and this is
largely the subject of this volume. In this chapter, the authors introduce the topic of
breast cancer survivorship and highlight the organization and content of this vol-
ume, briefly describing the contents of the subsequent chapters.

Keywords Breast cancer • Survivorship • Outcomes • Quality of life • Quality of care

Breast cancer is one of the most feared diseases, especially among women in North
America, yet it has become an exemplar of success in the war against cancer.1 Not
too long ago, most breast cancers were detected by the woman herself (substantially
larger than 2 cm) and had already spread to the axillary lymph nodes. Just 40 years
ago we were still using radical surgical approaches for the treatment of breast can-
cer, declaring that we had “got it all” surgically, even though metastatic disease
would appear within a few years after surgery. The concept of adjuvant chemo-
therapy and endocrine therapy slowly evolved over several decades of systematic
investigation through clinical trials, and we even experimented with high dose che-
motherapy as adjuvant therapy.

1
Please note, while we acknowledge that men are diagnosed with breast cancer as well, we will
focus on the experience of women as so much more information is available on their outcomes.
P.A. Ganz (*)
UCLA Schools of Medicine and Public Health, Jonsson Comprehensive Cancer Center,
Los Angeles, CA, USA
e-mail: [email protected]
P.J. Goodwin
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 1

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_1
2 P.A. Ganz and P.J. Goodwin

Today, there has been a significant shift in the stage of newly-diagnosed breast
cancer to negative node disease, and we have refined our knowledge of the disease
biology, such that risk stratification by molecular subtypes allows us to define more
tailored and often less toxic therapies. The multidisciplinary clinical approach to the
management of breast cancer (surgery, radiology, pathology, medical oncology,
radiation therapy, and reconstructive surgery), as well as the translational approach
to breast cancer research, are now the models for other cancer sites. While we can
argue about whether or not intensive mammographic screening has led to overdiag-
nosis, identifying low risk conditions that may cause no harm, there is no question
that the overall outcomes for women with breast cancer diagnosed today are sub-
stantially better than when many of us started our oncology training several
decades ago.
As a consequence of the advances, there has been a striking decline in breast
cancer mortality over the past two decades (Siegel et al. 2014). A secondary out-
come is the growing number of breast cancer survivors who now number nearly 3
million in the US and represent 41 % of female cancer survivors (Desantis et al.
2014). These women live in our communities, share our workplaces, teach our chil-
dren, and may be a spouse or loved one. Almost everyone has acquaintances who
have had breast cancer, and most of those affected are no longer hiding their experi-
ence from others, unlike the situation 50 years ago when the first women with breast
cancer could not talk about it in public and had trouble finding support for each
other. On the other hand, there are still many women living with metastatic breast
cancer who are being maintained on treatment for long periods of time and who are
hoping for the next therapeutic breakthrough. In the United States, nearly 40,000
women are lost to breast cancer each year, and we clearly need to do a better job
eliminating premature death and suffering from this disease.
As survival outcomes improve, many survivors are at risk for non-breast cancer
related diseases. One recent study that examined deaths in postmenopausal women
with hormone receptor positive breast cancer participating in a trial of extended
adjuvant endocrine therapy found that non-breast cancer deaths accounted for 60 %
of all deaths; this proportion was higher in women over 70 years of age (72 %) and
lower in younger women (48 %) (Chapman et al. 2008). Second cancers and cardio-
vascular disease were the commonest non-breast cancer causes of death. Because
obesity is associated with increased postmenopausal breast cancer risk, survivors
may be at increased risk of obesity associated conditions such as diabetes. These
observations underscore the importance of maintaining overall health in breast can-
cer survivors, and suggest that secondary prevention strategies, including adoption
of a healthy lifestyle and appropriate management of non-breast cancer related
health issues, such as hypertension and lipid disorders, should be considered high
priorities. The diagnosis of cancer has been considered a “teachable moment”
(Demark-Wahnefried et al. 2005), a time when many women re-evaluate their pri-
orities and may be more amenable to making lifestyle and other changes (including
smoking cessation, weight loss, enhanced physical activity, and adoption of a
healthy diet) that will lead to improved health. Exploitation of this teachable
moment may yield important benefits.
1 Breast Cancer Survivorship: Where Are We Today? 3

In this volume, we have been given an opportunity to focus on a wide range of

outcomes associated with the diagnosis and treatment of breast cancer. This work is
the product of an innovative collaboration between the Breast Cancer Research
Foundation (BCRF) and Springer, as part of its Advances in Experimental Medicine
and Biology series. The charge to the authors was to produce a work that provides
perspective and commentary, and not the traditional review article that so often is
found in multi-authored edited volumes. All of the authors are BCRF funded
researchers who are working in the topic areas that they are writing about. Many of
the author teams are active research collaborators, but several of the chapters have
brought together scientists who have not previously worked together and were
asked to do so for the purpose of this effort. For those of you who may know some
of the authors, you will likely hear their personal voice come through—something
we encouraged to make this book different and to emphasize the goal of providing
a perspective on the field and where the research is today and where it needs to be
going. As such, those of you who read this volume will be disappointed if you are
expecting a thorough review of a chapter topic—this was not our goal.
The title of this volume—Improving Outcomes for Breast Cancer Survivors—
actually has two meanings: the word “improving” is both an adjective and a verb
as used to describe the book’s content. We are faced with a large and growing
population of breast cancer survivors whose outcomes are much improved over a
generation ago. In the long term, many of these survivors experience quality of life
that is comparable to that of women without breast cancer (Hsu et al. 2013), but
this experience is not universal. We need to work on improving outcomes for those
survivors who suffer from persistent symptoms and side effects after treatment
ends, and for those with recurrent or persistent disease who remain on long term
therapy. In the section that follows, we briefly highlight how the BCRF authors
address specific content areas, so as to direct your attention to the expert opinion
this volume contains.
In three early chapters in the book, we have chosen to highlight the needs of
several special populations among breast cancer patients and survivors. While the
average age of breast cancer diagnosis is 61 years in the United States, and it is still
largely a disease of women of European origin in the US and Canada, it affects
women of all ages and all ethnic and racial subgroups. In fact, it is the leading cause
of cancer in women worldwide. Age at diagnosis can have a tremendous effect on
how women cope and adjust to a breast cancer diagnosis, as well as to the toxicities
they experience from treatments. In a chapter devoted to younger women (Chap. 2,
Ganz et al.) the unique needs and concerns of this population are addressed, includ-
ing life stage, premature menopause, reproductive and fertility concerns, risk of
hereditary cancers, as well as the unique emotional needs of younger women.
Importantly, because of the long life span these women face after breast cancer
treatment, preventing and reducing the risk for late effects of cancer treatment is
critical. In parallel, the older woman with breast cancer may be extremely vigorous
or, at the other extreme, burdened with comorbid conditions when cancer is diag-
nosed. In Chap. 3, Hurria and Muss, highlight the unique needs of older women
with breast cancer and how we need more research to better understand how to man-
4 P.A. Ganz and P.J. Goodwin

age treatment and potential toxicities in this population. The importance of main-
taining functional independence in this population is a central goal. For both older
and younger patients with breast cancer, there is a paucity of research targeting their
specific needs and concerns, and the authors highlight areas that need our attention.
Lastly, in Chap. 4 on Disparities in Care Across the Cancer Control Continuum,
Paskett alerts us to the many gaps in knowledge related to the experience of vulner-
able populations (racial/ethnic groups, older women, women from rural and urban
areas) who are most likely to experience disparities in care related to breast cancer.
In some settings it is a lack of institutional (health system) resources for early detec-
tion and prompt treatment, in others there are patient level factors that lead to poorer
outcomes including attitudes, behaviors, culture and limited financial resources/
access to care. There is much to be done, and there are important US national efforts
that are now focusing on many of these problems.
In the next section of the book, we focus on key symptoms/syndromes that are
frequent consequences of breast cancer treatment. In Chap. 5, scientific collabora-
tors Bower and Ganz provide important insights into the biological mechanisms
associated with cancer-related fatigue and cognitive dysfunction, both of which are
nearly universal during the primary treatment of breast cancer (surgery, radiation,
chemotherapy) and are persistent in a about 25 % of survivors long after treatment
ends. Their pioneering work has demonstrated a close biological linkage between
these two common symptoms, with a focus on the development and evaluation of
interventions to mitigate post-treatment fatigue and cognitive complaints. However,
much more research needs to be done. Much less is known about the biological
mechanisms associated with the development of chemotherapy-induced peripheral
neuropathy (Chap. 6 by Schneider et al.). This is especially concerning given the
frequent use of taxanes in contemporary adjuvant therapy regimens. Addressing
this important gap in knowledge, as well as understanding who is at greatest risk
for neuropathy, will be important steps to reducing the frequency with which long-
term breast cancer survivors suffer with ongoing symptoms. A lack of animal mod-
els for studying this toxicity is an important gap. These authors allude to the fact
that we have now traded the rare complications of leukemia and cardiac dysfunc-
tion from anthracyclines for the persistent numbness and pain associated with tax-
ane chemotherapy in as many as one quarter of patients, who receive this common
adjuvant therapy.
Aromatase inhibitor induced arthralgias are another common symptom experi-
enced by large numbers of breast cancer patients and survivors, and this topic is ably
addressed in Chap. 7 by Hershman et al. Musculoskeletal pain and stiffness in asso-
ciation with this widely prescribed endocrine therapy occurs at a much higher rate
(40–50 %) than initially described in the phase three randomized trials that led to
the approval of these agents. These authors explored potential mechanisms for these
symptoms, as well as possible strategies to identify those at high risk. Unfortunately,
this symptom co-occurs with many chronic comorbid conditions of aging, compro-
mising the functional independence that is so important among older women. In
Chap. 8, Paskett addresses the challenges associated with the prevention, detection
and treatment of lymphedema. Fortunately, this is one symptom that has become
1 Breast Cancer Survivorship: Where Are We Today? 5

much less frequent in the past decade with the more widespread use of sentinel node
biopsy and less frequent radiation of the axilla when it is not necessary. Nevertheless,
for those women who develop swelling of their arm either early or late in the course
of survivorship, it is often difficult to manage and the swelling becomes a constant
reminder of their cancer and its treatment. There remain many gaps in knowledge of
how best to prevent and manage this unfortunate complication of breast cancer
treatment. In Chap. 9, Barton and Ganz, highlight the challenges of delivering thera-
pies for breast cancer where these highly effective therapies often precipitate meno-
pause and its associated symptoms, along with infertility and disruptions in sexual
health and functioning. There is considerable understanding of the biology of many
of these symptoms based on research on the menopause in healthy women, but
strategies to mitigate common symptoms may not be appropriate in breast cancer
patients. The authors note that “reducing the untoward effects of cancer treatment
on the reproductive health of breast cancer survivors is the ultimate goal,” and strat-
egies need to be developed to provide more personalized therapies to meet the needs
of individual patients.
Several chapters explore comorbidities and other aspects of the woman herself
(often called host factors) that may relate to breast cancer outcomes. Some of these
host characteristics are amenable to change, potentially leading to improved out-
comes, while others are not. Understanding the contributions of these factors to
breast cancer outcomes, including treatment toxicities, may impact choice of treat-
ment. When modifiable, change may lead to improved outcomes.
In Chap. 10, Ambrosone et al. review the revolution that has occurred in classify-
ing breast cancers, based on their genetic profiles. This has led, for example, to the
recognition of intrinsic subtypes (e.g. luminal A and B, basal, HER2, normal) that
have different biology, treatment responsiveness and outcomes. Additional work
has explored DNA copy number variations, mutation profiles and expression pat-
terns overall and within these intrinsic subtypes that are of potential utility in the
development of targeted treatments. These authors discuss the potential importance
of germline factors, such as polymorphisms in the CYP2D6 gene, a gene that is
responsible for activation of tamoxifen to endoxifen. Although genotyping for
CYP2D6 variants is not widely used (because the link between genotype and
tamoxifen benefit has not been convincingly established), the concurrent use of
tamoxifen and strong CYP2D6 inhibitors (such as serotonin reuptake inhibitors) can
lead to reduced tamoxifen benefit and is not recommended. It is hoped that additional
research, including genome wide association studies will identify genetic factors
associated with metabolism and toxicity of a broader range of breast cancer drugs.
Research into the potential contributions of environmental factors related to DNA
methylation and function, and of Vitamin D exposure to cancer outcomes is also
discussed. The goal of this broad area of research is the development of more person-
alized breast cancer treatment, maximizing efficacy while minimizing toxicity.
Hong and colleagues (Chap. 11) address the important issue of comorbidity in
breast cancer patients, discussing the impact of comorbidity on treatment selection
and outcomes (both breast cancer related and overall). Comorbidity is most common
in older survivors, and is associated with less intense treatment, greater treatment
6 P.A. Ganz and P.J. Goodwin

toxicity, poorer quality of life and increased risk of death from breast cancer or other
causes. Given the growing number of breast cancer survivors who live long periods
of time after their diagnosis, proper management of comorbidities is an important
clinical issue. Involvement of primary care physicians, and co-ordination of care
between oncologists and these physicians is critical to the management of survivors
with comorbidities. Many studies of comorbidity have used cancer registries or
administrative databases that have restricted availability of information about
younger women, disease severity and treatment that may limit the scope of research
that can be performed; future research will need to overcome these limitations. Key
research priorities include improved management of comorbidities and evaluation
of the effect of this improved management on outcomes, evaluation of potential
effects of medications used to treat comorbidities (e.g. metformin, NSAIDs) on
outcomes, and investigation of comorbidities in susceptible populations.
In Chap. 12, Goodwin et al discuss the potential contribution of modifiable
lifestyle factors (weight, diet, physical activity, alcohol) to breast cancer outcomes
while in Chap. 13 Irwin and colleagues focus on diet, physical activity and weight
management interventions in breast cancer survivors. Together, these chapters high-
light the growing recognition that lifestyle may contribute to breast cancer out-
comes. Overweight and obesity have been associated with poor outcomes in over 50
studies over the past 35–40 years; more recent work has suggested physical activity
may be associated with better outcomes. Lifestyle change, notably increased physi-
cal activity, dietary change and weight loss are feasible and may have beneficial
effects on fitness, quality of life and treatment-related symptoms. Ongoing interven-
tion research is discussed and potential biologic mediators of lifestyle effects on
outcome identified. These chapters discuss ongoing areas of controversy and stress
the need for well-designed intervention trials that will formally test the effects of
lifestyle interventions, notably weight loss, on breast cancer outcomes. Both groups
of authors identify research priorities, including translational biomarker studies,
and they advocate for adequately powered intervention trials that will provide defin-
itive evidence regarding effects of lifestyle change on breast cancer outcomes.
The next series of chapters highlights survivorship issues that warrant special
attention, including cardiac dysfunction, psychosocial adjustment, quality of care
and survivorship in the face of metastatic disease. These broad issues have emerged
as important research and clinical priorities, and they will likely continue to be
major areas of focus over the next decade.
Fabian discusses the important issue of cardiac dysfunction in breast cancer sur-
vivors in Chap. 14. Breast cancer patients may be at increased risk for cardiovascu-
lar disease at diagnosis due the presence of risk factors such as obesity and physical
inactivity. Two major classes of drugs (anthracyclines and HER-2 targeted agents)
that are most commonly associated with cardiac dysfunction are reviewed.
Anthracyclines are directly cardiotoxic with age, higher cumulative dose, co-
morbidity and African American ethnicity being associated with increased cardiac
toxicity. In contrast, HER-2 targeted agents can promote reversible cardiotoxicity
by interfering with neuregulin binding to HER-2 receptors on cardiac myocytes.
Fabian advocates for research to develop a standard nomenclature for cardiac
1 Breast Cancer Survivorship: Where Are We Today? 7

dysfunction (suggesting a decline in LVEF of at least 10 % or to a level below 50 %,

as a commonly used definition), to identify cardioprotective treatment regimens and
to generate more accurate models to predict risk of cardiac dysfunction, potentially
including measures of global left ventricular strain and troponin. She also discussed
treatment of cardiotoxicity and preventive approaches that incorporate drugs such
as ACE inhibitors and beta-blockers, as well as manpower issues in the burgeoning
area of cardio-oncology.
In Chap. 15, Stanton and Bower discuss psychosocial adjustment in breast can-
cer survivors. In addition to the commonly recognized negative psychosocial
sequelae (e.g. depression, anxiety, Post-Traumatic Stress Disorder), they discuss the
growing recognition of the potential for positive growth after breast cancer diagnosis.
They introduce trajectories of adjustment and recovery during the initial months and
years after diagnosis, but comment that anxiety regarding recurrence often persists
after other symptoms have resolved. They suggest that greater disease impact and
engagement may be important correlates of positive psychological outcomes,
including “strengthened inter-personal relationships, life appreciation, commitment
to priorities, spirituality, personal regard, and attention to health behaviors”. Stanton
and Bower discuss key directions for psychosocial and biobehavioral intervention
research, prioritizing issues such as understanding biopsychosocial mechanisms of
intervention benefits, the use of stepped-care interventions to allow delivery to those
who would benefit most, and extending research to less well studied minorities,
socially and financially disadvantaged groups.
Ganz and Stanton focus on the complexities of survivorship in women with met-
astatic breast cancer in Chap. 16, including those who present with metastatic dis-
ease at diagnosis and those who develop metastases after initial potentially curative
treatment. They estimate that there may be up to 160,000 individuals living with
metastatic breast cancer in the US and suggest that younger patients may be dispro-
portionately represented. Although women dealing with metastatic disease face a
broad range of issues that are relevant in this population (including life threat and
uncertainty, interpersonal challenges, physical symptoms such as pain and fatigue
as well as psychological symptoms such as depression, anxiety and adjustment dis-
orders), most attain positive psychological health. Recognizing the profound het-
erogeneity of the course of disease, with survival ranging from months to decades,
these authors advocate for early palliative and psychosocial support in addition to
ongoing expert oncologic management. They highlight the need for more system-
atic research in this population, with a focus on psychosocial, quality of life and
symptom endpoints, as well as how to best integrate palliative care into standard
disease management and how to best address practical issues such as the costs of
medical care, the potential to continue working, and how to deal with family issues.
The focus on women living with metastatic breast cancer is an important emerging
area in survivorship research—it highlights a somewhat understudied and under-
served population of survivors.
Hershman and Ganz close out this volume with a discussion of quality of survi-
vorship care in Chap. 17. They adopt a broad definition of survivorship—from
diagnosis through the balance of life, including those close to the woman with
8 P.A. Ganz and P.J. Goodwin

cancer—and they discuss challenges in the delivery of quality care, highlighting the
contributions of clinical guidelines in the establishment and dissemination of qual-
ity care. Examples of common gaps in quality care include discussions of fertility/
premature menopause with younger patients, the potential for long term toxicity,
non-adherence to oral endocrine therapy and the need for formal survivorship care
planning. Challenges for survivors include the cost of care. The need for evidence-
based, cost-effective follow-up, avoiding unnecessary testing and minimizing dis-
parities in treatment and outcomes are discussed. Finally, key areas of ongoing and
future research are reviewed, including the need to reduce over-diagnosis and over-
treatment as well as appropriate survivorship care planning that focusses on com-
munication, involvement of primary care physicians, attention to psychosocial
issues and individualization of the process rather than on a “one size fits all” care
plan document.
In summary, this is a very unique volume in that it presents in one place the spec-
trum of non-mortality outcomes from breast cancer treatment in a comprehensive
way, with attention to unique populations (older, younger, living with metastatic
disease) and common toxicities. Improving outcomes for breast cancer survivors is
the goal, and the contributing authors provide a perspective on what we know and
where the research should be heading. The BCRF has invested extensively in fund-
ing a broad portfolio of research during the past two decades, and we are pleased to
be able to share this portion of the portfolio with the scientific, advocacy and lay
community.

References

Chapman JA, Meng D, Shepherd L, Parulekar W, Ingle JN, Muss HB, Goss PE (2008) Competing
causes of death from a randomized trial of extended adjuvant endocrine therapy for breast
cancer. J Natl Cancer Inst 100(4):252–60. doi:10.1093/jnci/djn014
Demark-Wahnefried W, Aziz NM, Rowland JH, Pinto BM (2005) Riding the crest of the teachable
moment: promoting long-term health after the diagnosis of cancer. J Clin Oncol 23(24):
5814–30
Desantis C, Ma J, Bryan L, Jemal A (2014) Breast cancer statistics, 2013. CA Cancer J Clin
64(1):52–62. doi:10.3322/caac.21203
Hsu T, Ennis M, Hood N, Graham M, Goodwin PJ (2013) Quality of life in long-term breast cancer
survivors. J Clin Oncol 31(28):3540–8. doi:10.1200/JCO.2012.48.1903
Siegel R, Ma J, Zou Z, Jemal A (2014) Cancer statistics, 2014. CA Cancer J Clin 64(1):9–29
Chapter 2
Special Issues in Younger Women
with Breast Cancer

Patricia A. Ganz, Julienne E. Bower, and Annette L. Stanton

Abstract Although women less than 50 years old make up less than 25 % of the
patient population with breast cancer in industrialized countries, they have unique
clinical and psychosocial issues that must be addressed as part of their oncology care
to ensure the best health and psychosocial outcomes after treatment. Preserving fer-
tility is a major issue for many younger women who have either not had children or
would like to have additional children after treatment. Dealing with the disruption of
a cancer diagnosis at a young age is challenging physically, socially and emotionally,
and the health care system does not always address these patients’ concerns. Because
younger women have the potential for a long life expectancy after cancer treatment,
preventing and reducing the risk for late effects of cancer treatment is very impor-
tant. We discuss these and a range of other issues throughout this chapter.

Keywords Younger women • Fertility • Psychosocial distress • Premature

menopause • Hereditary breast cancer

Introduction

In Western industrialized countries, breast cancer is primarily a disease of post-

menopausal women, with incidence patterns showing a modest premenopausal
peak in the fifth decade of life, but a much more substantial incidence peak in the
seventh and eighth decades. For a woman who is age 30, the probability of develop-
ing breast cancer in the next 10 years is 0.44 % or 1 in 228, while at age 70 the 10

P.A. Ganz (*)

UCLA Schools of Medicine and Public Health, Jonsson Comprehensive Cancer Center,
Los Angeles, CA, USA
e-mail: [email protected]
J.E. Bower • A.L. Stanton
Departments of Psychology and Psychiatry/Biobehavioral Sciences, Jonsson Comprehensive
Cancer Center, University of California, Los Angeles, CA, USA
e-mail: [email protected]; [email protected]

© Breast Cancer Research Foundation 2015 9

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_2
10 P.A. Ganz et al.

Table 2.1 Age-specific probabilities of developing invasive female breast cancera

If current age is The probability of developing breast cancer in the next 10 years is (in %) Or 1 in:
20 0.06 1,732
30 0.44 228
40 1.45 69
50 2.31 43
60 3.49 29
70 3.84 26
Lifetime risk 12.29 8
Adapted from Desantis et al. (2014) with permission
a
Among those free of cancer at the beginning of the age interval. Based on cases diagnosed between
2008 and 2010. Percentages and “1 in” numbers may not be numerically equivalent due to round-
ing. Probabilities derived using the National Cancer Institute DevCan software (version 6.7.0)

years probability is 3.84 % or 1 in 28 (Desantis et al. 2014) (Table 2.1). Thus, when
cancer occurs in a very young woman it is a rare and unexpected event. She has no
peers who have the disease, and she may be at a time in life where she has not com-
pleted her education or professional development, and may or may not be in a long-
term partnered relationship. If she is without children, cancer treatment may
substantially disrupt her childbearing plans; if she already is a parent, she may fear
for her ability to successfully raise her children, and not leave them prematurely.
For women who are in their 40s, cancer treatments may precipitate early meno-
pause, and the disruptions of cancer treatments often add stresses to normal mid-life
issues and career challenges.
Younger women are a heterogeneous group, at various developmental stages, and
as such, their concerns and needs differ substantially from more mature women who
have likely had friends who have experienced breast cancer, and for whom years of
screening mammography and educational campaigns have alerted them to the possi-
bility of breast cancer occurring. In this chapter, we will provide a description of the
diverse characteristics of younger women with breast cancer, including the tumor and
treatment variations, the reproductive consequences of treatments, the social and psy-
chological sequelae, and their higher risk of mortality from breast cancer. We subse-
quently will examine the many research challenges and opportunities that management
of this target population requires, including the tailoring of treatments to reduce the
burden of long term toxicities, better management of psychological health, as well as
better access to fertility preservation, health promotion and cancer prevention.

Who Are the Younger Women with Breast Cancer?

Breast cancer in women younger than 50 makes up about 25 % of the incident breast
cancer cases each year (Desantis et al. 2014) (see Table 2.2). Fewer numbers of inci-
dent cases occur if one uses earlier age cut-points, as noted previously. In a recent
systematic review of the unique psychosocial needs of younger women with breast
cancer, we used age 50 years as the cut-point for the review due to the paucity of
2 Special Issues in Younger Women with Breast Cancer 11

Table 2.2 Estimated new female breast cancer cases and deaths by
age, United States, 2013a
Age In situ cases Invasive cases Deaths
<40 1,900 10,980 1,020
<50 15,650 48,910 4,780
50–64 26,770 84,210 11,970
65+ 22,220 99,220 22,870
All ages 64,640 232,340 39,620
Adapted from Desantis et al. (2014) with permission
Source Total estimated cases are based on 1995–2009 incidence rates
from 49 states as reported by the North American Association for
Central Cancer Registries. Total estimated deaths are based on data
from the US mortality data, 1995–2009, National Center for Health
Statistics, Centers for Disease Control and Prevention
a
Rounded to nearest 10

literature focused solely on very young women (Howard-Anderson et al. 2012).

45 years is probably a more appropriate age to use as a cut point for linking to other
studies of young adults with cancer, which use 39 years as the upper age limit
(Brinton et al. 2008; Tricoli et al. 2011). However, in detailed interviews with younger
women with breast cancer, classification of “young” was more often associated with
life stage and challenges, rather than chronological age (Dunn and Steginga 2000).
While there is no official definition of “young breast cancer patient” we will focus on
the diversity of clinical and psychosocial features of women with breast cancer who
are less than 50 years at diagnosis. However, a CDC program and federal legislation
that has called attention to this group of patients using an age of less than 45 years at
diagnosis (http://www.cdc.gov/cancer/breast/young_women/index.htm) Although
we acknowledge that younger men may be affected by breast cancer, this is such a
small group, for which even less is known, that we confine our discussion to women.
The complexity of discussing this special population relates foremost to the diver-
sity of life stage of development interacting with chronological age. The experience
of the rare young woman diagnosed with breast cancer while in college is extremely
different from the mother of teenage children who is in her early 40s. However, within
these several decades of risk that these two women mark, the emotional, educational,
professional and reproductive issues may be similar and be independent of chrono-
logical age. The ability to accept the cancer diagnosis, complete treatment, remain
adherent to endocrine therapy if required, and continue with education or work, may
be more tied to emotional maturity and financial resources, which may or may not be
related to chronological age. Also, younger women with breast cancer have a higher
likelihood of hereditary breast cancer, where knowledge of the potential risk for the
disease is known (i.e., by family history if not by established mutation); however,
many women diagnosed at a young age may first learn of having a germ line mutation
for breast cancer at the time of cancer diagnosis, without prior knowledge of the dis-
ease in any relatives, especially if this is passed through the paternal line. The rate of
germ line mutations of BRCA1 are considerably higher in younger women than in
older women, and TP53 mutations may also be responsible for breast cancer in these
12 P.A. Ganz et al.

Table 2.3 Predicted probabilities of a BRCA1 mutation based on age and tumor
characteristics
Age (years) All histologies (%) ER-negative and high-grade tumors (%)
<30 8 35
31–34 5 26.5
35–39 2 6.6
40–44 1.5 3.7
45–49 1 2.5
50–59 0.3 0.9
ER Estrogen receptor
Adapted from Gabriel and Domchek (2010) with permission

women (Gabriel and Domchek 2010) (Table 2.3). Increasingly, breast cancer gene
panels are being used to assess these younger women, and in the future, we may have
a better explanation for the occurrence of cancer at such a young age. Also, among
these women may be survivors of a prior childhood cancer in which radiation treat-
ment to the thorax or total body was included (Moskowitz et al. 2014). Such women
are also among the younger breast cancer patients and survivors.
One of the other challenges among younger women is the co-occurrence of breast
cancer and pregnancy—largely due to the later age of marriage and childbearing
among well-educated women (Litton et al. 2013; Partridge et al. 2004; Theriault and
Litton 2013). Deferring pregnancy until an older age is a recent phenomenon in
Western industrialized countries. These breast cancers may be diagnosed during
pregnancy or in the first years after childbirth. Large tumors and delays in diagnosis
are common due to the natural changes that occur in the breast as part of pregnancy
and lactation. Clearly, these cancers are already present in the breast prior to the
pregnancy, but come to clinical recognition with the stimulation of hormones during
pregnancy. The increased challenge of delivering antineoplastic treatments during
pregnancy, as well as the high risk management of the mother and fetus, can add to
the stress of the cancer diagnosis and treatment for young women. And of course, for
most young women of reproductive age who are diagnosed with breast cancer, the
concerns about preserving fertility may influence decision-making about treatments,
(Ruddy et al. 2014) including finding clinicians to provide these services in a timely
manner, as well as having the financial resources to pay for these services.

Is Breast Cancer Biologically Different in Younger Women?

Genetic and genomic discoveries during the past 15 years have allowed us to sub-
type breast cancer molecularly and develop classifications that are useful with regard
to biology and therapy. Survival outcomes for women younger than 35 have been
historically poor (Keegan et al. 2013), although most of the improvements related to
introduction of adjuvant chemotherapy were most apparent in younger women. For
some time, it has been known that the frequency distribution of hormone receptor
positive breast cancer is lower in younger women than post-menopausal women, but
2 Special Issues in Younger Women with Breast Cancer 13

100%
6.9% 5.9%
10.3%
90% 10.7%
14.9%
80% 17.9%
11.7%
70% 14.3%

60% 22.8%
Proportion

50%

40%
71.6%
63.9%
30%
49.0%
20%

10%

0%
15-39 40-49 50+
Age ( year
years)

Fig. 2.1 Proportion of breast cancer subtypes among California women by age group, 2005–2009.
Hormone receptor (HR) positive and human epidermal growth factor receptor 2 (HER2) negative
(blue), HR+/HER2+ (red), HR-/HER2+ (green), and triple negative (purple). Adapted from
Keegan et al. 2012 with permission

recent gene expression studies have more extensively characterized the distribution
of hormone receptor positive, triple negative, double negative and HER2 positive
tumors (Keegan et al. 2012) (Fig. 2.1). Also, some of these subtypes vary by race/
ethnicity, most notably the high proportion of triple negative and basal cell pheno-
types in African American and Latino women, as well as the higher rates of incident
breast cancer in African American women before age 40 compared to other ethnic
groups (Brinton et al. 2008). In addition, the higher rate of incident stage IV meta-
static breast cancer among younger age women compared to older women compli-
cates the initial treatment and management (Johnson et al. 2013).

Treatment of Breast Cancer in Younger Women

All of the age and life stage variables described earlier will influence the treatment
of young women, beyond the tumor stage and biological features, which would be
the dominant consideration in older women. If the younger woman carries a
14 P.A. Ganz et al.

deleterious BRCA1/2 mutation, she may opt for bilateral mastectomy at the time of
initial surgery, even though breast conservation could be considered. The young
woman’s treatment decision-making may also be influenced by her marital status
and whether she has completed childbearing. In addition, we see some women opt-
ing for very aggressive chemotherapy regimens, even in the setting of small tumors
with favorable characteristics, due to their desire to stay alive to raise children or
pursue other meaningful goals. Other younger women may avoid treatments because
they fear their toxicity, such as infertility. Because younger women often have more
advanced stage disease at diagnosis, they will more likely be subjected to post-
mastectomy or axillary radiation, which may contribute to the burden of survivor-
ship symptoms. In our experience, younger women opt for disability during
treatment more frequently than older women. The experience can be physically and
emotionally overwhelming.
The psychosocial challenges of getting young women through treatment may be
considerable. As alluded to earlier, the emotional and financial resources needed to
cope with treatments which often last more than a year, are substantial. Finally,
adherence to endocrine therapy is a particularly challenging problem, as often che-
motherapy has induced transient or permanent amenorrhea, and the addition of
tamoxifen increases the likelihood of greater vasomotor symptoms (Ganz et al.
2011), as well as sexual dysfunction in some. Several studies document a relation-
ship between younger age and nonadherence to endocrine therapy. Factors such as
low social support, a perceived lack of understanding of endocrine therapy and lack
of the opportunity to ask questions at diagnosis, and a greater number of meno-
pausal symptoms are associated with nonadherence [e.g., (Cluze et al. 2012)].
Premature menopause and infertility are a frequent consequence of treatments in
young women, and prolonged treatments may also interfere with the timing of sub-
sequent childbearing. Specifically, the 5 years of endocrine therapy with tamoxifen
may make it difficult to fit in a pregnancy, especially if a woman is in her late 30s.
Although recent data do not suggest increased risk for breast cancer recurrence with
childbearing, (Azim et al. 2012, 2013) this is still a major concern for some women.
This is especially an issue for women with DCIS for whom treatment decisions may
be quite difficult. We discuss fertility and reproductive concerns in greater detail in
the Chap. 10. Premature menopause may lead to other health consequences such as
weight gain and menopause-related symptoms.

Risk of Mortality and Late Effects from Breast

Cancer and Its Treatments

Breast cancer is the leading cause of death among women 40–59 years (Siegel
et al. 2014) so that fear of recurrence and death from cancer is a reality for
younger women with breast cancer. This is in spite of the significant advances
in treatment with chemotherapy and targeted therapies. Many of the women liv-
ing for long periods of time with metastatic breast cancer are younger women
2 Special Issues in Younger Women with Breast Cancer 15

(see Chap. 15 on metastatic breast cancer survivors). Younger women are also
at greatest risk for experiencing the long-term and late effects of cancer treat-
ment, similar to childhood cancer survivors, as they have a long time horizon of
survival in which these long-term and late effects may occur. For example, frac-
tures from early osteoporosis, cardiac failure, and second cancers (breast and
non-breast) can occur. The extent to which the breast cancer treatments received
as a young woman may accelerate various aspects of organ aging is uncertain at
this time. Clearly, some of the manifestations of cognitive difficulties may por-
tend accelerated brain aging, and both structural and functional brain changes
have been observed in breast cancer survivors several decades later (Koppelmans
et al. 2012a, b). Thus, younger women need to be viewed as a high-risk popula-
tion at risk for future health events, and should be considered for systematic
cancer prevention and control interventions. This is particularly true for
BRCA1/2 carriers in whom second cancers of the breast and Fallopian tubes/
ovaries can be prevented or their risk reduced.

Quality of Life, Psychological, and Behavioral Concerns

Breast cancer has a more negative impact on quality of life among younger women,
particularly in the psychosocial and emotional domains (Cimprich et al. 2002; Ganz
et al. 2003; Howard-Anderson et al. 2012; Mor et al. 1994). Younger women with
breast cancer report worse mental health-related quality of life than both age-
matched women without breast cancer and older women with breast cancer
(Howard-Anderson et al. 2012). Younger women also report elevated levels of dis-
tress and depressive symptoms following cancer diagnosis, which may persist into
survivorship (Avis et al. 2012, 2013). Higher levels of depressive symptoms in
younger women are due to a variety of factors, including more aggressive treatment
(though differences remain after controlling for type of treatment), a lower sense of
peace and meaning in life, and particularly greater illness intrusiveness (Avis et al.
2012, 2013). Indeed, younger women report higher levels of illness intrusiveness in
all domains of life, including health, diet, work, recreation, financial situation, rela-
tionships, and sex life, which are closely tied to depression. Further, younger women
perceive cancer as more threatening (Vinokur et al. 1990) and report greater fear of
cancer recurrence (Lebel et al. 2013) than older women.
In terms of physical symptoms, younger women report higher levels of bodily
pain, vasomotor symptoms, fatigue, and sleep disturbance (Avis et al. 2012, 2013;
Bower et al. 2000; Ganz et al. 2003; Palesh et al. 2010). These symptoms likely
contribute to the increased depression and distress observed in younger women, and
also have independent (negative) effects on quality of life. Indeed, fatigue is now
recognized as one of the most common and distressing side effects of cancer treat-
ment, as discussed in Chap. 6. Fatigue, depression, pain, and sleep problems not
only erode quality of life but may also influence adherence to treatment, and possi-
bly survival (Groenvold et al. 2007).
16 P.A. Ganz et al.

Many women are able to find some benefit from their experience with cancer,
including positive changes in relationships with others, an enhanced feeling of self-
worth and mastery, and a deepened appreciation for life. Younger women are par-
ticularly likely to report these positive changes (Koutrouli et al. 2012), perhaps
because breast cancer may be one of the first highly stressful events they have expe-
rienced. Among younger women, finding benefit is facilitated by approach-oriented
coping strategies and a sense of optimism about the future (Boyle et al. 2015). Thus,
although the experience of breast cancer can be particularly devastating for younger
women, they may experience more positive life changes in the aftermath of the
experience, which prompts an increased appreciation of the preciousness (and fleet-
ingness) of life.

Social Consequences

The experience of breast cancer challenges young women’s interpersonal spheres,

deepening some relationships and diminishing others. As an “off-time” non-
normative event, being diagnosed with breast cancer under age 50 can carry several
social consequences (Adams et al. 2011). Specifically, the young woman who has
no one among her similarly aged peers who has had breast cancer can feel isolated
and have few models for adaptive coping. Moreover, friends and co-workers may
not know how to provide effective support, having never encountered another young
woman with breast cancer. The threat of mortality might become real for the first
time in some social network members, leading even well-intentioned friends to
avoid the young woman. Greater social support is associated with better psycho-
logical adjustment in young women with breast cancer (see Howard-Anderson et al.
2012 review). Even when among other breast cancer survivors, however, young
women can feel alone; younger breast cancer survivors report feeling more isolated
and less satisfied with cancer support groups due to their age (Thewes et al. 2004).
When diagnosed in young adult women, breast cancer also prompts develop-
mental interpersonal challenges, as documented in clinical and qualitative reports
(Corney et al. 2014; Schnipper 2003). Just as they are attaining adult indepen-
dence, very young women with breast cancer can find themselves relying on their
parents, other family members, and friends for care. At the same time, young
breast cancer survivors who are mothers can feel that they are slighting their chil-
dren’s care. Women who have not forged relationships with intimate partners can
experience anxiety about doing so and feel that treatments delay precious time for
establishing adult relationships. Questions are common about when to raise the
issue in a dating relationship, whether potential partners will be rejecting, and
how to consider having children.
Existing intimate partner relationships also are affected by the breast cancer
experience for young survivors (Baucom et al. 2005; Lewis et al. 2012). The threat
of mortality often is paramount, with each partner afraid of the potential losses that
can accompany cancer, as the assumption of a long life together is called into question.
2 Special Issues in Younger Women with Breast Cancer 17

Plans for having children can change, as can caretaking for children or elderly
parents. Sexual intimacy also is affected. Young, partnered breast cancer survivors
are less sexually active and have more body image and sexual problems than are
similarly aged healthy women, although it is important to note that approximately a
third of young survivors do not report problems in those realms (Fobair et al. 2006).
Relationship, sexual, and body image problems all are related to lower quality of
life in young survivors, likely with reciprocal causality (Avis et al. 2005). The
potential for strengthening the relationship also can occur as the couple faces the
cancer experience together.

Research Challenges and Opportunities

In much of the world, breast cancer is primarily a disease of younger women,

whereas in North America and Europe, younger women are in the minority because
of the high incidence of postmenopausal breast cancer. Understanding the biologi-
cal and psychosocial context of breast cancer in younger women is one of our cen-
tral challenges. To the extent that risk factors for poor outcomes after a breast cancer
diagnosis can be modulated by interventions directed at biological or behavioral
factors, then research needs to focus on identifying those risk factors and develop-
ing specific post-treatment cancer control interventions. They may be as simple as
providing information regarding normative psychosocial experiences of younger
women with breast cancer or more complex, such as reducing tobacco and alcohol
use, promoting adherence to endocrine therapy, or providing evidence-based ther-
apy to women or couples to reduce anxiety and depression and enhance well-being.
The double-edged sword of the benefits of amenorrhea for reduction in risk of breast
cancer recurrence, and its negative consequences for women who want to have chil-
dren, may interfere with effective treatment strategies.
Among the things we must do for all breast cancer patients, but particularly for
younger women, is to tailor cancer treatments so that we do not over treat with very
toxic therapies that have no benefit. For example, patients with small tumors and
favorable, low risk tumors are unlikely to receive benefit from multi-agent chemo-
therapy. Yet, that is often the normative treatment for a younger premenopausal
woman. Both she and the physician want to do “everything.” This may also include
prophylactic mastectomy and oophorectomy in women who are not at hereditary risk
for breast and ovarian cancer. Finding better ways to clarify actual risk and to com-
municate it will be critical (Institute of Medicine 2013). In contrast, there are some
younger women who will avoid receiving recommended therapies either due to their
belief systems or because they are unable to cope with the diagnosis in an effective
way (see below for psychological challenges). Patients’ active engagement in medical
decision-making and care is critical for support of clinical decisions that best fit the
needs, values and preferences of the patient. For this patient population, having con-
comitant expert mental health support as part of the treatment team is crucial in light
of the evidence of their heightened psychosocial morbidities (Adler and Page 2007).
18 P.A. Ganz et al.

Identification of Psychological Risk Groups in Need

of Intervention

In light of the evidence that younger breast cancer survivors as a group are more
likely than older women to experience cancer as psychologically disruptive, all
younger women stand to benefit from education regarding what to expect after
diagnosis of and treatment for breast cancer, including strategies for managing the
attendant life changes. Patient age does not appear to influence the efficacy of psy-
chosocial interventions for distress and quality of life in adult cancer survivors
generally (Faller et al. 2013). However, it is possible that interventions for younger
women with breast cancer, specifically directed toward and tailored to address their
predominant concerns, might produce more robust effects than current evidence-
based approaches for the general population of adults with cancer. Development of
effective strategies for promoting healthy behaviors, including physical exercise,
healthy eating patterns, and adherence to endocrine therapies, also are warranted
for young survivors.
Intervention development for young breast cancer survivors who are at particular
risk for untoward psychological outcomes also is needed. Within the group of young
breast cancer survivors, a number of psychosocial factors are associated with poorer
psychological outcomes, including low social support, more cancer-related intru-
sive thoughts and feelings regarding cancer, and abruptly experienced menopausal
symptoms, among others. Unfortunately, most research regarding risk and protec-
tive factors for positive quality of life in young survivors is cross-sectional in design,
which precludes causal inference. Targeting survivors who might be in most need of
intervention, such as socially isolated or depressed young women, is an important
future direction for intervention.

Development of More Specialized Approaches to the Younger

Patient in Practice Settings

Just as the geriatric or pediatric cancer patient may need specialized services, so are
there a number of critical services that need to be offered to younger women. First,
honest and careful discussion of the reproductive health implications of the planned
cancer treatment is essential. Just as we consider breast reconstruction as a covered
benefit of rehabilitation from cancer treatment, fertility preservation should be orga-
nized, available, and potentially financed at an affordable rate. While there are likely
only small numbers of patients who will need this service, its availability reinforces
to the woman that she is expected to survive and that she may be able to have a fam-
ily or more children in the future. Fortunately, increasing numbers of younger sur-
vivors now are able to have children either naturally or through preservation
mechanisms.
2 Special Issues in Younger Women with Breast Cancer 19

We need to provide survivorship care for young women that focuses on their
long time horizon after breast cancer, addressing lifestyle, health behaviors, and
emotional well-being. Such care can maximize their chance of a healthy life includ-
ing prevention of cancer recurrence if possible, and early detection of second can-
cers should they occur. Many younger women avoid mammograms because the first
one did not detect their initial cancer. Effective and trusting long-term relationships
with oncology professionals and knowledgeable primary care providers are neces-
sary to address the health promotion and disease prevention that is a necessary part
of follow-up for younger women. Finally, we should re-assess family history and
re-evaluate the need and opportunity for genetic counseling and testing in younger
women, as these options may have been overlooked initially in the rush to treat. As
survivors, women will benefit from new knowledge about hereditary predisposition
syndromes that may affect their future health and that of their family members.
In closing, younger women have been the beneficiaries of the major advances in
the treatment of breast cancer, including adjuvant chemo- and hormonal therapies,
hereditary predisposition testing, breast reconstruction, and breast conservation
treatments. However, they are most at risk for psychological difficulties as a result
of a breast cancer diagnosis and can benefit from information and psychosocial
resources to help them adapt and cope with the untimely diagnosis. Because of their
extended potential life span, they are especially vulnerable to the long term and late
consequences of cancer treatment. As a result, cancer survivorship care planning
should be an important component of young women’s post-treatment care (see
Chap. 17), to help mitigate preventable conditions that may result from or be exac-
erbated by cancer treatments.

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Chapter 3
Special Issues in Older Women with Breast
Cancer

Arti Hurria and Hy Muss

Abstract The true face of breast cancer is more commonly that of an older woman.
The rapid aging of the US population is contributing to an increasing number of
breast cancer cases in older adults today, as well as an increase in the number of
breast cancer survivors who carry the long-term side effects of breast cancer treat-
ment. The number one problem facing older women with breast cancer today is that
they are not receiving the same benefits from treatment advances as younger women.
This disparity in outcomes highlights the great need for studies that specially include
older women with breast cancer in order to guide informed decisions regarding the
most efficacious treatment options. Novel study designs are needed to fill these gaps
in knowledge which include metrics that provide a detailed understanding of the
individual beyond chronologic age, and which identify areas of vulnerability for
which targeted interventions can be employed. In studying cancer therapeutics in
older adults, metrics of success, beyond disease-free and overall survival should be
included, such as the feasibility of delivering the therapy, as well as the impact of
treatment on functional independence and cognition. Ultimately, this framework
will lead to evidence-based “personalized” medicine for the older adult.

Keywords Older patient • Breast cancer • Cancer survivors • Cancer and aging
• Geriatric assessment

Introduction

Breast cancer is a disease associated with aging. The median age of diagnosis is 61 and
the median age of death is 68 [NCI (National Cancer Institute) 2010]. The lifetime risk
of developing breast cancer increases dramatically with age, with a cumulative

A. Hurria, M.D. (*)

City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA
e-mail: [email protected]
H. Muss, M.D.
University of North Carolina, Chapel Hill, NC, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 23

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 1,
DOI 10.1007/978-3-319-16366-6_3
24 A. Hurria and H. Muss

lifetime risk of 12 % (Siegel et al. 2014). Although social media often highlights breast
cancer in younger women, the true face of breast cancer is more commonly that of an
older woman. This will become even more apparent over the next 20 years as the can-
cer incidence rises with the aging of the US population (Smith et al. 2009).
The baby boomers began to turn age 65 in the year 2011, leading to rapid growth
in the number of individuals age 65 and older. From 2010 to 2050, this population
is projected to increase from 40 million (13 % of the US population) to 89 million
individuals (20 % of the US population) (Smith et al. 2009). Together, the associa-
tion of breast cancer with aging and the aging of the US population will contribute
to an increased number of breast cancer cases in older adults, as well as an increase
in the number of breast cancer survivors who carry the long-term side effects of
breast cancer treatment (Fig. 3.1) (Smith et al. 2009; Parry et al. 2011; Siegel et al.
2012, 2014; DeSantis et al. 2014).

Fig. 3.1 Projected cases of all invasive cancers in the United States by age and sex [Reproduced
with permission from Smith et al. (2009)]
3 Special Issues in Older Women with Breast Cancer 25

Fig. 3.2 US breast cancer death rates from 1980 to 2007. Larger decrease in breast cancer mortal-
ity seen in younger vs. older patients [Reproduced with permission from Smith et al. (2011)]

Although breast cancer is associated with aging, older women are not receiving
the same benefits from treatment advances as younger women (Smith et al. 2009,
2011). Breast cancer death rates decreased by 1.14 % per year in women age ≥75
from 1990 to 2007, compared with 2.49 % a year in women age 20–49 (Fig. 3.2)
(Smith et al. 2011). Although overall breast cancer death rates are decreasing, the
improvements in mortality are driven by greater decreases in younger not older
women, and highlight the age-related disparities in breast-cancer outcomes. In this
manuscript, we review the key knowledge gaps in treatment of older women with
breast cancer and their survivorship issues; and propose ways for future research to
fill these gaps to improve the overall health and well-being of older adults who are
breast cancer survivors.

Describing Older Women with Breast Cancer

Older women with breast cancer are a heterogeneous group. With aging there is a
decline in physiologic function and an accumulation of comorbid conditions,
breast cancer often being one of many other competing health problems (Kimmick
et al. 2014). For early stage disease in particular, older women are more likely to
die of a comorbid condition other than breast cancer (Fig. 3.3). Therefore, a key
part of decision-making is weighing the risk of morbidity and mortality from breast
cancer vs. other diseases (Patnaik et al. 2011). Tools such as e-prognosis can help
26 A. Hurria and H. Muss

Fig. 3.3 Causes of death for patients age 70 and older with breast cancer based on stage [Adapted
from Schairer (2004)]

estimate overall life expectancy; however, these tools have not been validated
among patients with breast cancer (Yourman et al. 2012). Tools such as Adjuvant
Online can calculate the risk of breast cancer recurrence and mortality, but do not
include a detailed assessment of the specific competing comorbid illnesses facing
the older adult. A single tool that synthesizes the risk of breast cancer mortality
versus mortality from other causes, as well as the potential benefits and risks of
treatment in the face of competing comorbidities is not currently available and is a
key area for research.
Aging is a heterogenous process associated with decline in organ function and
physical function; however, the rate of decline is unique to each individual, and
chronological age is a poor measure of overall fitness. Older women with breast
cancer vary widely in their functional states, ranging from an 80-year-old marathon
runner to a 70-year-old patient with dementia and degenerative joint disease.
A more detailed assessment of an older adult, as captured by a geriatric assessment,
is needed in order to derive an understanding of physiologic or functional age
(Freyer et al. 2005; Hurria et al. 2011; Dale et al. 2012; Extermann et al. 2012;
Aparicio et al. 2013; Mandelblatt et al. 2013). This assessment evaluates individual
functional status, comorbidity, cognitive function, psychological state, social sup-
port, nutritional status, medications, and socioeconomic status. Taken together, this
assessment provides a detailed understanding of the individual beyond chronologic
age, and identifies areas of vulnerability for which targeted interventions can be
employed. Performing this assessment is a key part of “knowing” an older patient
with breast cancer.
3 Special Issues in Older Women with Breast Cancer 27

Is Breast Cancer Biologically Different in an Older Adult?

Overall there are several favorable changes that occur in breast cancer biology with
increasing age: an increase in proportion of tumors that are lower grade, estrogen
and progesterone receptor positive, and HER2 negative (Diab et al. 2000). However,
these age-related differences are modest, and as in younger patients, tumor biology
should be utilized to drive decision-making regardless of age. For older women with
hormone-receptor positive, HER2 negative tumors, the tumor phenotype found in
about 70 % of older women, gene-based assays (Oncotype and others), which are
independent of patient age, can be utilized to estimate the risk of breast cancer
relapse and the benefits of adjuvant chemotherapy in addition to endocrine therapy
(Paik et al. 2004). Among triple-negative cancers, older adults derive survival ben-
efits from chemotherapy, because the risk of relapse is highest in the first 3 years,
a timeframe in which other comorbid illness are unlikely to impact life expectancy,
except in the very sick (Elkin et al. 2006; Muss et al. 2009). In addition and as with
younger patients, a review of the older patient’s personal and family history of can-
cer is essential in order to appropriately refer the patient for a genetics consultation
to evaluate for a hereditary predisposition.

Therapeutic Considerations for Management of Breast

Cancer in Older Adults

The main therapeutic options for the treatment of breast cancer are the same across
the aging spectrum. However, specific studies have guided the approach to care of
the older adult and whether therapeutic decisions could be altered based on patient
age and tumor type. The key motivators driving the development of these studies
include: (1) determining whether alternative strategies can be utilized that would
produce similar efficacy with a lower risk of toxicity, and (2) evaluating whether
treatment would be associated with a meaningful decrease of breast cancer morbid-
ity or mortality during the patient’s remaining life span.

Local Therapy

The approaches to local therapy are similar between younger and older adults. The
surgical treatment of early stage breast cancer is an integral part of therapy, given a
low risk of surgical morbidity in all age groups. A key consideration in many older
adults is whether to recommend breast radiation after breast-conserving surgery.
Radiation is known to decrease the risk of local recurrence; however, its overall
benefit must be considered in the context of competing comorbidities and life
expectancy. This question was studied among patients age ≥70 who were treated
28 A. Hurria and H. Muss

with breast-conserving therapy and endocrine therapy for stage I disease and tumors
that were hormone receptor positive and node negative. In patients randomized to
radiation therapy or none, after 12 years of follow-up the omission of radiation was
associated with a modest increase in the risk of a local recurrence (10 % versus 2 %)
but no difference in overall survival. The majority of deaths were caused by comor-
bidities other than breast cancer (Hughes et al. 2010). However, gaps in knowledge
remain regarding this approach in older patients with larger tumors. Of note, despite
the results of this randomized trial, translation into clinical care has been limited,
and most women continue to receive postoperative radiation (Soulos et al. 2012).
Additional studies are needed to determine how to expedite the translation of
research findings into practice, and to pinpoint the barriers to translation.
Among those where radiation therapy is warranted, barriers and challenges to
receipt of radiation need to be considered including whether the patient has trans-
portation, and whether a caregiver is needed to accompany the patient. These chal-
lenges can be amplified in an older adult who is dependent on others for
transportation or who has difficulty attending a daily appointment because they are
the primary caregiver for another family member such as a spouse. Randomized
studies have evaluated the role of hypofractionated breast radiation therapy, and
demonstrate the efficacy of such an approach (Haviland et al. 2013; Eblan et al.
2014). Additional studies are needed to identify which older patients truly need
radiation therapy and whether shorter courses could yield similar benefits with less
resource requirement.

Systemic Treatment Considerations

Chemotherapy CALGB 49907 is a landmark study evaluating adjuvant treatment

in the care of older adults. This randomized trial in women age 65 and older evalu-
ated the efficacy and toxicity of standard chemotherapy (AC or CMF) versus single-
agent capecitabine (Muss et al. 2009). Compared with most adjuvant treatment
studies, which evaluate whether more treatment improves efficacy (i.e., if AB is the
standard, is AB + C superior to AB?), CALGB 49907 evaluated whether less ther-
apy (i.e., single-agent, orally administered capecitabine) was as effective as
standard-of-care intravenous polychemotherapy. The study results demonstrated a
superiority of standard adjuvant intravenous polychemotherapy (AC or CMF) for
both disease-free and overall survival, thus reinforcing the importance of utilizing
standard regimens among patients age 65 and older.
There were several unique components in this study, including the consideration
of drug dosing based on organ function, additional safety parameters to decrease the
risk of toxicity, and a rich correlative component evaluating the impact of therapy
on quality of life, adherence, and geriatric assessment parameters (such as function,
comorbidity, and cognition) (Partridge et al. 2010; Kornblith et al. 2011; Freedman
et al. 2013).
3 Special Issues in Older Women with Breast Cancer 29

A novel component in the design of CALGB 49907 was the development of a

parallel registry study, CALGB 366901, led by Dr. Jeanne Mandelblatt. The ratio-
nale for this observational cohort study was to understand the factors, including
patient preferences, that influenced adjuvant treatment decisions in older adults with
breast cancer. This study demonstrated that patient preference for chemotherapy
and a higher rating of physician communication were associated with chemotherapy
receipt (Mandelblatt et al. 2010). Furthermore, physician decision styles also influ-
enced the treatment chosen. In particular, the oncologists’ preference for chemo-
therapy was associated with patients’ subsequent receipt of chemotherapy treatment.
Those patients who preferred to have more of the oncologist’s input in treatment
decisions were more likely to receive chemotherapy. Both patient and physician
decision styles were independently associated with chemotherapy use (Mandelblatt
et al. 2012). The measures included in CALGB 49907 were similar to those utilized
in 369901, allowing for a comparison of characteristics and outcomes of patients
who enrolled in these two studies with inclusion of detailed geriatric assessment
measures.
Additional studies of adjuvant chemotherapy for breast cancer in older adults are
needed. This is particularly true because the risks of adjuvant breast cancer treat-
ment are greater in older adults. An evaluation of four adjuvant breast cancer trials
performed in the Cancer and Leukemia Group B over a quarter of a century demon-
strated that although patients age 65 and older received the same benefits as younger
patients from more versus less aggressive chemotherapy regimens, older women
had a higher risk of treatment toxicity, a greater likelihood of not being able to com-
plete the treatment course, and an increased risk of treatment-related mortality
(Crivellari et al. 2000; Muss et al. 2007). These risks must be weighed in the
decision-making process, and studies of novel regimens are needed. CALGB 49907
can serve as a model for future studies in terms of design, implementation, and suc-
cessful execution of an adjuvant treatment trial in older adults. Trials designed spe-
cifically for older patients should be expanded.
Trastuzumab The gaps in knowledge regarding the selection of adjuvant regimens
in patients with pre-existing comorbidities are particularly relevant for novel tar-
geted therapies that are introduced in the adjuvant setting, as they seldom have been
evaluated in older adults. For example, adjuvant trastuzumab, in conjunction with
chemotherapy, is now the standard of care for most patients with Her2 positive
breast cancer. However, the studies that set this standard included few older adults,
and patients with cardiac comorbidities were excluded (Piccart-Gebhart et al. 2005;
Romond et al. 2005; Slamon et al. 2011). Furthermore, among those patients
enrolled, older age and comorbidities common to the older patient population (pre-
existing hypertension, high body mass index, and low/normal baseline left ventricu-
lar ejection fraction) have been noted to be risk factors for toxicity (Tan-Chiu et al.
2005; Suter et al. 2007; Perez et al. 2008). Studies of the late cardiac effects of
chemotherapy have been performed in the cooperative group setting (Ganz et al.
2008). Similar studies are needed with targeted therapies which carry a risk of long-
term cardiac complications. (This topic is covered in detail by Fabian in Chap. 13).
30 A. Hurria and H. Muss

Endocrine Therapy Endocrine therapy remains a mainstay of therapy for

hormone-receptor positive disease, and the efficacy is similar across the aging spec-
trum [Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) 2005].
Adherence to therapy is necessary in order to derive optimal benefit, suggesting that
this should be an area of focus for older individuals where polypharmacy is com-
mon. For an older adult, the main treatment considerations and survivorship issues
for aromatase inhibitors revolves around the impact of therapy on comorbidities
including bone health, joint pain and musculosketal symptoms, and potential car-
diac risk; while for tamoxifen the major risks are thromboembolism and endome-
trial cancer (Perez et al. 2006; Cuppone et al. 2008; Eastell et al. 2008; Amir et al.
2011; Mieog et al. 2012). As the benefits of prolonged endocrine therapy beyond 5
years are becoming apparent, studies of the long-term side effects of prolonged
therapy and interventions to decrease these side effects are needed, especially in
older women whose life expectancy can dramatically decrease with increasing age
(Goss et al. 2005).

Approach to Metastatic Disease

Overall, the goals of treatment for metastatic disease are the same across all age
groups. Since breast cancer is treatable but not curable, the goals of treatment
include preserving function, minimizing symptoms, maintaining quality of life, and
prolonging survival. Just as with younger patients, there is an overall desire to inte-
grate new therapies, but the challenge is the low representation of older adults on
FDA registration trials, and therefore limited guidelines on how to dose these medi-
cations in the geriatric population (Talarico et al. 2004; Scher and Hurria 2012).
Furthermore, there have been almost no studies performed in frail older adults, lead-
ing to a major gap in knowledge.

Research Needs

Overcoming Barriers to the Enrollment of Older Adults

in Clinical Trials

As with most cancers, older adults continue to be underrepresented on clinical

research studies; as a result there is scant evidence-based data regarding treatment
and survivorship issues facing older adults with breast cancer (Lewis et al. 2003;
Murthy et al. 2004; Unger et al. 2006). This is particularly true among older patients
with breast cancer enrolling in adjuvant treatment trials. Among four cooperative
group adjuvant trials for node-positive breast cancer conducted over a quarter of a
century, only 8 % of participants were age ≥65, and only 2 % were age ≥70
(Muss et al. 2005). Furthermore older adults are underrepresented on FDA
3 Special Issues in Older Women with Breast Cancer 31

registration trials, so there is inadequate evidence-based data available on how to

dose these drugs in older patients (Talarico et al. 2004; Scher and Hurria 2012).
A study performed in Cancer and Leukemia Group B evaluated the barriers to
clinical trial enrollment in a matched sample of patients (older vs. younger adults)
with breast cancer who had the same treating physician. This study demonstrated
that older adults were less likely to be offered a clinical trial but were as likely to
accept enrollment if offered (Kemeny et al. 2003). A survey of treating physicians
highlighted concerns regarding treatment-related toxicity and the need for specific
trials in older adults with safety parameters in place (Kornblith et al. 2002).
Education regarding the potential benefits of clinical trial enrollment in older
adults is needed, but a multicenter study showed that education alone will not
increase clinical trial enrollment, and a multifaceted approach is necessary
(Kimmick et al. 2005).

Understanding the Impact of Treatment on Functional

and Cognitive Aging

Traditional clinical trials focus on metrics of disease-free and overall survival. For
an older adult, the impact of treatment on functional status and cognition may be as,
if not more, important to their decision-making process (Braithwaite et al. 2010;
Dale et al. 2012; Mandelblatt et al. 2013; Sehl et al. 2013). Measures of functional
status, as captured in a geriatric assessment pre-treatment, predict cancer treatment
toxicity and survival. Furthermore, among older adults with breast cancer, a decline
in functional status in the 2 years following diagnosis has been associated with
poorer overall survival (Sehl et al. 2013).
There is a biologic rationale for concern that cancer treatment may accelerate the
aging process. Aging and chemotherapy, in particular, are associated with a variety
of similar biologic changes including DNA damage, inflammation, oxidative stress,
and cellular senescence. A cross-sectional study of breast cancer survivors
demonstrated that prior chemotherapy was associated with an increase in p16 INK4a
expression, a potential molecular marker of aging, which equated to approximately
10 years of chronological aging (Muss et al. 2009; Sanoff et al. 2014). The potential
medical, functional, and social impact of these biologic findings is unknown, and
further research is needed to address this knowledge gap (Pallis et al. 2014).
There is emerging data suggesting that receipt of cancer therapy may be associ-
ated with decrements in cardiopulmonary function, which persist throughout the
survivorship years. A study of breast cancer survivors, who were on average 7 years
post diagnosis demonstrated reductions in cardiovascular fitness in comparison to a
non-cancer control group (mean 55 years; SD 10 years) (Lakoski et al. 2013).
Furthermore, another study demonstrated that patients with breast cancer have a
marked impairment in peak oxygen consumption (a measure of aerobic consump-
tion) in the survivorship years (Jones et al. 2012). These data demonstrate that adju-
vant chemotherapy is likely associated with aging of the cardiopulmonary system.
32 A. Hurria and H. Muss

These findings are seen across the aging spectrum and are especially germane to
older patients.
There is a dearth of knowledge regarding cancer treatment impact on cognitive
aging, as the majority of studies to date have been performed in younger adults
(Hurria et al. 2006; Yamada et al. 2010; Koppelmans et al. 2012; Mandelblatt et al.
2013). Studying the cognitive effects of cancer therapy in older adults is complex
because breast cancer is only one of many other factors (such as comorbid medical
conditions, lifestyle, and genetics) that can affect cognitive function. However,
emerging literature is demonstrating an interaction of cancer treatment, aging, and
cognitive function/reserve which highlights the importance of studying the cogni-
tive effects of cancer therapy in older adults (Ahles et al. 2010). The age at which an
individual is treated (i.e., the more vulnerable brain with decreased cognitive
reserve) may also have an impact on the risk of cognitive decline. Research is
needed to understand how cancer therapy affects cognitive aging both during the
acute post-treatment phase and in the survivorship years. Interventions to maintain
or minimize therapy’s potential harm to cognition are needed.
Clinical and biological markers of functional age and cognition (as captured in a
geriatric assessment) are vital components to be included in breast cancer trial
design, at baseline as well as longitudinally. Interventions to maintain function and
independence, such as home-based exercise interventions, have proven efficacious,
and additional research is needed to understand both the physical and cognitive
impact of such interventions and to evaluate the “dose” of the intervention that is
needed to obtain and sustain a positive effect (Demark-Wahnefried, et al. 2006).

Social, Emotional, and Financial Considerations of Breast

Cancer in Older Adults

There are unique social considerations for the older adult with breast cancer.
Questions that arise during the treatment planning process usually include: If the
older adult lives alone, who would bring them to the hospital in the event of an
emergency? Can the patient and family afford caregiver support? Is the patient a
caregiver for someone else (spouse, children, grandchildren)? Who would provide
that care if the patient is unable to do so? Does the patient still drive? If not, who
will provide transportation for treatment-related visits? These questions are not nec-
essarily unique to patients with breast cancer, and need to be considered when car-
ing for any older adult with cancer. However, studies are needed among patients
with breast cancer to more accurately quantify the potential impact of a treatment
course on both the patient’s and caregiver’s well-being, and on patients and families
planning for treatment.
The emotional impact of breast cancer in older adults is related to the patient’s
physical function, mental function, and psychosocial adjustment. For example, after
surgery, older women with impaired mental health, physical functioning, and emo-
tional social support have poorer psychosocial adjustment and self-perceived
health 1 year later (Ganz et al. 2003). Other studies demonstrate that emotional
3 Special Issues in Older Women with Breast Cancer 33

wellbeing is associated with enhanced physical function, emotional social support,

and the quality of the medical interactions (Clough-Gorr et al. 2007). Therefore
studying the emotional impact of cancer therapy in an older adult requires a thor-
ough understanding of the other potential factors that play a role in the patient’s
emotional wellbeing.

Preparing to Care for an Aging Population with Breast Cancer

The challenge facing the field of medical oncology is the projected shortage of indi-
viduals to care for this growing population of older adults with cancer. By 2020, the
demand for oncologists (driven primarily by the aging population and increase in
cancer survivors) will grow by 48 %; however, the supply of healthcare workers will
only grow by 14 % (Hortobagyi 2007). At the same time, the number of geriatri-
cians is predicted to decline, despite the aging of the US population (IOM 2008).
This workforce shortage will lead to a limited number of physicians with expertise
in geriatrics able to provide collaborative care. In order to bridge that gap, the rec-
ommendations from the Institute of Medicine (IOM) titled “Retooling for an Aging
America: Building the Health-Care Workforce” state “…to meet the health-care
needs of the next generation of older adults, the geriatric competence of the entire
workforce needs to be enhanced…innovative models need to be developed and
implemented…”(IOM 2008) The report concludes that all members of the health-
care team must have knowledge of geriatrics in order to meet the needs of the aging
patient. Key members of the team are “informal caregivers,” often family members,
who play an integral and often unrecognized role in the healthcare team.
Research is needed to develop an educational curriculum containing the key prin-
ciples of geriatric care that are needed across all disciplines, as well as the specific
principles that are unique to the discipline being educated. Furthermore, competencies
need to be developed to serve as a metric as to whether that content has been success-
fully learned. Novel means of delivering content to an expanding workforce will need
to be evaluated. In particular, special attention must be paid to caregivers, who are a
critical part of the healthcare team but require both education and ongoing guidance in
order to participate in the care of an older adult. These issues are not unique to patients
with breast cancer; however, they are a major component for providing quality cancer
care across the trajectory of the disease (Institute of Medicine 2013).

Conclusions

In summary, although progress has been made in the treatment of older adults with
breast cancer, several gaps in knowledge exist. A biopsychosocial model can be
utilized to summarize some of the key gaps in knowledge. Specifically, markers
of risk for adverse treatment outcomes are needed which include biological,
34 A. Hurria and H. Muss

functional, and psychosocial factors. These markers, in addition to an understand-

ing of the patient’s physiology and organ function, could lead to more refined thera-
pies that are targeted to the “stage of aging” in addition to the stage and biology of
the tumor (Dale 2009). This framework could be utilized to evaluate the risks and
benefits of treatment regimens in frail, pre-frail, and healthy older patients. An eval-
uation of the risks includes quantifying the impact of therapy on function and cogni-
tion, metrics which may be more important to older adults than disease-specific
parameters. With any treatment plan, the feasibility of delivering the treatment is a
key outcome. Feasibility should be assessed in terms of both whether treatment
toxicity and/or psychosocial factors limit treatment delivery. Ultimately, this frame-
work will lead to evidence-based “personalized” medicine for the older adult.

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Chapter 4
Breast Cancer Among Special Populations:
Disparities in Care Across the Cancer Control
Continuum

Electra D. Paskett

Abstract Disparities in breast cancer risk factors, access, and treatment patterns
are responsible for disparities in incidence, mortality and other measures of the
impact of breast cancer among different population groups. Moreover, differences
in culture and role definition impact various areas of aging and quality of life.
Populations most impacted by disparities include women of racial/ethnic groups,
older women, and women from rural and urban areas. More research is needed to
document and address disparities across the cancer control continuum among a
variety of populations that suffer disparities.

Keywords Breast cancer • Special populations • Cancer control continuum • Breast

cancer disparities

Introduction

While Breast Cancer (BC) is relatively a “rare” disease, some populations suffer
from a disproportionate burden of incidence, mortality, risk factors, or late stage
disease. These populations, the elderly, racial/ethnic minorities, rural, low socioeco-
nomic status (SES) populations, women in developing nations, and lesbian/gay/
transgender women, face disparities. Disparities, or differences that should not
exist, that impact BC survival are evident across the cancer control continuum, from

E.D. Paskett (*)

Division of Cancer Prevention and Control, Department of Internal Medicine,
College of Medicine, Columbus, OH 43201, USA
Division of Epidemiology, College of Public Health, Columbus, OH 43201, USA
Comprehensive Cancer Center, Ohio State University,
Suite 525, 1590 North High Street, Columbus, OH 43201, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 39

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_4
40 E.D. Paskett

etiology through survivorship. This chapter will focus on first, highlighting disparities
across and within many of these populations, second, discuss research that examines/
addresses these disparities, and finally, suggest challenges and directions for future
research to reduce/eliminate breast cancer disparities.

Breast Cancer Disparities

Worldwide, the incidence of BC is higher in more developed countries, such as The

United States (U.S.) and Canada, Australia/New Zealand, as well as countries in
Western Europe compared to less developed nations including those in Middle/
Eastern Africa as well as Eastern Asia (Age-standardized rate (ASR) = 71.7/100,000
women vs. 29.3/100,000 women, respectively); however, the ratio of the mortality
rate to incidence rate is higher in less developed regions compared to more devel-
oped regions (0.4 vs. 0.24, respectively) (Youlden et al. 2012). Similarly, 5 year
relative survival between developed and less developed nations show vast differ-
ences (e.g. 89.2 % in the U.S. vs. 38.8 % in Algeria) (Youlden et al. 2012). These
disparities are probably the most striking and are due to the lack of population-
based mammographic screening in less developed regions, as well as differences in
access to state-of-the-art treatments and cultural barriers impacting detection and
treatment, respectively. Economic conditions greatly impact access to early detec-
tion and treatment services. Unstable economic conditions lead to difficulty in
obtaining an adequate oncology workforce in addition to problems in securing
resources such as electricity as well as equipment necessary for early detection and
treatment. Survivorship and palliative care services are almost non-existent in these
developing regions, making estimates nearly impossible (Coughlin and Ekwueme
2009; Harford et al. 2011; American Cancer Society 2013).
Even in the U.S., our model for a developed nation, breast cancer disparities are
evident across the cancer control continuum. The most reported disparities
are among those of racial/ethnic minority groups (See Table 4.1), older women,
women from lower SES groups, and women who reside in urban areas (Table 4.2).

Table 4.1 Examples of breast cancer disparities across the cancer control continuum
Etiology Prevention Early detection Follow-up Treatment Survivorship
• Biology • Chemo- • Mammography • Access • Adjuvant • Treatment
and prevention chemotherapy side effects
• Risk • MRI • Quality • Radiation • Adherence
factors therapy to adjuvant
hormone therapy
• Self-exam • Timeliness • Surgery • Coping skills
of therapy • Body image
• Social support
• Acculturation
• Quality of life
4 Breast Cancer Among Special Populations… 41

Table 4.2 Average annual (2006–2010), age-adjusted invasive female breast cancer incidence and
mortality rates per 100,000 women, and 5-year relative survival probabilities among race groups
and Hispanics/Latinos
Incidence rate Mortality rate 5-year survival
Population (per 100,000) (per 100,000) probability (%)
White 127.4 22.1 90.4
African-American 118.4 30.8 78.9
Asian/Pacific Islander 84.7 11.5 91.4
Hispanic/Latino 91.1 14.8 87
American Indian/Alaska Native 90.3 15.5 85.4
Source Cancer statistics review, 2013

However, due to limitations in the definition of SES and rural residence, limited data
are available across the continuum. Thus, this chapter is limited by available data.

Disparities Across the Cancer Control Continuum

Etiology and Prevention

An examination of risk factors for poor-outcome disease can provide some clues to
these disparities. For example, modifiable risk factors, e.g. obesity, pregnancy, and
postmenopausal hormone use, are differentially distributed among populations
where we see disparities, e.g. African American and Hispanic women are more
likely to be overweight/obese vs. white women, however, most of the literature in
this area has provided inconclusive results. Furthermore, what we know about the
uptake of chemoprevention, diet, exercise and prophylaxis, including genetic test-
ing and surgery, in most of these minority populations is lagging behind that of
white women as well as women residing in more urban, as opposed to rural, areas.
Studies of non-modifiable risk factors, e.g. genetics, have provided more conclusive
results. Germline mutations, for example, BRCA1 mutations, result in higher risk
for triple negative cancers (American Cancer Society 2013). Despite advancements
in genetic testing leading to reductions in morbidity and mortality associated with
breast cancer, research suggests that African American and minority women are
significantly less likely to receive genetic counseling and testing in comparison to
white women (Howlander et al. 2014). Health care reform now requires that insur-
ance cover the cost of genetic testing. However, for populations of women who are
not covered by health insurance, genetic testing is incredibly expensive, typically
costing around $3,400. Exorbitant costs associated with genetic testing clearly place
minority and impoverished women at a certain disadvantage for breast cancer out-
comes (Hall and Olopade 2006; Johns Hopkins Medicine Breast Center; Susan
G. Komen Testing for BRCA1 & BRCA2 Mutations).
42 E.D. Paskett

Triple Negative Breast Cancer (TNBC), accounts for 10–20 % of invasive BC,
but has poorer prognosis than luminal tumors and treatment options are more
limited (Boyle 2012). Risk of TNBC is roughly three times higher among non-
Hispanic black women and pre-menopausal women (Boyle 2012). Moreover, a
study from Ghana found that there might be a genetic predisposition to TNBC
among women of African ancestry (prevalence of TNBC 82 % in Ghana, 33 %
among African American women and 10 % among white American women)
(Boyle 2012). Similarly, among Asian/Pacific Islander women, the risk of ER/PR
positive tumors is higher among Korean women vs. Hawaiian women (Li et al.
2002). Both Hispanic and American Indian/Alaskan Native women have larger
tumors and more advanced disease at diagnosis (Mejia de Grubb et al. 2013; Von
Friederichs-Fitzwater et al. 2010).

Screening Behavior

While guidelines have changed over time, clearly average-risk women over age 50
should have a mammogram every 2 years; moderate to high risk women should
consult with their physician as to when to start screening, what modality (MRI vs.
mammography) and how often. In addition, access to high quality imaging services
and prompt/proper follow-up of abnormalities found should be available to all pop-
ulations. Access to breast cancer screening as well as differences in quality of care
among black and white women have contributed greatly to observed disparities in
breast cancer mortality. For example, from 1999 to 2003 in Chicago, the mortality
rate for breast cancer was 49 % higher among black women compared to white
women. In 2003, the mortality rate increased to 68 % higher among black women
compared to white women (Hirschman et al. 2007). Explanations for this observed
disparity have focused on gaps in education, access to screening, as well as differ-
ences in quality of care between black and white women. Research suggests that
white women in Chicago are more likely than black women to attend academic and
private healthcare facilities, as well as more likely to have their mammograms read
by specially trained radiologists (Ansell et al. 2009).
Disparities in mammography use are hard to determine because of the reliance
on self-reported use in the most commonly used metric for screening utilization, the
Behavioral Risk Factor Surveillance System (BRFSS). Self-reports of recent mam-
mography use are actually highest among African-American women (77 %) than
white women (75 %), however, verification of self-reports drop these rates to 59 %
vs. 65 %, respectively [Frieden and Centers for Disease Control and Prevention
(CDC) 2012]. For example, in Chicago, self reported mammogram screening rates
have been similar for blacks and whites since 1996 despite the dramatic difference
in breast cancer mortality rates. However, poor and black women tend to over-report
screening by as much as 30 % (Hirschman et al. 2007). Asian Pacific/Islander
women in general have a 74 % prevalence rate (self-reported); however, disparities
exist in mammography prevalence among Asian subgroups e.g. South Asian women
4 Breast Cancer Among Special Populations… 43

(40 %) vs. Japanese Women (71 %) (Frieden and Centers for Disease Control and
Prevention (CDC) 2012; Lee et al. 2002). For American Indians/Alaskan Natives
(AI/AN), rates are at 69 %, and geographical differences have also been noted, i.e.
AI/AN women from Alaska had higher screening rates than those living in the
Southwest [Centers for Disease Control and Prevention (CDC) 2012; Schumacher
et al. 2008]. Hispanic women also report moderate screening rates, 70 %; compared
to non-Hispanic women (Lim et al. 2009; Lopez-Class et al. 2011; Native American
Cancer Research Corporation Native Americans and Cancer). The women from
these other racial/ethnic groups are more likely to face cultural barriers to receiving
screening, e.g. prefer traditional holistic medicine to Western medicine or have
modesty concerns. Ultimately, no single intervention will have the ability to reduce
mortality associated with breast cancer in disparity stricken areas such as Chicago.
Only through a multifaceted approach that addresses issues such as cultural differ-
ences, increased health education, access to care and decreasing barriers to screen-
ing, will the mortality gap begin to narrow.

Stage at Diagnosis

Stage at diagnosis is an indicator of both quality of care (e.g. good mammography

use and follow-up), as well as outcomes following treatment. Many studies have
demonstrated that women living in rural areas are diagnosed at later stages com-
pared to urban breast cancer patients (Monroe et al. 1992; Nguyen-Pham et al.
2014; Amey et al. 1997; Howe et al. 1992). Moreover, rural African-American
women are diagnosed at later stages compared to rural white and urban white and
African-American women (Amey et al. 1997). Asian women, on the other hand, are
more likely to be diagnosed at Stage 1 compared to African-American women,
American Indian/Alaskan Native, and Hispanic women; however, again within
Asian subgroups there are disparities in not only stage of diagnosis, but age at diag-
nosis, and tumor grade (see Tables 4.3) (Li et al. 2002; Mejia de Grubb et al. 2013;
Von Friederichs-Fitzwater et al. 2010; Yi et al. 2012).

Follow-up for Abnormal Screening Tests

Prompt and proper follow-up for any abnormalities detected on screening is crucial
to improving outcomes. Issues such as access (e.g. facilities, proper technology,
insurance coverage, transportation), quality state-of-the-art facilities, proper testing,
and competent providers are crucial to the receipt of follow-up care. Studies have
documented longer intervals for follow-up after an abnormal mammogram for
African-American women, even with similar insurance status, compared to white
women [Centers for Disease Control and Prevention (CDC) 2012]. Language barri-
ers also contribute to disparities in follow-up in non-English speaking women
44 E.D. Paskett

Table 4.3 Average annual (2007–2011), age-adjusted invasive female breast cancer incidence
rates per 100,000 women, percent late (regional and distant) stage at diagnosis, and 5-year relative
survival probabilities according to metropolitan/non-metropolitan residence
Incidence rate Percent late 5-year survival
Population (per 100,000) stage (%)a probability (%)
Metropolitan 122.1 73.6 89.1
Non-metropolitan 111.2 72.5 86.9
Source For incidence and stage: Surveillance, Epidemiology, and End Results (SEER) program
(www.seer.cancer.gov) SEER*Stat Database: Incidence—SEER 18 regs research data + Hurricane
Katrina impacted Louisiana cases, Nov 2013 sub (2000–2011) “Katrina/Rita population adjustment”—
linked to county attributes—total U.S., 1969–2012 counties, National Cancer Institute, DCCPS,
surveillance research program, surveillance systems branch, released April 2014, based on the
November 2013 submission; for survival: Surveillance, Epidemiology, and End Results (SEER)
Program (www.seer.cancer.gov) SEER*Stat Database: Incidence—SEER 18 regs research
data + Hurricane Katrina impacted Louisiana cases, Nov 2013 sub (1973–2011 varying)—linked to
county attributes—total U.S., 1969–2012 counties, National Cancer Institute, DCCPS, surveil-
lance research program, surveillance systems branch, released April 2014, based on the November
2013 submission (National Cancer Institute Surveillance)
a
Percent late stage excluded unstaged/unknown stage tumors

(Karliner et al. 2012; Austin et al. 2002; Janz et al. 2009; Sammarco and Konecny
2010; Nápoles et al. 2011; Yanez et al. 2011). Rural women are less likely to receive
follow-up testing, probably due to lack of access and facility factors (Schootman
et al. 2000; Goldman et al. 2013). Finally, a study among Medicare beneficiaries
found that facilities serving more vulnerable populations had lower follow-up rates
for women with abnormal screening tests.

Interventions to Address Disparities

Important policy interventions occurred in the 1990s to improve mammography use

among vulnerable populations. First, the Centers for Disease Control and Prevention
(CDC) started the National Breast and Cervical Cancer Early Detection Program
(NBCCEDP) which made free or low-cost mammograms available to low-income,
under and uninsured women. Between 1991 and 2006, 1.8 million received breast
cancer screening through the NBCCEDP (Hoerger et al. 2011). This program also
provides follow-up care after abnormal testing and initial treatment. A recent analy-
sis of data indicated that NBCCEDP is doing a good job in getting women in for
timely and quality follow-up [Centers for Disease Control and Prevention (CDC)
2012]. One problem with NBCCEDP is that only a fraction (fewer than 20 %) of
eligible women in the U.S. utilize NBCCEDP due to the funding caps on this pro-
gram (NBCCEDP Breast Cancer Expert Panel 2005).
Secondly, the National Cancer Institute (NCI) developed the Cancer Control
Plan, Link, Act, Network with Evidence-based Tools (PLANET) Research-Tested
Intervention Programs (RTIPs) which stores research-tested interventions for
improving the use of screening (including breast cancer screening) in underserved
4 Breast Cancer Among Special Populations… 45

populations (Sood et al. 2007). For example, the North Carolina—Breast Screening
Program (NC-BSP) and Forsyth County Cancer Screening Project (FoCaS) are two
programs on RTIPs that provide interventions for improving breast cancer screen-
ing among African-American women (Earp et al. 2002; Paskett et al. 1999). Other
RTIPs programs are available for Alaskan Native, American Indian, Asian, Hispanic,
Pacific Islander and non-Hispanic White women. Programs are free to download;
however, few data exist on the effect of diffusion and implementation of RTIPs.
Other successful interventions for reaching vulnerable populations for improv-
ing mammography use include utilizing patient navigators (PN) to reduce barriers
such as modesty and cultural issues, and including spiritual and religious themes
(Freeman 2006; Paskett et al. 2012). For women living in rural areas, mobile mam-
mography (Gardner et al. 2012), free/reduced services (Lane and Martin 2012), as
well as agents of change (e.g. lay advisors, PN, public health nurses) (Paskett et al.
2006) have proven successful to improve uptake of mammography. Funding to con-
tinue these efforts is a significant challenge.

Treatment

Disparities in treatment have been well-documented. African-American, American

Indian and Hispanic women are less likely to have surgery, more likely to refuse
surgery, and less likely to receive radiation therapy (RT) compared to non-Hispanic
white women (Li et al. 2003). Women from Appalachia (a predominately rural area)
have higher rates of mastectomy and lower rates of RT after breast cancer surgery
compared to non-Appalachian women (Freeman et al. 2012). Women >70 years and
women without insurance were also less likely to receive adjuvant RT (Freeman
et al. 2012). Disparities also exist within Asian/Pacific Islander groups for receipt of
surgery and RT (Yi et al. 2012). Quality of treatment is also a factor. Fewer African-
American women start treatment within 30 days (69 %) compared to white women
(82 %); and receive lower quality treatment (Centers for Disease Control and
Prevention (CDC) 2012). This is a significant problem, as a modeling study esti-
mated that up to 19 % of the mortality difference between African-American and
non-Hispanic white women could be eliminated if the same treatment was provided
to both groups (Centers for Disease Control and Prevention (CDC) 2012).
Differences in response to treatments, such as Tamoxifen, may also be responsible
for some of the disparities in outcomes (American Cancer Society 2013). This area
needs to be further explored.

Issues of Survivorship

Issues of survivorship include side effects of treatment, adherence to adjuvant

hormone therapy, coping skills, body image, social support, acculturation and quality
of life. Hispanic women have been found to suffer more from pain, fatigue, depres-
sion, and financial hardship related to treatment compared to non-Hispanic women
46 E.D. Paskett

(Fu et al. 2009; Graves et al. 2012). American Indian/Alaskan Native women also
report problems related to pain, fatigue, depression and hair loss (Burhansstipanov
et al. 2010). Latina Spanish speaking women are more likely to discontinue adjuvant
hormone therapy compared to white women (Livaudais et al. 2012).
Coping skills allow women to adjust to both physical and emotional distress dur-
ing and following a cancer diagnosis and treatment. There are significant ethnic,
racial and cultural differences in coping strategies used to respond to these stressors.
For example, positive and negative forms of coping were more common among
women of color than white women; negative coping was more likely to be associ-
ated with increased levels of distress and poorer survival (Yoo et al. 2014). Rural
breast cancer patients are more likely to use behavioral disengagement, which is
related to depressive symptoms compared, to urban patients (Schlegel et al. 2009;
Collie et al. 2005).
Factors significantly related to coping strategies, such as religion and spiritual
practices, are actually more relevant for minority and rural women. Some practices,
e.g. spirituality and family support, actually are helpful in African-American popu-
lations, whereas spirituality has little impact on most non-Hispanic white women or
negative effects in Asian/Pacific Islander, Hispanic, and American Indian/Alaskan
Native women (Austin et al. 2002; Gaston-Johansson et al. 2013; Ashing-Giwa
et al. 2013a; Daley et al. 2012; Ndikum-Moffor et al. 2013).
Body image and femininity are domains often impacted by breast cancer diagno-
sis and treatment. Most studies have been conducted among African-American
women, and indicate that body image concerns were very important to their treatment
decisions (Yoo et al. 2014; Hawley et al. 2009). Asian/Pacific Islander women report
negative feelings towards their bodies after cancer surgery, so much so, that they
report loss of self-worth, unhappiness and depression, and avoid looking at their
bodies in the mirrors (Ashing-Giwa et al. 2013a). American Indian/Alaskan Native
women associate hair loss due to chemotherapy as a sign of loss of spiritual strength
which could result in isolation from the tribe (Burhansstipanov et al. 2010).
Social support is seen different in vulnerable populations—more African-
Americans report receiving social support from God whereas non-Hispanic whites
report receiving support from family and friends (Gaston-Johansson et al. 2013). In
Asian culture, women are seen as nurturers not dependents, thus Asian breast cancer
survivors may have unmet social support needs (Ashing-Giwa et al. 2013a). Latina
women report the family as the main source of social support, however, with a
breast cancer diagnosis, women report less acceptance by their husbands, possibly
due to a change in gender roles and perceived femininity, resulting in lower per-
ceived social support (Lopez-Class et al. 2011; Ashing-Giwa et al. 2004).
Acculturation also impacts survivorship. Lower acculturated Latinas report poorer
health after breast cancer and more functional limitations and poorer mental health
(Janz et al. 2009; Sammarco and Konecny 2010; Nápoles et al. 2011; Yanez et al.
2011). Native American languages have no word for cancer, but it translates to “the
disease for which there is no cure.”(Native American Cancer Research Corporation
Native Americans and Cancer) Language barriers compound acculturation issues
and produce long-lasting problems with access and adherence (Graves et al. 2012;
Ashing-Giwa et al. 2013b).
4 Breast Cancer Among Special Populations… 47

Studies of quality of life among survivors are rare in populations other than
white and African-American women (Ashing-Giwa et al. 2013a). Most African-
American survivors report a positive growth from their breast cancer experience
which favorably impacted their quality of life compared to white survivors (Russell
et al. 2008). Differences were found among Asian/Pacific Islander survivors. For
example, Chinese-American survivors had significantly greater medical concerns
that negatively impacted their quality of life compared to Japanese-American sur-
vivors (Ashing-Giwa et al. 2013a). Hispanic breast cancer survivors report lower
mean quality of life compared to women of other races/ethnicities. One study
reported 53 % of Hispanic survivors have elevated depressive symptoms (Ashing-
Giwa et al. 2013b). Rural women also report high levels of helplessness/hopelessness
and at higher risk for lowered quality of life (Reid-Arndt and Cox 2010; Koopman
et al. 2001).

Future Research Opportunities and Challenges

There are opportunities and challenges at every point across the cancer control
continuum among vulnerable populations. Overall, our progress suffers due to incon-
sistent and poorly utilized definitions of SES, race/ethnicity and rural residence.
For example, in many medical settings, race/ethnicity is not captured correctly or
completely, limiting our ability to effectively understand and identify disparities.
Secondly, access to preventive, detection and treatment services for all populations is
problematic. This concern is reflected in the Institute of Medicine (IOM) report:
Delivering high-quality cancer care: charting a new course for a system in crisis,
which outlines the difficulties of providing adequate cancer care in an age of growing
need, due to complexities of cancer treatment, a shrinking workforce, and increasing
costs [IOM (Institute of Medicine) 2013]; thus, this is a huge challenge to vulnerable
populations. Unfortunately, the ACA may not be able to fully remove barriers to
access for all populations.
In terms of research, there are many opportunities to reduce disparities across the
cancer continuum. As discussed earlier in this chapter, there are gaps in our knowl-
edge regarding etiology, prevention, and chemoprevention strategies in many
vulnerable populations. While diet, exercise, chemoprevention with tamoxifen/
raloxifene, and prophylactic mastectomy have been examined for efficacy, few stud-
ies have either (1) tested these options in large samples of vulnerable populations to
extend efficacy claims; or (2) examined ways to promote uptake of successful strat-
egies, (i.e. tamoxifen in vulnerable populations, dietary strategies, etc.) Questions
about what dietary components are protective or causative, what type of exercise is
important and how much one needs to exercise, as well as when weight matters—
e.g. adolescence, young adulthood or post menopausal—must also be further
explored in all populations. Studies into the acceptability and impact of prophylac-
tic mastectomy/oophrectomy for mutation carriers in different racial/ethnic groups
need to be conducted.
48 E.D. Paskett

Early detection strategies mainly center on mammography. The role of magnetic

resonance imaging (MRI) and even the role of self-examination in certain cultures
need to be explored. All populations are under the Healthy People 2020 goals for
regular mammography screening, however, more accurate assessments of the preva-
lence of regular mammography need to be found rather than relying on self-reports
from the BRFSS, as these self-reports may be less reliable in vulnerable populations
[Centers for Disease Control and Prevention (CDC) 2012; U.S. Department of
Health and Human Services (1953)]. Access to quality mammography, financial
barriers, cultural issues, and awareness of the need for regular exams are pressing
issues among vulnerable populations. More dissemination and implementation of
successful evidence-based interventions needs to occur systematically, such as
wider availability of the NBCCEDP to all eligible women.
Treatment is impacted by biology and access. More research, as well as more
representation in clinical trials, is needed into biological responses to treatment
across all vulnerable populations However, the state-of-the-art treatments are less
likely to be available in those vulnerable populations. Thus, access, whether because
of availability or financial limitations, must be assured. The use of PN’s who can
remove barriers to timely and quality care, should be universally accepted by the
health care system to address disparities in treatment. As evidenced by the Delaware
Experiment for colorectal cancer, PN’s and universal access to screening, follow-up
and treatment do eliminate disparities (Grubbs et al. 2013).
Furthermore, survivorship is a large area, mainly unexplored in the vulnerable
populations discussed in this chapter. Quality of life, adherence to treatment regi-
mens, coping, social support and body image are only some of the areas where more
research is needed, especially in subgroups, to identify and intervene on disparities.
Survivorship plans may be an intervention to test, as these can be tailored to the
needs of each woman and followed with the assistance of a PN.
A large gap in our knowledge is at the end of the cancer control continuum. Little
is known about palliative, hospice and end of life care in vulnerable populations.
While it is known that the demands for these services exceeds the supply, little is
known about what vulnerable populations know about these services, their specific
needs, and what special access problems they face (Lewis et al. 2011). These are all
areas where future research can be directed.
In summary, while many of the statistics documenting disparities in BC inci-
dence, mortality, and stage of diagnosis are well-known, the reasons for all dispari-
ties noted are not as well studied. Moreover, interventions need to be tested and
implemented, with policy and diffusion strategies, for BC disparities across the can-
cer control continuum to be reduced and eventually eliminated.

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Chapter 5
Symptoms: Fatigue and Cognitive Dysfunction

Julienne E. Bower and Patricia A. Ganz

Abstract Fatigue and cognitive complaints commonly occur during adjuvant

chemotherapy treatment of breast cancer. Fatigue is also associated with radiation
therapy, and can occur with surgery alone. Both of these symptoms may persist
beyond the initial treatment of breast cancer and they have taken on greater promi-
nence with the growing number of breast cancer survivors. These symptoms are
most troublesome when patients try to resume their pre-illness activities (e.g., work,
household responsibilities) and find that they are limited. Recovery may take months
to years, but in some women these symptoms persist indefinitely and can be very
distressing. In this chapter we review what is known about the etiology and biology
of these two common symptoms, discuss potential interventions, and describe
future research challenges.

Keywords Fatigue • Cognitive complaints • Breast cancer • Chemotherapy •

Radiation therapy • Inflammation

Overview of the Problem

Fatigue and cognitive complaints are two of the most common and distressing
symptoms reported by women with breast cancer. After two decades of research on
cancer-related fatigue, we have a good understanding of the characteristics, preva-
lence, and course of this symptom and are beginning to elucidate mechanisms, risk
factors, and effective treatments among women with breast cancer (Bower et al.
2000, 2006; Bower 2005, 2014). We also have a growing appreciation of the com-
plexity of fatigue, which shows significant inter-individual variability in its severity

J.E. Bower (*)

Departments of Psychology and Psychiatry/Biobehavioral Sciences, Jonsson Comprehensive
Cancer Center, University of California, Los Angeles, CA, USA
e-mail: [email protected]
P.A. Ganz
UCLA Schools of Medicine and Public Health, Jonsson Comprehensive Cancer Center,
Los Angeles, CA, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 53

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_5
54 J.E. Bower and P.A. Ganz

and expression. In parallel, cognitive complaints emerged as a frequent post-treatment

problem in the late 1990s, particularly in women who received high-dose chemo-
therapy (Ganz 1998; van Dam et al. 1998). Our understanding of the etiology, char-
acteristics, prevalence, and course of cognitive difficulties is not as advanced as the
knowledge-base related to fatigue; however, recent advances in neuroimaging have
accelerated our understanding of the impact of breast cancer treatments on cerebral
functioning. Importantly, research that the authors have jointly conducted over the
past decade has begun to identify a common biology for both of these clinical symp-
toms that is associated with inflammation. In this chapter, we will briefly review
descriptive research on cancer-related fatigue and treatment associated cognitive
changes in breast cancer patients, provide an overview of research on mechanisms,
and highlight key issues to be addressed in future research.

Description of Cancer-Related Fatigue

Research on cancer-related fatigue began with qualitative descriptions of this symp-

tom in the late 1980s and then progressed to more quantitative examination of its
prevalence, course, and correlates. Studies conducted with breast cancer patients
have documented increases in fatigue during treatment with radiation (Irvine et al.
1998) and with chemotherapy (Jacobsen et al. 1999), although chemotherapy-
induced fatigue is somewhat more severe. Fatigue typically improves in the year
after treatment completion, although a significant minority of patients continue to
experience fatigue for months or years after successful treatment (Bower et al. 2000;
Cella et al. 2001). In a survey study we conducted with almost 2000 breast cancer
survivors who were between 1 and 5 years post-diagnosis, we found that one-third
reported elevated fatigue (Bower et al. 2000). In a follow-up study with this sample,
we found that 20 % of study participants continued to report elevated fatigue up to
10 years after breast cancer diagnosis (Bower et al. 2006). Fatigue has a negative
impact on work, social relationships, mood, and daily activities and causes signifi-
cant impairment in overall quality of life during and after treatment among women
with breast cancer (Andrykowski et al. 1998; Bower et al. 2000; Broeckel et al.
1998; Curt et al. 2000). Fatigue also predicted shorter recurrence-free and overall
survival in a sample of breast cancer patients (Groenvold et al. 2007).
Patient reports suggest that cancer-related fatigue is more severe, more persis-
tent, and more debilitating than “normal” fatigue caused by lack of sleep or overex-
ertion and is not relieved by adequate sleep or rest (Poulson 2001). Indeed, studies
have confirmed that the intensity and duration of fatigue experienced by cancer
patients and survivors is significantly greater than healthy controls and causes
greater impairment in quality of life (Andrykowski et al. 1998; Cella et al. 2002;
Forlenza et al. 2005; Jacobsen et al. 1999). Cancer-related fatigue is multi-
dimensional and may have physical, mental, and emotional manifestations includ-
ing generalized weakness, diminished concentration or attention, decreased
motivation or interest to engage in usual activities, and emotional lability (Cella
5 Symptoms: Fatigue and Cognitive Dysfunction 55

et al. 2001). Fatigue is strongly correlated with depressive symptoms as well as

sleep disturbance, pain, and cognitive function, although patients experience fatigue
as a distinct and central symptom.

Description of Cognitive Complaints After Breast Cancer

Treatments

The first reports of cognitive complaints associated with breast cancer treatments
began with the more widespread use of adjuvant chemotherapy, accentuated by the
adoption of high dose adjuvant chemotherapy (Phillips and Bernhard 2003). In an
early review of this problem (Phillips and Bernhard 2003), Phillips and Bernhard
note the strong association of post-treatment cognitive impairment with adjuvant
chemotherapy, primarily in cross-sectional studies, with lack of clarity regarding the
extent to which premature menopause or adjuvant tamoxifen may have contributed
to patient reported complaints. In addition, they raise the question regarding the
extent to which these complaints overlap with psychological factors. In a cross-
sectional study from a clinical trial comparing neuropsychological tests and quality
of life in women who had received either high dose or standard dose adjuvant che-
motherapy, those exposed to the high dose chemotherapy were 8.2 times more likely
to have cognitive impairment than breast cancer patients who did not receive chemo-
therapy, and 3.5 times higher than patients receiving standard adjuvant chemother-
apy (van Dam et al. 1998). These results were not affected by depression, fatigue, or
time since treatment, and suggested a dose response effect for the neuropsychologi-
cal changes. These women were in their 40s and almost all became menopausal and
were receiving tamoxifen. A neurophysiological study done in a subgroup of these
patients also reflected changes consistent with a dose effect (Schagen et al. 2001).
Additional studies, with small numbers of patients, and with cross-sectional designs
(reviewed by Phillips and Bernhard), suffered from similar limitations in being able
to determine causal attribution of neurocognitive test abnormalities to chemotherapy
exposure, change in menstrual status, or use of tamoxifen. These studies and others
(Castellon et al. 2004, 2005) also failed to find significant relationships between
self-reported cognitive complaints and neurocognitive testing, and raised the issue
of anxiety and depression as confounding factors.
Given these emerging findings, and lack of consensus about how best to study
this increasing clinical problem, a group of investigators working in the field came
together in April 2003, spurred on by patient advocates who were becoming alarmed
about increasing reports of cognitive impairment after treatment. This workshop led
to a report (Tannock et al. 2004) that summarized the state of current research,
including a number of longitudinal investigations underway or planned, designed to
identify prospective changes in cognitive function associated with chemotherapy
treatments. In addition, there was a call for more studies to elucidate mechanisms,
as well as the addition of assessments in the setting of clinical trials. Breast cancer
survivors and advocates emphasized the impact of cognitive impairment on quality
56 J.E. Bower and P.A. Ganz

of life and recovery after treatments. Subsequently, this group of investigators,

supported in part by funding from an advocate organization, formed the International
Cognition and Cancer Task Force, which has met every second year, and has pro-
vided a forum for scientific discussion that has moved the field forward substan-
tially (Vardy et al. 2008; Wefel et al. 2011).
Several excellent reviews summarize the findings with regard to cognitive
impairment after breast cancer (Ahles 2012; Ahles et al. 2012; Jim et al. 2012).
Most studies confirm only subtle changes in cognitive function after exposure to
adjuvant chemotherapy on neurocognitive testing, most often manifest as a failure
to demonstrate improvement with repeated testing (practice effects) that are seen in
control subjects. The domains most often affected as shown in a meta-analysis are
verbal ability and visuo-spatial ability (Jim et al. 2012). However, classification of
neurocognitive tests into specific domains varies across papers. Other studies have
identified processing speed as an affected domain, especially in association with
aging and tamoxifen (Ahles et al. 2010). Abnormalities associated with cerebral
function have also been corroborated in a series of brain imaging studies in breast
cancer patients studied longitudinally, prior to and after chemotherapy administra-
tion (Deprez et al. 2011, 2012; McDonald et al. 2010, 2012). Most recently, there is
convincing evidence that self-reported cognitive complaints are also manifested in
cerebral imaging changes in breast cancer patients (Deprez et al. 2012, 2014; Kesler
et al. 2011). Our own studies have demonstrated that about 20 % of non-depressed,
younger post-treatment early stage breast cancer patients have higher memory and
executive function cognitive complaints than healthy controls, and that this is asso-
ciated with both chemotherapy and radiation treatments as well as significant differ-
ences in domain specific verbal memory and executive function neurocognitive
performance (Ganz et al. 2013b). In further studies of this same group of patients,
we have found that the initiation of endocrine therapy is associated with increased
language and communication complaints (Ganz et al. 2014). For this group of
patients, there was a strong association of these complaints with past hormone ther-
apy, as well as an interaction between past hormone therapy and breast cancer tar-
geted endocrine treatment. Further work needs to be done to understand the relative
contribution of endocrine therapy to post treatment cognitive complaints. However,
overall, these data suggest that patient reports of cognitive difficulties are genuine
and reflect changes in brain function that can be identified with sensitive neuroim-
aging procedures. What are the best self-report tools to capture these complaints,
and how to separate them from fatigue and depressive symptoms that may overlap,
is an important future research question (discussed below).
The pattern and trajectory of cognitive complaints and clinical cognitive decline
post-treatment may be influenced by multiple factors and are dependent on initial
cognitive reserve, influence of acute and chronic anxiety (as at time of diagnosis and
with initial treatments), followed by changes in hormonal mileu as well as influ-
enced by potential direct toxicities of treatments, and persistent elevations of inflam-
matory markers. Underlying this may be genetic susceptibility to cognitive decline
from known markers (i.e. APOE4) as well as other factors (Ahles 2012; Ahles et al.
2012; Mandelblatt et al. 2014).
5 Symptoms: Fatigue and Cognitive Dysfunction 57

The major obstacle associated with more regularly assessing cognitive function
as a treatment toxicity or for symptom management, has been the perceived burden
of assessing cognitive function with extensive batteries of neurocognitive tests.
However, the emerging research demonstrating the validity of self-reported com-
plaints may help to advance the regular assessment of this treatment toxicity along
with other patient reported outcomes.

Mechanisms for Fatigue and Cognitive Dysfunction: Focus

on Inflammation

Fatigue in breast cancer patients is multi-factorial and may be influenced by a vari-

ety of demographic, medical, psychosocial, and biological factors. We have found
that younger, unmarried women who have a lower household income report higher
levels of fatigue (Bower et al. 2000), suggesting that contextual factors (e.g., absence
of partner who can provide instrumental and emotional support) may influence the
experience of this symptom. Other potential contributing factors include medical
comorbidities, medications, nutritional issues, physical symptoms, and physical
deconditioning, among others (Mitchell 2010). For example, we found that heart
disease was a significant predictor of persistent post-treatment fatigue in a large
sample of breast cancer survivors (Bower et al. 2006). However, fatigue often occurs
in patients who are otherwise healthy and have few if any of these contributing fac-
tors, suggesting that other processes may also be at work. Of note, treatment-related
factors (e.g., type of treatment, dose-intensity) are not consistently associated with
fatigue, particularly in the post-treatment period.
A variety of biological mechanisms for cancer-related fatigue have been pro-
posed and investigated over the past two decades (Barsevick et al. 2010; Morrow
et al. 2002). These include anemia, cytokine dysregulation, hypothalamic-pituitary-
adrenal (HPA) axis dysregulation, five hydroxy tryptophan (5-HT) neurotransmitter
dysregulation, and alterations in adenosine triphosphate and muscle metabolism,
among others (Barsevick et al. 2010). With respect to cognitive function, Ahles and
Saykin (2007) reviewed potential mechanisms for the development of cancer-
related cognitive changes, which included endocrine factors (reductions in estrogen
and testosterone), DNA damage and telomere length, cytokine dysregulation and
disruption in the blood brain barrier. The mechanism that is common across both
conditions is cytokine dysregulation, and specifically inflammation.
The possibility that inflammatory processes may be involved in the etiology of
cancer-related fatigue and cognitive problems draws from basic research on
neural-immune signaling. This body of work has demonstrated that peripheral
inflammatory cytokines can signal the central nervous system to generate symptoms
of fatigue and other behavioral changes (Dantzer et al. 2008; Haroon et al. 2012;
Miller et al. 2008) (see Fig. 5.1). Signals from the peripheral immune system are
conveyed to the central nervous system through several routes, including direct neu-
ral activation via the afferent vagus nerve, transport of peripheral cytokines across
58 J.E. Bower and P.A. Ganz

Fig. 5.1 Model for explaining the influence of cancer and its treatments on common behavioral
alterations including fatigue and cognitive dysfunction [Reproduced with permission from Miller
et al. (2008)]

the blood-brain barrier via carrier molecules, and interaction of circulating cyto-
kines with brain cytokine receptors in areas that lack a functional blood-brain bar-
rier (i.e., circumventricular organs) and with brain vascular endothelial cells that
release second messages to stimulate cytokine production in the brain (Irwin and
Cole 2011). Cytokine signaling leads to changes in neural activity, physiological
processes (e.g., fever), and behavior, including changes in energy/fatigue and cog-
nitive function (Miller et al. 2013). In animal models, induction of pro-inflammatory
cytokines leads to decreased motor activity (presumably a behavioral manifestation
of fatigue) and altered cognition, as well as reduced food and water intake, social
withdrawal, and anhedonia.
These behavioral changes have been collectively described as “sickness behav-
ior” and are thought to represent a motivational shift designed to facilitate recovery
and prevent the spread of infection (Dantzer and Kelley 2007; Irwin and Cole 2011).
In humans, pharmacologic doses of cytokines given for treatment of cancer or hepa-
titis C are associated with significant increases in fatigue, cognitive problems, and
other markers of sickness (depressed mood, sleep disturbance) (Capuron et al. 2000;
Kirkwood 2002; Valentine et al. 1998). Experimental studies of cytokine induction
in healthy individuals have documented similar effects, with subjects reporting
increased fatigue and cognitive disturbance following endotoxin administration that
are correlated with elevations in circulating concentrations of pro-inflammatory
cytokines (Reichenberg et al. 2001; Spath-Schwalbe et al. 1998). Further, pharma-
cologic agents that block the pro-inflammatory cytokine TNFα lead to reduced
fatigue among individuals with inflammatory conditions (Tyring et al. 2006), and in
5 Symptoms: Fatigue and Cognitive Dysfunction 59

pilot studies with cancer patients (Monk et al. 2006) (though fatigue can also be a
side effect of these agents in certain patient populations). Together, this evidence
provides a strong biological rationale for inflammation as a potential mechanism
underlying cancer-related fatigue and cognitive disturbance.

Studies of Inflammation and Fatigue in Cancer Patients

In the cancer context, investigators have proposed that tumors and the treatments
used to eradicate them can activate the pro-inflammatory cytokine network, leading
to symptoms of fatigue and cognitive disturbance (Cleeland et al. 2003; Miller et al.
2008; Seruga et al. 2008). In the pre-treatment period, the tumor itself may be a
source for pro-inflammatory cytokines (Aggarwal et al. 2009; Coussens and Werb
2002) while during treatment, cytokines may be produced in response to tissue
damage from surgery, radiation, or chemotherapy (Aggarwal et al. 2009; Stone
et al. 2003). The inflammatory response may persist well after treatment comple-
tion as the host tries to deal with persisting pathogenesis and alterations in
homeostasis.
A growing number of studies have examined the association between circulating
markers of inflammation and fatigue during and after breast cancer treatment. In a
study of breast cancer patients assessed prior to chemotherapy (but after surgery),
fatigue was associated with elevations in CRP, a marker of systemic inflammation
(Pertl et al. 2013). In a study of breast and prostate cancer patients undergoing radia-
tion therapy, we found that patients reported increases in fatigue that were corre-
lated with increases in circulating inflammatory markers (CRP, IL-1 receptor
antagonist) (Bower et al. 2009). Similarly, increases in fatigue were correlated with
increases in the inflammatory cytokine IL-6 among breast cancer patients undergo-
ing chemotherapy (Liu et al. 2012). Documenting an association between inflam-
matory markers and on-treatment-related fatigue is complicated by dynamic
changes in the cellular immune system and inflammation that occur during the acute
phase of cancer treatment. Investigators have found more reliable associations
between inflammatory activity and fatigue after treatment completion. In a series of
cross-sectional studies with breast cancer survivors, we have documented elevations
in inflammatory markers among women who report elevated fatigue at 1 month
(Bower et al. 2011b), 2 years (Collado-Hidalgo et al. 2006), and 5 years (Bower
et al. 2002) post-treatment. Consistent with these results, several other groups have
found significant elevations in CRP among breast cancer survivors with persistent
fatigue (Alexander et al. 2009; Alfano et al. 2012; Orre et al. 2011). At the molecu-
lar level, leukocytes from fatigued breast cancer survivors show increased expres-
sion of genes encoding proinflammatory cytokines and other mediators of
immunologic activation, as well increased activity of proinflammatory NF-κB/Rel
transcription factors, which might structure the observed differences in the expres-
sion of inflammation-related genes (Bower et al. 2011a).
60 J.E. Bower and P.A. Ganz

Studies of Inflammation and Cognitive Function in Breast

Cancer Patients

In parallel to the studies of fatigue, there are increasing reports that have focused on
the potential role of inflammation in the etiology of cognitive impairment after
breast cancer. Early reviews of potential mechanisms identified inflammation as a
possible etiology (Ahles and Saykin 2007) and studies in rodents provide strong
support for inflammatory mechanisms (Seigers and Fardell 2011). While some che-
motherapeutic agents may cross the blood brain barrier and cause direct toxicity
(e.g., especially the CMF regimen, with methotrexate and fluorouracil), the mecha-
nism by which both chemotherapy and radiation cause injury is likely through the
production of reactive oxygen species and tissue damage, that result in systemic
inflammation as well as stimulation of local microglial inflammation within the
brain. Indeed, several studies of breast cancer patients have demonstrated relation-
ships between systemic levels of inflammation and brain imaging structural and
metabolic changes (Kesler et al. 2013b; Pomykala et al. 2013). Animal models stud-
ies support these findings (Seigers et al. 2013), and an inflammatory basis of cogni-
tive changes associated with cancer treatments would be consistent with age related
cognitive changes of which this may be a manifestation (Ahles 2012). Since only a
subgroup of patients with breast cancer appear to be vulnerable to cognitive difficul-
ties, as with age-related variation in cognitive decline, similar host factors and sus-
ceptibilities may be relevant (see below).
To develop an understanding of the potential role of inflammation and cognitive
dysfunction in women with breast cancer, we recruited a cohort of women with
newly diagnosed breast cancer who had completed primary adjuvant chemotherapy
and/or radiation therapy, but enrolled prior to the start of endocrine therapy if
planned. The Mind Body Study (MBS) cohort of 191 patients was less than 66 years
of age, and excluded women with significant depressive symptoms, history of cen-
tral nervous system disorders, conditions with chronic inflammation, or with use of
immunosuppressive therapy (see details in Bower et al. 2011b; Ganz et al. 2013a,
b). We observed post-treatment elevations of soluble TNFα receptor II (sTNFR2)
levels at study enrollment that declined over the subsequent 12 months of follow-up,
with elevations only noted in the patients who had received chemotherapy (Ganz
et al. 2013a). We should note that there was a parallel association between fatigue
and sTNFR2 in this same sample at the baseline assessment (Bower et al. 2011b),
and we see the co-occurrence of these two symptoms in the longitudinal follow-up
of this sample (unpublished data). The changes in TNF over the 12 months were
correlated with self-reported memory complaints, as well as changes in PET scan
glucose metabolism in a small subgroup of patients, with normalization of metabo-
lism in the inferior frontal gyrus as TNF levels decreased between baseline and 12
months later. More detailed evaluation of sTNFR2 and other proinflammatory cyto-
kines in the PET scan study are reported separately in an additional publication,
where we observed positive correlations between metabolism in the medial prefron-
tal cortex and anterior temporal cortex with both memory complaints and cytokine
5 Symptoms: Fatigue and Cognitive Dysfunction 61

markers only in patients who received chemotherapy (Pomykala et al. 2013). Of

note, Kesler et al. (2013b) have found an association between decreased hippocam-
pal volume on MRI in breast cancer survivors and elevated TNFα and IL-6, along
with decreased verbal memory performance on cognitive testing, in comparison to
a healthy control group.

Host Factors that May Increase Risk for Fatigue

Although cancer-related fatigue is common, it does not affect all patients (see
Table 5.1). Clinicians have no doubt observed that certain patients are more suscep-
tible to fatigue, and empirical studies have now documented considerable variability
in reports of fatigue before, during, and after treatment. This variability was nicely
illustrated in a longitudinal prospective study of breast cancer patients who were
followed for 6 months after cancer treatment (Donovan et al. 2007). Using growth
mixture modeling, two groups of patients were identified on the basis of their fatigue
scores. One group, which comprised approximately 30 % of the sample, reported
consistently low levels of fatigue across the assessment period, including in the
immediate aftermath of treatment. The other group reported elevated fatigue at
treatment completion, which declined over the assessment period but remained sig-
nificantly higher than the low fatigue group. Of note, disease- and treatment-related
factors did not determine group membership in this study; instead, body mass index
and coping strategies were significant predictors of group membership. Other stud-
ies have similarly found no evidence that cancer-related fatigue is associated with

Table 5.1 Host factors Fatigue

associated with fatigue and
Pre-treatment fatigue
cognitive dysfunction
Pre-treatment sleep disturbance
History of depression
Loneliness
Early life stress
Physical inactivity
High body mass index
Catastrophizing coping style
Genetic factors (e.g., SNPs in inflammation-related
genes)
Neuroendocrine dysregulation
Cognitive dysfunction
Pre-treatment diminished cognitive reserve, low
educational status
History of head trauma
Comorbid conditions (e.g., diabetes, vascular
disease)
Genetic factors (e.g., APOE-4, COMT, SNPs in
inflammation-related genes)
Older age (?)
62 J.E. Bower and P.A. Ganz

type of cancer treatment, particularly in the post-treatment period. Together, these

findings strongly suggest that host factors play an important role in the development
and persistence of cancer-related fatigue.
Longitudinal studies have begun to identify predictors of cancer-related fatigue.
These include pre-treatment fatigue, pre-treatment sleep disturbance, history of
depression, loneliness, early life stress, physical inactivity, and body mass index
(Bower 2014). In addition, patients who engage in negative thoughts or “catastroph-
ize” about their fatigue (e.g., I tell myself I don’t think I can bear the fatigue any
more), report elevated fatigue during and after treatment. Thus, psychosocial and
behavioral factors may set the stage for more severe and persistent cancer-related
fatigue. Importantly, some of these factors are amenable to intervention, including
physical inactivity, high BMI, and catastrophizing.
Genetic factors have also been linked to cancer-related fatigue. Most of the stud-
ies in this area have taken a candidate gene approach, focusing on single nucleotide
polymorphisms (SNPs) in inflammation-related genes including IL1B, IL6, and
TNF given evidence linking circulating inflammatory markers and fatigue. We
examined whether polymorphisms in these genes were associated with fatigue
within 1 month after treatment, using data from breast cancer survivors enrolled in
the MBS study. Consistent with hypotheses, we found that women with the “high
expression” versions of these genes reported higher levels of fatigue (Bower et al.
2013a). Similarly, in a small sample of breast cancer survivors assessed several
years after treatment, polymorphisms in ILB and IL6 were associated with persis-
tent post-treatment fatigue (Collado-Hidalgo et al. 2008). There is also preliminary
evidence that polymorphisms in inflammation-related genes are associated with
fatigue among patients undergoing radiation therapy, including many breast cancer
patients (Aouizerat et al. 2009; Miaskowski et al. 2010).
Alterations in the HPA axis may contribute to cancer-related fatigue, either
directly or through effects on inflammatory processes. We found that breast cancer
survivors with persistent fatigue had a flatter diurnal cortisol slope (with elevated
levels of cortisol in the evening) as well as blunted cortisol responses to psycho-
social stress that were correlated with alterations in inflammatory activity (Bower
et al. 2005a, b, 2007) Further, genome-wide transcriptional profiling of leukocytes
from fatigued breast cancer survivors showed a marked down-regulation of genes
with response elements for the glucocorticoid receptor, suggesting a state of func-
tional GR resistance which may contribute the tonic upregulation of NF-κB
observed in fatigued survivors (Bower et al. 2011a). Fatigue is also associated
with alterations in the autonomic nervous system in breast cancer survivors,
including lower heart rate variability (an indicator of parasympathetic activity)
and elevated norepinephrine (an indicator of sympathetic activity) (Crosswell
et al. 2014; Fagundes et al. 2011). Importantly, because all of these studies have
been cross-sectional investigations of breast cancer survivors, it is impossible to
determine whether neuroendocrine alterations play a causal role in the develop-
ment and persistence of this symptom, or arise as a consequence of fatigue and
inflammatory activity.
5 Symptoms: Fatigue and Cognitive Dysfunction 63

Longitudinal studies that examine risk factors for cancer-related fatigue are still
quite limited and few have followed patients from pre-treatment in to the post-
treatment period; fewer still have examined mechanisms that underlie effects of
these risk factors on fatigue. To advance research in this area, longitudinal studies
are required that track patients before, during, and after treatment and include com-
prehensive assessment of biobehavioral risk factors and underlying mechanisms.
This approach will facilitate the identification of distinct trajectories of fatigue, risk
factors for fatigue onset and persistence, and the mechanisms that underlie their
effects, paving the way for targeted interventions.

Host Factors and the Risk for Cognitive Impairment

Less is known about the host factors associated with the risk of cognitive impair-
ment after breast cancer treatments (see Table 5.1). Ahles and Saykin (2007)
reviewed potential mechanisms for the development of cognitive changes and these
included genetic susceptibility, endocrine factors (reductions in estrogen and testos-
terone), DNA damage and telomere length, cytokine dysregulation and disruption in
the blood brain barrier. Among these mechanisms, genetic susceptibility has been
studied by several groups. Ahles has reported on the association of the APOE-4
allele, found in Alzheimer’s disease, with cancer-related cognitive dysfunction in
long-term breast and lymphoma survivors treated with chemotherapy (Ahles et al.
2003). In another sample of breast cancer patients followed prospectively, Small
et al. (2011) found that patients with the catechol-o-methyltransferase (COMT)
genotype Val + allele had greater cognitive difficulties with attention, verbal fluency
and motor speed, with an interaction with chemotherapy for attention. COMT-
Val + carriers are thought to metabolize dopamine more rapidly and this might be
the putative mechanism. In our MBS study, we have found that a genetic risk score
of SNPs for IL1B, IL6, and TNF was significantly associated with memory com-
plaints as well as fatigue (Bower et al. 2013b). Other groups have also found similar
associations (Merriman et al. 2013, 2014).
Other contributing factors could be those influences associated with age-related
cognitive decline and cognitive reserve may be reduced in individuals with lower
education or prior comorbid conditions leading to subclinical brain injury (Ahles
2012; Mandelblatt et al. 2014) (see Fig. 5.2). It is likely that the cognitive complaints
that patients report after treatment exposure are a manifestation of having to work
harder (recruit more areas of the brain) to retrieve information, multi-task, and per-
form executive tasks. These are similar to what happens with age-related cognitive
decline (Maillet and Rajah 2013). In addition to these factors, age-related vascular
disease, diabetes, and hormonal changes may contribute to these problems. However,
it is most interesting the manifestations of symptomatic cognitive difficulties are
most notable in younger women, similar to what is seen with fatigue. It may be that
the everyday demands put upon younger women exacerbate these complaints,
whereas older women may be less likely to notice subtle changes in function.
64 J.E. Bower and P.A. Ganz

Neurocognitive Function

No cancer

Cancer Phase-shift hypothesis

survivor The trajectory of cognitive dysfunction
parallels normal aging
Nonfrail survivor
Accelerated aging hypothesis
Cancer survivor The trajectory of cognitive dysfunction
is accelerated in comparison to normal aging.

Frail Survivor Reliability theory hypothesis

The trajectory of decline interacts with frailty level;
Time those with lower reserve have the steepest
trajectory of decline in comparison to those
with normal aging.

Fig. 5.2 Trajectories of cognitive decline based on theories of aging and frailty phenotype
[Adapted from Mandelblatt et al. (2014)]

What Are the Potential Intervention Strategies to Consider

for Management of Fatigue or Cognitive Complaints?

Interventions for Cancer-Related Fatigue

A diverse range of treatment approaches have been used to address cancer-related

fatigue during and after cancer treatment, including physical activity, psychosocial,
mind-body, and pharmacological interventions. Perhaps because the etiology of
cancer-related fatigue is multi-factorial and still poorly understood, there is cur-
rently no “gold standard” for treatment of this symptom. Still, a number of these
approaches have been shown to be beneficial in reducing cancer-related fatigue, as
reviewed below. The recently published ASCO Guideline on Fatigue in Cancer
Survivors outlines the intervention strategies that should be considered (Bower
et al. 2014). A number of randomized controlled trials have examined the effect of
exercise on cancer-related fatigue. Overall, meta-analyses of these trials indicate
that exercise is effective in reducing fatigue, with effect size estimates ranging from
−0.27 to −0.38, indicating a moderate effect (Cramp and Byron-Daniel 2012; Puetz
and Herring 2012). Beneficial effects of exercise have been observed in trials con-
ducted with patients during and after treatment, indicating that exercise can be help-
ful at different stages of the disease trajectory. Aerobic exercise regimens seem to
be particularly beneficial. Guidelines from the American College of Sports Medicine
(ACSM) recommend that cancer patients and survivors engage in at least 150 min
of moderate intensity aerobic activity each week, consistent with recommendations
for the general population (Schmitz et al. 2010). ACSM guidelines further recom-
mend that exercise should be tailored to the individual cancer patient to account for
exercise tolerance and specific diagnosis, and that patients be closely monitored to
safely progress exercise intensity and avoid injury.
5 Symptoms: Fatigue and Cognitive Dysfunction 65

Psychosocial interventions are also effective in reducing fatigue, particularly

interventions that provide education about fatigue and contributing factors (e.g.,
physical activity, sleep disturbance) and address dysfunctional fatigue-related
thoughts and behaviors. Among women undergoing radiation or chemotherapy for
breast cancer, individualized educational and cognitive-behavioral approaches that
specifically targeted fatigue buffered the increase in fatigue observed among control
patients (Montgomery et al. 2009, 2014; Yates et al. 2005). A brief psychoeduca-
tional intervention that provided information about fatigue and modeled adaptive
coping strategies (e.g., physical activity) also led to reductions in fatigue among
women who had recently completed breast cancer treatment (Stanton et al. 2005).
More intensive and targeted treatments have shown benefit for survivors with severe
and persistent post-treatment fatigue. These include individual cognitive-behavioral
therapy focused on perpetuating factors for persistent fatigue (Gielissen et al. 2006),
and a web-based, tailored education program providing information on cancer-
related fatigue as well as energy conservation, physical activity, sleep hygiene, dis-
tress management, nutrition, and pain control (Yun et al. 2012). Mind-body
interventions have also demonstrated efficacy for treating cancer-related fatigue in
cancer survivors (see Table 5.2). In particular, specialized programs of acupuncture
(Molassiotis et al. 2012), yoga (Bower et al. 2012), and mindfulness (van der Lee
and Garssen 2012) led to significant reductions in fatigue among survivors with
persistent post-treatment fatigue.
In terms of pharmacologic interventions, there is mixed evidence for the effec-
tiveness of psychostimulants (e.g., methylphenidate) and other wakefulness agents
(e.g., modafinil) as treatments for cancer-related fatigue (Minton et al. 2008, 2011).
Several large trials of these agents have yielded negative effects, though subgroup
analyses suggested that patients with severe fatigue may show some benefit (Jean-
Pierre et al. 2010; Moraska et al. 2010). However, there is very limited evidence of
their effectiveness in reducing fatigue in patients who are disease free following
active treatment. American ginseng may hold promise for treating cancer-related
fatigue, particularly among patients undergoing treatment, but more research on this
agent is needed (Barton et al. 2013). Of note, very few of the pharmacologic trials
have focused specifically on breast cancer patients or survivors.

Interventions for Cognitive Complaints

There have been relatively few studies designed to provide intervention for cogni-
tive dysfunction in cancer survivors, and most of them have been conducted in
breast cancer. The first study by Ferguson et al. (2007) was a single arm, individu-
ally delivered cognitive behavioral therapy (CBT) approach to memory problems.
Due to feasibility and improvements in objective and subjective evaluation, this was
expanded to a phase II randomized wait-list controlled trial (Ferguson et al. 2010)
that showed trends towards improvement in some aspects of quality of life and
memory, but was not definitive. We recently conducted a pilot feasibility trial of a
 66

Table 5.2 Randomized controlled trials of mind-body interventions using cancer-related fatigue as an entry criteria
Intervention
Author, publication date Participants Intervention type duration Control group(s) Results
Bower (2011) 31 breast cancer Iyengar yoga; group 12 weeks, 2 Health education Decrease in fatigue in yoga
survivors with moderate format; focused on postures sessions per group group vs. controls at
to severe fatigue thought to be effective for week post-intervention; group
reducing cancer-related differences maintained over
fatigue (restorative poses, 3 month follow-up
supported back bends,
supported inversions)
Johns (2014) 35 cancer survivors with Mindfulness-based stress 7 weeks, 1 Wait list Decrease in fatigue in
moderate to severe reduction; group format; session per week mindfulness group vs.
fatigue (85.7 % breast) provided training in controls at post-
mindfulness meditation and intervention; group
psycho-education about differences maintained over
cancer-related fatigue 1 month follow-up
Molassiotis (2012) 302 breast cancer Acupuncture; individual 6 weeks, Usual care (fatigue Decrease in fatigue in
survivors with moderate sessions; needled 3 1 session per information acupuncture group vs.
to severe fatigue; all standardized points week booklet) controls at
post- chemotherapy post-intervention
van der Lee (2012) 100 cancer survivors Mindfulness-based 9 weeks, Wait list Decrease in fatigue in
with severe fatigue cognitive therapy; group 1 session per mindfulness group vs.
(58 % breast) format; provided training in week controls at post-
mindfulness meditation and intervention; improvement
using mindfulness to maintained over 6 month
manage automatic negative follow-up
thoughts about fatigue
J.E. Bower and P.A. Ganz
5 Symptoms: Fatigue and Cognitive Dysfunction 67

5 week, group intervention, cognitive rehabilitation program adapted from strate-

gies used in older adults with mild cognitive impairment (Ercoli et al. 2013). This
single arm study in 27 breast cancer survivors demonstrated feasibility as well as
improvement in self-report and neurocognitive testing up to 6 months post interven-
tion. A small sub-study showed significant normalization of EEG patterns in women
who participated in the intervention. Recently, we completed a phase II randomized
controlled trial of the same intervention compared to a wait-list control group, and
showed highly significant improvements in self-report, neurocognitive tests, and
EEG in the intervention group compared to the control group, which was sustained
out to 2 months post-intervention, along with improvements in EEG correlating
with those who had improved cognitive complaints (Ercoli et al. 2015). These very
encouraging findings suggest there is a physiological basis for the improvement in
cognitive complaints and test performance.
Other groups have applied computerized technologies to improve cognitive
function in breast cancer patients. Kesler et al. (2013a) in a pilot study which ran-
domized 41 breast cancer survivors to a computerized training program focused on
executive functioning and memory found significant improvements in those who
received the training compared to those who did not. Von Ah et al. (2012) examined
a computer-based memory or processing speed training program compared to a
wait-list control group of breast cancer survivors. They found that the processing
speed training improved that outcome and memory immediately post-intervention
and 2 months later. The memory training improved memory performance on neuro-
psychological testing.
There has also been exploration of psychostimulants to improve fatigue (Jean-
Pierre et al. 2010) and secondarily cognitive function, but the findings are not con-
clusive (Kohli et al. 2009). Other investigators have attempted to examine
methylphenidate without success, in terms of adequate recruitment to a treatment
trial (Mar Fan et al. 2008). Any such therapy would have to have minimal side
effects if it is given chronically, and many breast cancer survivors are averse to con-
tinue taking medication long-term if it is not truly necessary or very helpful. Thus
behavioral strategies have greater appeal.

What Are the Research Challenges Associated with These Two

Common Symptoms?

One of the critical challenges in the area of cancer-related fatigue and cognitive
dysfunction is determining the underlying mechanisms for these symptoms.
Although cross-sectional research has shown a positive association between inflam-
matory activity and fatigue in cancer patients and survivors, the causal nature of this
association has not been determined. In particular, it is unknown whether inflamma-
tion causes fatigue (as observed in experimental models of sickness behavior), or
whether inflammation is a consequence of fatigue (perhaps due to reductions in
physical activity, alterations in sleep, or other behavioral/physiological changes).
68 J.E. Bower and P.A. Ganz

One challenge to advancing research in this area is the lack of animal models of
cancer-related fatigue (Dantzer et al. 2012). To directly address the causal role of
inflammation in a human model, we conducted a small pilot study to evaluate the
acute effects of infliximab, a monoclonal antibody against TNF, in five breast can-
cer survivors with severe, persistent fatigue. Participants completed daily diaries for
2 weeks before and after receiving a single dose of infliximab to assess changes in
the severity and duration of daily fatigue. All five women reported reductions in
daily fatigue, including a mean 1.9 point decrease in “worst” fatigue from pre- to
post-treatment. These preliminary findings are promising and could be pursued in a
larger randomized, placebo-controlled trial to determine the causal role of inflam-
mation in cancer-related fatigue. However, anti-cytokine therapies have well-known
side effects that may limit their use among women with breast cancer. In addition,
given the multi-factorial nature of fatigue, it is likely that only certain women will
respond to these (or other) anti-inflammatory agents. Indeed, a recent trial of inflix-
imab for depression found that only those patients with elevated inflammation at
treatment onset showed a positive response to this medication (Raison et al. 2013).
Similarly, only patients with elevated inflammation are likely to show reduced
cancer-related fatigue (and improvements in cognitive function) following anti-
inflammatory therapies. Patients whose fatigue is driven by cognitive processes,
such as catastrophizing, may be more responsive to cognitive-behavioral therapies,
whereas those fatigue is driven by deconditioning may be responsive to exercise. Of
course, these treatments may have multiple targets; for example, in our yoga trial
with fatigued breast cancer survivors, women in the intervention group reported
higher self-efficacy to manage fatigue symptoms and lower inflammatory activity,
both of which may have contributed to their reduced fatigue (Bower et al. 2012,
2014). Identifying appropriate treatments for individual patients is an important
challenge for future research. In addition, determining the factors that influence
fatigue onset vs. persistence may be helpful in determining which type of interven-
tions may be most helpful during vs. after treatment.
Another topic of considerable interest for research on cancer-related fatigue and
cognitive disturbance is the intersection of aging and cancer (Dale et al. 2012).
Similar biological processes are involved in aging, fatigue, and cognitive function,
including inflammation (Mandelblatt et al. 2013). Indeed, cancer and its treatment
may accelerate age-related changes in inflammatory activity and other physiologi-
cal processes, which may contribute to fatigue and cognitive decline, particularly in
vulnerable individuals. Cancer patients and survivors who suffer from fatigue and
cognitive problems may look biologically “older” than patients without these prob-
lems, which may make them more susceptible to age-related declines in physical
and mental function. However, few studies have probed the overlap between age-
related processes and cancer-related behavioral disturbances. In addition, potential
common and specific mechanisms for fatigue and cognitive function have not been
carefully examined.
Clinically, in our practice with breast cancer survivors, persistent fatigue and/or
cognitive difficulties often co-occur. In some women, one symptom is more promi-
nent than the other. In our various research studies focused on women with cognitive
5 Symptoms: Fatigue and Cognitive Dysfunction 69

complaints seeking rehabilitation services, increased fatigue, sleep disturbance and

impaired physical function are all self-reported as moderate to severe, even though
these complaints are not prominently mentioned. What has been most reassuring to
women has been our ability to explain the possible biological factors underlying the
development of either persistent fatigue or cognitive complaints, as they frequently
feel isolated and rejected by the medical community and even support groups,
where other women do not have similar complaints. They are often labeled as being
depressed, when they clinically are not, and they are very hard on themselves for
not being able to function and work the way they did before their cancer diagnosis
and treatment. With the emerging evidence from neuroimaging studies that there are
functional cerebral abnormalities associated with breast cancer treatment (espe-
cially chemotherapy), it will be critical to develop a better understanding of the
natural history of these changes and to determine who is most vulnerable for persis-
tent difficulties that do not resolve or worsen over time. The MBS cohort study is
one study, but more are needed. In addition, we need to begin to intervene early in
the course of the treatment to try to improve outcomes for women so that they can
resume their pre-illness functioning, especially for activities of everyday life which
can be compromised in many.
Given the substantial numbers of women who experience persistent fatigue and
cognitive difficulties after breast cancer treatment, we can no longer ignore this as a
potential toxicity of cancer treatment. Consent forms in clinical trials must address
this possibility, and patient reported assessments should be included in clinical trial
outcomes. Some of the newer targeted agents, such as everolimus, may have signifi-
cant impact on fatigue (Baselga et al. 2012) and cognitive difficulties have not been
assessed to our knowledge. While we have been successful in reducing the number
of women now exposed to adjuvant chemotherapy due to genomic profiles testing,
a substantial number will still receive treatments that may cause either fatigue or
cognitive difficulties and we need to gather this information to help in management
and decision-making regarding treatment.

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Chapter 6
Symptoms: Chemotherapy-Induced
Peripheral Neuropathy

Bryan P. Schneider, Dawn L. Hershman, and Charles Loprinzi

Abstract Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic,

treatment-induced toxicity that has the potential to impact quality of life and limit
the doses of curative intent therapy. This therapy-induced side effect is one of the
most troublesome in oncology clinical practices, considering the morbidity, the fre-
quency, and the potential irreversibility of this problem. Patients with breast cancer
are particularly impacted by this side effect as multiple agents commonly used for
this disease can cause neuropathy. In this chapter, we provide an overview of CIPN,
including: clinical predictors, frequency, and its impact on quality of life. Further,
we highlight the pathophysiology and review the literature to date for agents
designed to prevent or treat CIPN. We also highlight the most important ongoing
clinical and translational research questions that hope to help better predict and
prevent this toxicity. This includes optimizing the methods of assessment, using
host specific factors (Race and genetics) to predict those more likely to experience
CIPN, and determining how CIPN might impact clinical decisions toward therapy.

Keywords Neuropathy • CIPN (Chemotherapy-induced peripheral neuropathy) •

Taxanes • Breast cancer • Toxicity • Pharmacogenetics • PRO (Patient reported
outcomes)

B.P. Schneider (*)

Associate Professor of Medicine & Medical/Molecular Genetics, Indiana University Simon
Cancer Center, Indianapolis, IN, USA
e-mail: [email protected]
D.L. Hershman
Associate Professor of Medicine and Epidemiology, Herbert Irving Comprehensive Cancer
Center, Columbia University, 161 Fort Washington, 1068, New York, NY 10032, USA
e-mail: [email protected]
C. Loprinzi
Regis Professor of Breast Cancer Research, Division of Medical Oncology,
Rochester, MN, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 77

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_6
78 B.P. Schneider et al.

Overview

Chemotherapy-induced peripheral neuropathy (CIPN) is a problematic, treatment-

induced toxicity that has the potential to impact quality of life and limit the doses of
curative intent therapy (Cavaletti and Zanna 2002; Hershman et al. 2011). This
therapy-induced side effect is one of the most troublesome in oncology clinical
practices, considering the morbidity, the frequency, and the potential irreversibility
of this problem. Patients with breast cancer are particularly impacted by this side
effect as multiple agents commonly used for this disease can cause neuropathy.
Breast cancer-related drugs that often cause neuropathy include those used in the
metastatic setting such as: platinating agents, vinca alkaloids, eribulin, and ixabepi-
lone. Perhaps the most important class, however, are the taxanes which are com-
monly employed in both the curative setting and the metastatic setting (Ghersi et al.
2005; Nowak et al. 2004); a class of drugs with potential for serious and, at times,
long-lasting neuropathy (Hershman et al. 2011).
CIPN typically induces a sensory neuropathy with symptoms that reflect either a
gain in sensory neuronal function, a loss of function or a combination of both. The
most common symptoms that likely result from an increase function of a subset of
sensory neurons are paresthesias, tingling, pain/allodynia; whereas the most com-
mon symptoms that likely reflect loss of function are numbness and dulled sensation,
a loss of position and/or vibratory sense (Stubblefield et al. 2009; Cavaletti et al.
2013), and diminished reflexes. Motor neuropathy symptoms also occur, although
they are markedly less common (Argyriou et al. 2012). It is not clear whether motor
neuropathy is simply a severe variant of the same process or whether the mechanism
is completely different. Further, it is not clear why some patients experience pre-
dominantly symptoms of loss of function and others symptoms of enhanced excit-
ability or whether this matters when considering future preventive therapeutics.
Specific to the taxanes, the frequency and severity of peripheral neuropathy is
related to the specific drug, dose, schedule, and duration of therapy. From the large
adjuvant trials, the rates of taxane-induced neuropathy range from 15 to 23 % grade
2–4, as graded by the Common Terminology Criteria Adverse Event (CTCAE) sys-
tem (Hershman et al. 2011; Lee and Swain 2006). Patients with grade 2 neuropathy
have interference with function (e.g. difficulty buttoning a shirt), those with grade
3 have interference with activities of daily living (e.g. brushing teeth or bathing),
and those with grade 4 have permanent and disabling symptoms. In general the rates
are higher for paclitaxel, compared with docetaxel (while acute and hematologic
toxicities are more prevalent in the latter) (Sparano et al. 2008). The frequency and
severity of neuropathy increases with increasing dose for both agents. The fre-
quency of neuropathy is also schedule dependent with the weekly dosing for pacli-
taxel having more neuropathy when compared with every 3-week dosing; although
the former also has more anti-tumor efficacy against breast cancer (Sparano et al.
2008). The likelihood of neuropathy may be higher in patients who have other con-
tributing predispositions to neuropathy, such as diabetes mellitus (Gogas et al.
1996). Additionally, those patients who are obese and older age are at greater risk
(Rowinsky et al. 1993a, b). Finally, recent data suggest that African American
6 Symptoms: Chemotherapy-Induced Peripheral Neuropathy 79

patients might also be at a markedly higher risk for paclitaxel induced CIPN
(Schneider et al. 2011). Thus, special attention must be paid to these patient popula-
tions when preparing to treat them with a potentially neurotoxic agent.
In addition to the classic chronic CIPN caused by paclitaxel, usually presenting
in a stocking/glove distribution (Cavaletti and Zanna 2002; Stubblefield et al. 2009),
there are data to strongly support that the acute pain syndrome (which, for a long
time had been labeled as being from arthralgias/myalgias) is actually an acute form
of neuropathy (Loprinzi et al. 2011). This is similar to oxaliplatin causing an acute
neuropathy along with a more chronic neuropathy (Argyriou et al. 2012; Velasco
et al. 2014).
There are two major clinical tensions that relate to CIPN. One is the direct impact
on quality of life and functionality (Hershman et al. 2011). The second is the poten-
tial to limit the use of an effective agent. For the latter, this can mean the permanent
discontinuation of an effective drug when treating metastatic breast cancer and less
than desired dose-intensity in the curative setting. Specifically, a highly effective
adjuvant regimen for high-risk patients includes weekly paclitaxel, which unfortu-
nately also has one of the highest incidences of CIPN (Sparano et al. 2008). Thus, for
those at high risk for disease recurrence, a major concern is the patient’s inability to
tolerate the full dose/duration of therapy when the treatment is likely to be life-
saving. An equally problematic situation occurs when deciding on adjuvant treat-
ment in patients at very low risk for recurrence, but deemed eligible for chemotherapy.
The use of taxane-based regimens in this setting has become commonplace in order
to avoid anthracyclines (Jones et al. 2006). While this approach has removed the rare,
but serious risks of congestive heart failure and myelodysplasia/leukemia, it has
highlighted the marginal risk-benefit ratio for this patient population in whom the
incremental gain in curability may be quite small and the potential for a devastating,
permanent neurotoxicity may be larger. This problem is exacerbated by the inability
to predict, a priori, which patients might be preferentially affected by CIPN.
Understanding the mechanism for CIPN is critical toward identifying potential
targets for preventive and therapeutic interventions. The current understanding of
what causes CIPN is incomplete (Cavaletti et al. 1995; Flatters and Bennett 2006;
Jimenez-Andrade et al. 2006; Nakata and Yorifuji 1999; Pachman et al. 2011;
Persohn et al. 2005; Peters et al. 2007; Raine et al. 1987; Theiss and Meller 2000;
Witte et al. 2008). Taxanes promote microtubule stabilization, which causes cell
death by interfering with normal cell division. Similar aggregation of the microtu-
bules in the neuronal cell bodies may also lead to the disturbances in neuronal func-
tion by impacting microtubule based axonal transport, mitochondrial dysfunction,
or through direct damage to DNA. In pain models, damage to peripheral nerves
leads to spontaneous activation of afferent pain nerve fibers with an increase in volt-
age gated sodium and calcium channels as well as an up-regulation of a variety of
receptor proteins. The activation of the nerve fibers also causes hyper-excitability of
the dorsal column of the spinal cord and the dorsal horn (Baron et al. 2010).
Additionally, there is loss of GABA releasing neurons and descending inhibitory
pathways involving serotonin and norepinephrine, which further amplifies the cen-
tral sensitization. After central sensitization, input from even non-nociceptive nerve
fibers can be interpreted as painful (Baron et al. 2010). Much of the work to date has
80 B.P. Schneider et al.

been carried out in mouse or rat models. A limitation of this work has been the
inability to recapitulate some of the varied phenotypes. Thus, although models of
pain are robust, excellent models for paresthesias and numbness are lacking.

Clinical Research Questions

Prevention and Treatment Strategies

The major research questions to date have placed great emphasis on identifying
agents that might either treat or prevent neuropathy without adversely impact the
efficacy of the drugs. To date there have been 42 randomized controlled clinical tri-
als of agents to prevent CIPN (Hershman et al. 2014). Unfortunately, none of these
trials have provided any convincing evidence for a beneficial agent. The inability to
identify a successful protective agent is, in part, a reflection of our inability to fully
understand the mechanism of this toxicity.
There have also been multiple randomized trials, which have attempted to iden-
tify therapies that might treat the problem after it has occurred. Similar to the trials
designed to prevent CIPN, most of the trials for treatment of the toxicity have been
negative (Table 6.1) (Hershman et al. 2014). One of the most compelling studies,
however, was a trial that demonstrated superiority of duloxetine over placebo (Smith
et al. 2013a). This trial demonstrated a significant reduction in pain (p = 0.003) as
well as a suggestion of benefit on numbness and tingling. In an exploratory sub-
group analysis, however, the benefit was less clear for the taxanes compared with
oxaliplatin. Another relatively-positive result was seen with the use of a topical
cream composed of baclofen, amitriptyline, and ketamine (BAK) in a small ran-
domized trial (Barton et al. 2011). Based on the existing data, the American Society
of Clinical Oncology CIPN guideline committee (Table 6.2) recommended that cli-
nicians should consider duloxetine for CIPN (Hershman et al. 2014). Additionally,
this committee suggested that, although there were not as convincing data with
other agents, the following agents could be considered for a trial treatment in
selected patients: gabapentin/pregabalin, tricyclic antidepressants, and the
above-noted BAK cream (Hershman et al. 2014). Despite the relatively sparse data

Table 6.1 Summary of randomized controlled trials for the treatment of established chemotherapy
induced peripheral neuropathy Hershman et al. (2014)
Pharmacologic intervention Neurotoxic agent Reference
Duloxetine Taxane or platinum Smith et al. (2013a)
Gabapentin Vinca or platinum or taxane Rao et al. (2007)
Lamotrigine Vinca or platinum or taxane Rao et al. (2008)
Nortriptyline Cisplatin Hammack et al. (2002)
Vinca or platinum or taxane Kautio et al. (2008)
Topical amitriptyline, Vinca or platinum or taxane Barton et al. (2011)
ketamine ± baclofen (BAK) or thalidomide
6 Symptoms: Chemotherapy-Induced Peripheral Neuropathy 81

Table 6.2 ASCO practice guidelines for chemotherapy induced peripheral neuropathy Hershman
et al. (2014)
Prevention of CIPN
There are no established agents recommended for the prevention of CIPN in patients with
cancer undergoing treatment with neurotoxic agents. This is based on the paucity of high-
quality, consistent evidence and a balance of benefits versus harms
• Clinicians should not offer the following agents for the prevention of CIPN to patients with
cancer undergoing treatment with neurotoxic agents:
– Acetyl-L-carnitine (ALC)
– Amifostine
– Amitriptyline
– CaMg for patients receiving oxaliplatin-based chemotherapy
– Diethyldithio-carbamate (DDTC)
– Glutathione (GSH) for patients receiving paclitaxel/carboplatin chemotherapy
– Nimodipine
– Org 2766
– All-trans-retinoic acid
– rhuLIF
– Vitamin E
– Venlafaxine is not recommended for routine use in clinical practice. Although the
venlafaxine data support its potential utility, the data were not strong enough to
recommend its use in clinical practice, until additional supporting data become available
– No recommendations can be made on the use of N-acetylcysteine, carbamazepine,
glutamate, GSH for patients receiving cisplatin or oxaliplatin-based chemotherapy,
goshajinkigan (GJG), omega-3 fatty acids, or oxycarbazepine for the prevention of
CIPN at this time
Treatment of CIPN
For patients with cancer experiencing CIPN, clinicians may offer duloxetine
No recommendations can be made on the use of:
– ALC, noting that a positive phase III abstract supported its value, but this work has not
yet been published in a peer-reviewed journal, and a prevention trial suggested that this
agent was associated with worse outcomes
– Tricyclic antidepressants; however, based on the limited options that are available for
this prominent clinical problem and the demonstrated efficacy of these drugs for other
neuropathic pain conditions, it is reasonable to try a tricyclic antidepressant (e.g.
nortriptyline or desipramine) in patients suffering from CIPN after a discussion with the
patients about the limited scientific evidence for CIPN, potential harms, benefits, cost,
and patient preferences
– Gabapentin, noting that the available data were limited regarding its efficacy for treating
CIPN. However, the panel felt that this agent is reasonable to try for selected patients
with CIPN pain given that only a single negative randomized trial for this agent was
completed, the established efficacy of gabapentin and pregabalin for other forms of
neuropathic pain, and the limited CIPN treatment options. Patients should be informed
about the limited scientific evidence for CIPN, potential harms, benefits, and costs
– A topical gel treatment containing baclofen (10 mg), amitriptyline HCl (40 mg), and
ketamine (20 mg), noting that a single trial indicated that this product did decrease CIPN
symptoms. Given the available data, the panel felt that this agent is reasonable to try for
selected patients with CIPN pain. Patients should be informed about the limited
scientific evidence for the treatment of CIPN, potential harms, benefits, and costs
82 B.P. Schneider et al.

supporting these therapies, data regarding some of them on other forms of neuropa-
thy (i.e. diabetic neuropathy and acute post-herpetic neuralgia) influenced this rec-
ommendation. Opiates are also used for painful neuropathy without a good feeling
for the benefit/risk ratio regarding them.
A major limitation for the intervention trials to date is a limited understanding of
the underlying pathophysiology. If the goal of therapy is to repair an underlying
problem then lumping patients with different types of sensory or motor neuropathy
may be as inefficient as studying anti-HER2 therapies for all tumors regardless of
HER2 status.

Assessment of Neurotoxicity and Relationship to Mechanisms

As stated above, much of what we know about the frequency and severity of CIPN is
derived from the CTCAE as this has been widely employed in many of the large
clinical trials that have studied these agents. There are multiple limitations to this
reporting methodology (Hershman et al. 2011). This criterion is largely based on the
degree of impact on functionality. This is a practical criterion when considering the
need to dose reduce but is not overly helpful in distinguishing the various types/
manifestations of the process. This limits the ability to fully characterize the true
diversity and frequency of the toxicity. Importantly, it hinders correlative work aimed
at predicting the toxicity and unveiling the mechanistic underpinnings. If, indeed, the
various types of neuropathy symptoms reflect differences in unique pathophysiolo-
gies between the different neurotoxic chemotherapy agents, then correlative bio-
marker work requiring large sample sizes where CTCAE was used will suffer from
dilution of the true associations. Additionally, recent data suggest poor concordance
among raters for cancer therapy-induced toxicities (Cella et al. 2003, Cancer Therapy
Evaluation Program, August 9, 2006). Further, there is discordance in agreement
between clinician raters and the patients who experience these toxicities. Specific to
taxane-induced peripheral neuropathy, the use of patient reported outcomes (PROs)
correlate well with vibration threshold testing and are effective for both acute symp-
toms and over long-term follow-up (Hershman et al. 2011). With the recognition that
the toxicity profile is an important piece to optimize the therapeutic index, many of
the large studies have begun to incorporate PROs as a superior endpoint/phenotype.
Finally, and perhaps most importantly, many trials do not capture the long-term fre-
quency of CIPN. This is a big limitation as enduring or irreversible neuropathy may
be the most clinically important phenotype to identify and study.

Newer Research Strategies

There are a number of ongoing clinical trials to further identify agents that might
prevent or treat CIPN. In addition, other modalities are currently undergoing testing
such as acupuncture, topical menthol and cutaneous electro-stimulation devices. With
6 Symptoms: Chemotherapy-Induced Peripheral Neuropathy 83

anticipated new insights into the mechanism of CIPN, additional advances can be
made with rational selection of drugs. The identification of common mechanisms of
neuropathy caused across drug classes will be important for the development of drugs
that can be implemented broadly. Additionally, understanding the pathophysiology
for the spectrum of CIPN symptoms will be critical to optimal drug development.

Identifying Host Factors Related to Risk for CIPN

Another evolving area of research is the use of germline genetic variability (i.e.
SNPs, copy number variations, etc.) to predict drug-induced toxicity. This has
become a provocative area of research as variants can impact the metabolism, trans-
port, and excretion of drugs, but can also impact the target tissue (i.e., neurons). A
candidate study from an institutional series demonstrated an association between a
variant in a paclitaxel metabolizing enzyme, CYP2C8*3 and neuropathy (Hertz
et al. 2013). Another candidate approach from the adjuvant breast cancer trial
SWOG-0221, demonstrated an association between a SNP in FANCD2 and taxane
induced neuropathy (Sucheston et al. 2011). Recently, several large genome wide
association studies (GWAS) have been conducted from large clinical trials involv-
ing taxanes. The CALGB-40101 investigators identified a SNP in FDG4 that cor-
related with increased likelihood of paclitaxel-induced neuropathy (Baldwin et al.
2012). FDG4 is associated with the hereditary neuropathy condition of Charcot-
Marie-Tooth disease. Subsequent pathway and modeling work with this data set
have suggested that a hereditable predisposition to this toxicity may lie in genes
involved in axon outgrowth (Chhibber et al. 2014). Another trial specifically focused
on more rare variants using massively parallel sequencing of 20,794 genes associ-
ated with heredity neuropathy from patients who had received paclitaxel-based che-
motherapy (Beutler et al. 2013). The investigators reported an association between
EPHA5, ARHGEF10, and PRX and paclitaxel-induced neuropathy. It is hopeful
that the identification of genomic predictors might not only play a useful role in
predicting who will be at high or low risk of this toxicity but may also shed insight
into the biological underpinnings to help with future drug development. Further, the
integration of these genetic factors with other predictors such as race, weight, or
co-morbid states might allow for a truly personalized and successful predictor for
likelihood of this toxicity.

Future Directions

There are multiple areas of research progress to improve our approach to those who
might be at risk for CIPN and here we outline three immediate areas of need: education,
drug development, and predictive biomarkers.
For any toxicity, patient and physician education are paramount to successful
management. Physicians who fail to prioritize toxicities cannot adequately counsel
84 B.P. Schneider et al.

the true risk to benefit ratio of the therapies they plan to deliver. This is particularly
true in the case of adjuvant chemotherapy, where the vast majority of women can
expect to be long-term survivors. Additionally, this makes it difficult for patients to
prepare themselves mentally for potential challenges and hurdles that await them.
Recent data demonstrated that the counseled frequency and severity of neuropathy
could impact the specific regimen a patient might choose (Smith et al. 2013b).
Further, patients who had previously experienced neuropathy were actually more
likely to choose (less worried about) a regimen that would cause mild neuropathy
and markedly less likely to choose (more worried about) a regimen that would cause
severe neuropathy (Smith et al. 2013b). These data demonstrate that those patients
who experienced the toxicity are more nuanced in their decision-making based on
their personal understanding of the toxicity. This implies that physicians must strive
to educate patients in a more detailed fashion so that they might make the best pos-
sible decision for their therapy.
Improved drug development is also drastically needed. The bar is high, however,
for drugs that prevent or treat a specific side effect. The first hurdle is to identify
drugs that are highly effective. As outlined above this has not been an easy task, to
date, in part because the underlying pathophysiology is poorly understood. Second,
the preventive drug must not have significant toxicity. Many patients are willing to
accept substantial drug-induced toxicity for the payoff of increased cure rate, but
few like the idea of trading one drug side effect for another. Finally, the preventive
drug, ideally, will be affordable. In our current healthcare economic environment,
extremely expensive supportive care drugs will be less likely to be paid for by insur-
ance without substantial evidence of benefit and this may leave many patients
unable to afford the option.
Finally, genetic biomarkers to predict which patients are at highest risk or those
preferentially protected would be clinically valuable. As outlined above, there are
provocative genomic data from large clinical trials implementing taxanes that may
lead to such decision-making information in the future. However, there are several
hurdles that must be overcome before clinical implementation is possible.
Regarding this, it is clear that the findings from the studies done to date have
identified non-overlapping associations. This is not surprising as often the true-
positive associations aren’t necessary those with the top p-values. This makes over-
lapping of other rich data sets extremely important to identify the true positive
associations. Attempts at additional confirmation of these data may soon be on the
way. Several other GWAS have been completed across the Cooperative group sys-
tem that might allow for validation of the existing findings, including that from the
SWOG-0221 trial and ECOG-5103 trial (Schneider et al. 2011). This could provide
an amazing opportunity to perform a meta-analysis across these trials; and this has
been proposed. Another layer of complexity is that for complex pathophysiological
processes, the underlying predispositions might be multigenic. This requires sophis-
ticated pathway and modeling approaches. While much of the work to date has
focused on common variants (which likely will have modest effect sizes), it is also
very likely that rare variants (with large effect sizes) might also be important.
6 Symptoms: Chemotherapy-Induced Peripheral Neuropathy 85

Unfortunately, many of the standard GWAS platforms do not cover rare variants
and thus this exploration requires more deep sequencing approaches, as demon-
strated above.
Additionally, the ability to identify a true association depends not only on ade-
quate power and meticulous adherence to genomic quality control, but also consis-
tent and accurate phenotyping. As outlined above, many of the correlative studies
have been performed on trials where the CTCAE was the only methodology for case
definitions. The more recent integration of PROs, however, might provide a new
level of insight and biomarker discovery.
It will be important to develop a user-friendly decision-making tool to help guide
physicians regarding how to understand and react to these genomic markers. Unlike
many of the current genomic tests being used in breast cancer (i.e. Oncotype Dx),
the decision to react to a toxicity marker must also consider the patient’s risk of
disease and the alternative approaches available.
In conclusion, CIPN is a major problem for patients with breast cancer. Much
work is ongoing to identify predictive biomarkers, improve education, understand
the underlying pathophysiology, and to identify drugs to treat or prevent this unde-
sirable side effect.

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Chapter 7
Symptoms: Aromatase Inhibitor Induced
Arthralgias

Dawn L. Hershman, Charles Loprinzi, and Bryan P. Schneider

Abstract Recent clinical trials have demonstrated that aromatase inhibitors (AIs)
are slightly more effective than tamoxifen at reducing breast cancer recurrences.
However, breast cancer patients receiving AIs have a higher incidence of musculo-
skeletal symptoms, particularly joint pain and stiffness. Musculoskeletal pain and
stiffness can lead to noncompliance and increased utilization of health care resources.
There is a suggestion that the syndrome is the result of estrogen deprivation and may
share components with autoimmune diseases such as Sjögren’s syndrome. Several
factors may increase the likelihood of developing AI arthralgia, such as prior chemo-
therapy, prior hormone replacement therapy, and increased weight; there are incon-
sistencies with regard to the data on genetic predispositions to this syndrome. While
several studies have been done to evaluate interventions to treat or prevent AI arthral-
gia, no clear treatment has emerged as being particularly beneficial. Much of the
research has been limited by small sample size, difficulty blinding patients to placebo,
inconsistent definitions of the syndrome, multiple patient reported outcomes, lack of
objective outcome measures and heterogeneous patient populations. We are at the
early stages of research in characterizing, understanding etiology, preventing and
treating AI arthralgias; however much work is being done in this area which,
hopefully, will ultimately improve the lives of women with breast cancer.

Keywords Breast cancer • Aromatase inhibitors • Arthralgias

D.L. Hershman (*)

Associate Professor of Medicine and Epidemiology, Herbert Irving Comprehensive
Cancer Center, Columbia University, 161 Fort Washington, 1068,
New York, NY 10032, USA
e-mail: [email protected]
C. Loprinzi
Regis Professor of Breast Cancer Research, Division of Medical Oncology,
Rochester, MN, USA
e-mail: [email protected]
B.P. Schneider
Associate Professor of Medicine & Medical/Molecular Genetics,
Indiana University Simon Cancer Center, Indianapolis, IN, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 89

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_7
90 D.L. Hershman et al.

Overview

Due to early detection and improved treatments, there has been a 30 % reduction in
breast cancer (BC) mortality over the past two decades (DeSantis et al. 2014). The
increase in BC survival is largely due to the benefits of hormonal therapy in women
with hormone receptor (HR) positive breast cancer. Recent clinical trials have
demonstrated that aromatase inhibitors (AIs) are more effective than tamoxifen at
reducing BC recurrences (Baum et al. 2002; Goss et al. 2003, 2005; Howell et al.
2005; Thurlimann et al. 2005; Coombes et al. 2004). However, BC patients receiv-
ing AIs have a higher incidence of musculoskeletal symptoms, particularly joint
pain and stiffness. Musculoskeletal pain and stiffness leads to noncompliance and
increased utilization of health care resources (Henry et al. 2012.; Scudds and Mc
1998; Kewman et al. 1991; Carey et al. 1995). In a prospective study of 1,976
patients, a 10 % increase in arthralgia was associated with a 20 % increase risk of
non-compliance to AI therapy (Hadji et al. 2014). Since women with HR-positive
BC benefit from long-term hormonal therapy for 5–10 years, it is important to try to
minimize side effects, to enhance patient adherence and to improve quality of life
(QOL). Therefore, safe and effective treatments that alleviate these symptoms are
needed. There is no standard definition, consistent terminology or agreed upon out-
come measures for this condition. Some refer to it as AI Arthralgia (AIA) or AI
Musculoskeletal Syndrome (AIMSS) (Niravath 2013) (Fig. 7.1).
In large adjuvant trials involving AIs, the incidence of musculoskeletal disorders was
reported in 19–35 % of patients on AI’s and 12–29 % of patients on tamoxifen (Baum
et al. 2002; Goss et al. 2003). However, prospective cohort studies assessing symptoms
with patient reported outcome measures suggest that 40–50 % of women have either

Educate patient

Moderate-Severe
Mild Arthralgias
Arthralgias

Exercise, weight Check Vitamin D Prednisolone 5

Acupuncture
loss level mg daily x 7 days

If Vit. D deficient,
give 50,000 IU Vit Switch Al’s NSAID’s
D qweek x 12 w

Switch to
SSRI Therapy
Tamoxifen

Fig. 7.1 Possible management algorithm from Niravath (2013)

7 Symptoms: Aromatase Inhibitor Induced Arthralgias 91

new onset or worsening AI-related arthralgias (Crew et al. 2007; Henry et al. 2008,
2012). In a small prospective study of patients initiating AI therapy, the median time to
development of AI arthralgias was 7 weeks, and by 12 weeks 55 % of patients had at
least one complaint, and the incidence increased steadily over time (Shi et al. 2013).
Other prospective cohort studies have found a similar incidence (Laroche et al. 2014).
Several studies have suggested an association between the development of AI
arthralgias and improved disease free survival outcomes; however other studies
have not shown this association. For example, a retrospective analysis of the
ATAC data shows that women who developed arthralgia had a breast cancer recur-
rence HR of 0.65 (P = 0.001) when compared with women with no arthralgia
(Cuzick et al. 2008). Similarly, analysis of the TEAM trial showed improvements
in disease-free survival in patients who had arthralgia while on endocrine therapy
(Hadji et al. 2012). This is in contrast to the Intergroup Exemestane study that did
not find this association (Mieog et al. 2012). Measurement error is a real problem
with these studies, as they primarily rely on CTCAE reporting, and not patient
reported outcomes.

Etiology

Estrogen deficiency after menopause has been linked to an increase in several chronic
inflammatory conditions, including osteoporosis and osteoarthritis (OA) (Riggs and
Melton 1992; Sherwin 1996). Estrogen can influence chondrocyte formation on mul-
tiple levels by interacting with cellular growth factors, adhesion molecules, and cyto-
kines (Ushiyama et al. 1995; Rosner et al. 1982; Dayani et al. 1988). A dose-dependent
change in matrix protein turnover occurs when cultured chondrocytes are exposed to
estradiol (Richmond et al. 2000; Dayani et al. 1988; Blanchard et al. 1991; Rosner
et al. 1982). Production of interleukin-6 (IL-6) and type II collagen in articular chon-
drocytes is also affected by estradiol, suggesting it may affect cartilage metabolism
(Guerne et al. 1990; Claassen et al. 2006; Richette et al. 2003). Additional support that
estrogen deprivation results in this syndrome comes from studies showing that hor-
mone replacement with conjugated equine estrogens result in decreased joint pain,
pain severity and joint swelling in postmenopausal women (Chlebowski et al. 2013).
In addition, there may be an autoimmune component to the syndrome. Animal
models, where aromatase is knocked out, manifest symptoms similar to Sjögren’s
syndrome. In a study of patients referred to a rheumatologist, 50 % met the criteria
for sicca syndrome (Laroche et al. 2007). Several small studies have also evaluated
the influence AI therapy on inflammatory serum markers but results evaluating
CRP, IL-6, and TNFα have been inconsistent (Dougherty et al. 2005; Azria et al.
2007; Harputluoglu et al. 2008). Even in studies showing AI-related changes to
inflammatory markers, these changes were not correlated with the development of
AI arthralgia (Azria et al. 2007).
Studies assessing AI-induced arthralgias have shown a correlation between
PROs and objective findings. Morales et al. demonstrated that the subjective symp-
toms of AI-induced arthralgias in the hands are associated with physiologic changes
92 D.L. Hershman et al.

to joints and functional impairments (Morales et al. 2008). Women taking AIs are
more likely to have an increase in tenosynovial changes as seen on MRI, a decrease
in grip strength as measured by a sphygmomanometer, as well as increased pain and
stiffness as measured by self-administered questionnaires (Morales et al. 2008).
In a study conducted by Dizdar et al., women taking AIs had increased tendon
thickness and higher rates of effusions in hand joints/tendons on musculoskeletal
sonography, compared to women who never received AIs (Dizdar et al. 2009;
Lintermans et al. 2011). AI use is also associated with a greater incidence of carpal
tunnel syndrome of moderate intensity and short duration (Sestak et al. 2009). With
regard to pain sensitivity, the syndrome does not appear to result in impairment of
descending pain inhibitory pathways as measured by pressure pain testing or condi-
tioned pain modulation testing (Henry et al. 2014).

Risk Factors

The risk factors for developing AI-associated arthralgia are unclear. In some studies
high BMI, prior chemotherapy, and a history of hormone replacement therapy are
major risk factors for developing joint symptoms (Sestak et al. 2008). Other studies
show prior taxane chemotherapy, symptoms at the time of treatment initiation and
time from menopause are also associated with severity of AI arthralgias (Shi et al.
2013; Crew et al. 2007; Mao et al. 2011). One prospective cohort study found that
additional risk factors for the development of pain included higher levels of anxiety
and impaired quality of life at the time of initiation of therapy (Laroche et al. 2014).
The question of genetic susceptibility to toxicity has been addressed as well.
In a prospective cohort study of 343 post-menopausal women starting AI therapy,
single nucleotide polymorphisms (SNPs) in genes encoding for the metabolism of
estrogens (CYP17A1) and vitamin D (VDR, CYP27B1) were associated with self-
reported arthralgia (Garcia-Giralt et al. 2013). In addition, patients who had SNP’s
for multiple genes had the highest risk for AI arthralgia. A cross-sectional study in
390 patients also found that repeats in the CYP19A1 gene were associated with AI
arthralgias (Mao et al. 2011). A better understanding of genomic and clinical risk
factors can help identify patients who can be targeted for specific interventions to
prevent this syndrome. An ongoing ECOG prospective cohort study in 1,000 women
evaluating genomic predictors of AI arthralgias and early AI discontinuation should
further clarify this issue.

Treatment

The use of a non-steroidal anti-inflammatory agent, or simply switching to an alter-

native AI, are common clinical approaches for patients experiencing significant
arthralgias. Interestingly, approximately a third of patients will experience some
improvement in symptoms by simply switching to another AI (Henry et al. 2012).
7 Symptoms: Aromatase Inhibitor Induced Arthralgias 93

Table 7.1 Summary of trials for treatment or prevention of AI arthralgia

Therapy N Blinded Randomized Outcome
Supplements
Vitamin D 160 Y Y In this prevention trial, increased
(Khan et al. 2012) pain was observed in 38 % of
patients receiving vitamin D, versus
61 % on placebo (p = 0.008)
Glucosamine 53 N N 50 % of patients with ≥20 %
(Greenlee et al. 2013) reduction in pain
Omega 3 fatty acid 240 Y Y 50 % reduction in pain/stiffness
(Hershman et al. 2014) in both arms
Drugs
Duloxetinea 29 N N 74 % of patients had at least a
(Henry et al. 2011) 30 % decrease in average pain
Testosteronea 90 Y Y The higher dose of tested
(Birrell and Tilley 2009) testosterone dose decreased pain
more than did the placebo (p = 0.04)
Prednisolone 29 N N 67 % of patients reported symptom
(Kubo et al. 2012) improvement
Other
Acupuncturea, b 40 Y Y 50 % decreased pain in the active
(Crew et al. 2010) acupuncture arm, as opposed to no
change in the sham arm
Exerciseb 121 N Y 24 % decrease in pain scores with
(Irwin et al. 2013) exercise versus virtually no change
in the usual care group (p = 0.013)
a
Large randomized controlled trial ongoing
b
Additional studies also published; see text

There are, however, currently no proven treatments for AI-related arthralgias.

Researchers have investigated interventions that have been studied in patients with
chronic pain conditions, osteoarthritis and rheumatologic arthritis. Patients are often
not willing to take medications to treat side effects, that have the potential for addi-
tional side effects, so many have gravitated to natural products, mind-body interven-
tions and exercise. Many prospective trials are collecting blood and DNA to perform
analysis that will be critical in elucidating the mechanism of this side effect as well
as genetic susceptibility (Table 7.1).

Vitamin D

Vitamin D deficiency and insufficiency may contribute to musculoskeletal symp-

toms. In a prospective study, 60 women who were beginning adjuvant AI therapy
had baseline vitamin D (25OHD) levels measured. At the conclusion of 16 weeks of
letrozole, 52 % of women with baseline 25OHD levels >66 ng/ml reported no dis-
ability from joint pain, whereas only 19 % of those with levels <66 ng/ml had no
94 D.L. Hershman et al.

disabling joint pain (Khan et al. 2010). In a subsequent randomized VITAL trial
(Vitamin D for Arthralgias From Letrozole), 160 postmenopausal women with a
serum vitamin D level of <40 ng/mL were randomized to receive 30,000 IU of oral
vitamin D3 weekly for 24 weeks; the other was given a placebo. About 61 % of
controls and 38 % of those on vitamin D reported an increase in pain (P = .008)
(Khan et al. 2012).

Glucosamine Chondroitin

Glucosamine and chondroitin are popular dietary supplements frequently used with
the goal of treating arthritic pain. In a non-randomized phase II trial of glucosamine
and chondroitin to treat moderate-to-severe aromatase inhibitor induced joint pain,
approximately 50 % of participants self-reported a ≥20 % improvement in pain,
stiffness and function. The intervention was well-tolerated with minimal toxicities
and no changes in estradiol levels were observed (Greenlee et al. 2013). Nonetheless,
a placebo effect may be largely responsible for this finding.

Omega-3

Omega-3-fatty acids have anti-inflammatory effects and can be effective in decreas-

ing arthralgias from rheumatologic conditions. A placebo-controlled trial of 3.3 g
of Omega-3-fatty acids was conducted among 249 women on AIs with severe
(≥5 of 10) pain and or stiffness. Interestingly a 60 % improvement was observed
in the group randomized to Omega-3. However, a similar reduction was seen in the
placebo arm. At 24 weeks, both groups had about a 2-point improvement from
baseline on a 10 point scale (Hershman et al. 2014). This study demonstrates the
difficulty in relying on patient-reported outcomes and the strength of the placebo
effect. It also raises questions about the results of other trials where the interven-
tion could not be truly blinded.

Duloxetine

Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor used for

treating pain. A single-arm, open-label phase 2 study of duloxetine was studied in
women with breast cancer who developed new or worsening pain after treatment
with an AI. Twenty-one of twenty-nine evaluable patients (72.4 %) achieved at least
a 30 % decrease in average pain. The mean percentage reduction in average pain
severity was 60.9 % (Henry et al. 2011). Based on the results of this study, a
randomized placebo-controlled trial is being conducted in SWOG.
7 Symptoms: Aromatase Inhibitor Induced Arthralgias 95

Testosterone

A double blind placebo-controlled, randomized pilot study of a transdermal testoster-

one preparation supported that this approach was helpful for alleviating aromatase
inhibitor-induced arthralgias (Birrell and Tilley 2009). This trial involved 90 patients
with baseline AI arthralgia pain and/or stiffness be greater than 50 on a 0–100 point
pain scale. Patients were randomized into one of three study arms to receive a low
testosterone dose versus an intermediate testosterone dose versus a placebo. After 3
months, the pain scores decreased more in the intermediate dose testosterone arm
compared to the placebo arm (P = 0.04). Likewise, stiffness scores decreased more in
the intermediate dose testosterone arm, compared to the placebo arm (P = 0.06). While
serum testosterone concentrations increased in the groups getting testosterone, there
was no suggestion that estrogen concentrations were any higher with testosterone,
compared to the placebo arm. Based on these promising findings a phase III random-
ized placebo-controlled trial, using intradermal testosterone pellets, is being con-
ducted in women with AI arthralgias, through the Alliance cooperative group.

Prednisolone

Autoimmune diseases are often treated with low dose steroids, and as mentioned
above, there is some similarities between the arthralgia syndrome from AI’s and
Sjögren’s syndrome. To test this approach, patients with AI arthralgia were admin-
istered 5 mg of oral prednisolone once a day in the morning for only 1 week. Patients
were then asked to answer a questionnaire about joint pain symptoms at 1 week, 1
month and 2 months after the beginning of prednisolone use. Joint pain symptoms
improved in 67 % of patients immediately after prednisolone use, with 63 % still
reporting analgesic effect at 1 month, and 52 % at 2 months after beginning the
short-term use of prednisolone (Kubo et al. 2012).

Acupuncture

Acupuncture is a popular non-pharmacologic modality that has been shown to be a

useful adjunct in a range of painful conditions, including musculoskeletal pain
(Anonymous 1998). Small pilot trials for AI arthralgias have reported conflicting
results. A randomized, sham-controlled, blinded trial to assess the effect of a 6-week
intervention of acupuncture in 38 women with AI-associated joint symptoms
reported that true acupuncture group had a 50 % decrease pain compared to no
change in the sham acupuncture group (Crew et al. 2010). Other smaller studies
have suggested a benefit of both standard and electroacupuncture (Oh et al. 2013;
Mao et al. 2014). A larger multicenter randomized trial with a waitlist control, sham,
and true acupuncture is being conducted in SWOG.
96 D.L. Hershman et al.

Exercise

Several studies have suggested that exercise can reduce treatment-related adverse
effects. A randomized trial of 121 women with AI arthralgia reported that pain
scores decreased by 24 % at 12 months among women randomized to exercise vs.
no change among women randomized to usual care (mean baseline to 12-month
change: −1.27 + 0.34 vs. −0.01 + 0.35, respectively; P = .013). A dose–response
effect was also observed with greater exercise leading to less pain severity (Irwin
et al. 2013). In addition, a small pilot study of tai chi in 12 women with self reported
AI arthralgia demonstrated a reduction in pain (Galantino et al. 2013). Additional
work in this area is warranted, however, these studies are limited by the inability to
blind participants.

Switching

Two studies have been done suggesting switching AI’s can result in improvement of
symptoms. In one study, 60 % of patients that switched remained on the alternate AI
at 6 months, and 15 % had no complaints of joint symptoms (Briot et al. 2010).
Another study showed that 39 % of patients were able to tolerate the second AI
(Henry et al. 2012). Given the strong placebo effect, these results should be inter-
preted with caution with regard to the biologic effect of switching treatments.
Another approach is to switch to tamoxifen, a therapy with similar long-term
benefits.

Future Directions

There is enormous discrepancy between studies evaluating AI arthralgia due to lack

of uniformity in both subjective and objective outcome measures and inconsistency
in reporting. As a result priorities going forward might focus on uniform definitions,
a better understanding of the natural history, defining mechanisms and determining
effective treatment and prevention strategies. While there has been some work eval-
uating the syndrome, the heterogeneity in terminology and definitions can make
interpreting the findings difficult. A consensus on consistent terminology and
definition might help with future studies.
The original large phase III clinical trials resulting in drug approval did not
capture patient reported outcomes, which was a missed opportunity for under-
standing this syndrome in a large number of women. Because the symptoms were
often not attributed to the drug, these trials underestimated the degree to which
these side effects interfere with quality of life, adherence and function. Cohort
7 Symptoms: Aromatase Inhibitor Induced Arthralgias 97

studies have used a variety of patient reported outcomes such as the Brief Pain
Inventory (BPI), the Health Assessment Questionnaire (HAQ), the Western Ontario
and McMaster Universities Arthritis Index (WOMAC) and the Score for Assessment
and Quantification of Chronic Rheumatic Affections of the Hands (SACRAH).
Consistent outcome measures would allow for better consistency of interpreting
the results of interventional trials.
There are ongoing cohort studies, as the one being done through ECOG, where
1,000 patients are being followed at initiation of AI therapy and evaluated over the
course of a year. In addition DNA and serum are being collected to clarify if there
are genetic determinants of risk. This study should help clarify the short-term natu-
ral history. However the 1 year follow-up will limit the understanding of delayed
symptoms and poor adherence. Another shortcoming of this trial, as opposed to the
missed opportunity in the early randomized trials is that there is no placebo arm
with which to better understand any nocebo effect. In addition, understanding the
factors that contribute to improvement of symptoms in some patients, as opposed to
others, may help physicians make better therapeutic recommendations.
A clearer understanding of the mechanism behind AI arthralgia may result in
more targeted interventions or drug modifications that could reduce the develop-
ment of this secondary effect. However, it may be that the exact mechanism that
results in the drug effectiveness, i.e., the lowering of estradiol, may be the inciting
factor. Careful attention will need to be paid to the fact that improvements in symp-
toms could affect the efficacy of the therapy if directed to the mechanism of action.
As a result pure management of symptoms with interventions known to improve
pain or treat other forms of arthritis have been studied.
Understanding risk factors may help risk stratify patients for treatment with
tamoxifen or AI therapy, and may help target preventive interventions. Early sug-
gestions from a biologic perspective have focused on estrogen-related pathways and
polymorphisms in the aromatase pathway. It is clear that prior chemotherapy, prior
hormone replacement therapy and baseline psychological state may influence the
development of symptoms and adherence. These factors as well as genetic factors
may help determine which patients should avoid AIs upfront and be treated with
tamoxifen from the start. It will be crucial to understand if these individuals have a
different prognosis.
The optimal outcome measure and timing of assessments is unclear, therefore
clinical trials often vary from each other in primary outcome, duration and patient
populations. The issue of placebo effect, as demonstrated by the SWOG Omega-3
study makes clinical trials challenging, and should push the field to try to better
define objective as well as subjective definitions of this syndrome. Furthermore,
many clinical trials cannot be truly blinded and may result in inaccurate conclusions.
Interventional studies are subject to biases resulting from a very strong placebo
effect and a waxing and waning symptom course.
The ultimate goal of treating or preventing AI arthralgias is to improve quality of
life and increase adherence while maintaining efficacy, so these outcomes need to
be considered in prevention and treatment studies.
98 D.L. Hershman et al.

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Chapter 8
Symptoms: Lymphedema

Electra D. Paskett

Abstract Lymphedema is one of the main late effects from breast cancer treatment
affecting 3–60 % of breast cancer survivors. Primarily occurring in the hand, arm,
and/or affected breast, symptoms of lymphedema include swelling, pain, redness,
restriction of arm/hand movement, tightness and feelings of fullness. These symp-
toms not only may limit physical functioning but also negatively affect quality of life,
body image, social functioning, and financial status of breast cancer survivors with
lymphedema. Unfortunately, there are no standardized methods for prevention, diag-
nosis, and treatment of breast cancer-related lymphedema. Despite its prevalence and
lack of clinical guidelines, lymphedema is one of the most poorly understood, rela-
tively underestimated, and least researched complications of cancer treatment. This
chapter reviews the current problem of breast cancer-related lymphedema by investi-
gating prevention and risk reduction strategies, diagnosis, and treatment. In addition,
this chapter identifies future research opportunities focusing on prevention and risk
reduction strategies, quality of life and physical function, surveillance, patient educa-
tion, cost, diagnosis, and treatment. Challenges and recommendations for future
research in these areas, particularly among underserved populations, are discussed.

Keywords Breast cancer • Lymphedema • Swelling • Symptoms • Risk reduction •

Prevention • Diagnosis • Treatment

Introduction

Due to improved treatments and earlier detection of smaller, treatable tumors, there
are more breast cancer survivors living longer. Therefore, these women are at
increased risk for a multitude of late effects for a long time after diagnosis and treat-
ment. Lymphedema is one such effect of treatment for which women are at risk
during their lifetime. Lymphedema may occur in the hand, arm, and/or affected

E.D. Paskett, Ph.D. (*)

Department of Internal Medicine, The Ohio State University College of Medicine,
Columbus, OH, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 101

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_8
102 E.D. Paskett

breast due to surgery (node dissection, sampling or mastectomy/lumpectomy),

chemotherapy and/or radiation (Mortimer 1998; Rockson 2012). Causes are related
to the disruption of lymph flow caused by these treatment modalities.
The most known feature of lymphedema is swelling, however, pain, redness,
restriction of arm/hand movement, tightness and feelings of fullness are also
reported symptoms (Armer and Fu 2005; Ridner et al. 2012). The resulting impact
on women who experience these symptoms includes not only limitations in physical
functioning, but also quality of life, body image issues, social functioning, and in
some cases, employment disruption (McWayne and Heiney 2005; Shigaki et al.
2013; Cormier et al. 2009; Fu et al. 2013; Park et al. 2012). A better understanding
of the magnitude and risk factors for lymphedema are needed, as well as better ways
to detect lymphedema early and treat it.

Statement of Current Problem

What we know about lymphedema has been garnered from a variety of studies
focused on the prevalence of lymphedema and its risk factors. Previous studies have
estimated that anywhere from 3–60 % of breast cancer survivors are at risk for
lymphedema; however, these estimates vary by type of population studied, type of
axillary node dissection, measurements used, and length of follow-up from treat-
ment. For example, among women with sentinel node biopsy, the prevalence is
3–10 %, whereas among women with full axillary node dissection, reports of
lymphedema range from 20–60 %. In addition to treatment factors, obesity at diag-
nosis (Dominick et al. 2013; Ridner et al. 2011; Clark et al. 2005; Ozaslan and Kuru
2004), infection/injury (Clark et al. 2005), older age (Hayes et al. 2008), excessive
use of arm/hand, and hand dominance have been found to be potential risk factors
(Ridner et al. 2011; Soran et al. 2006; Mak et al. 2008). Disease-related factors also
play a role, such as nodal status and tumor factors (Dominick et al. 2013; McLaughlin
et al. 2008). Reported risk factors are presented in Table 8.1.
Health care costs, both to the patient and to society, have been less studied.
Breast cancer patients diagnosed with lymphedema incur an estimated $22,153

Table 8.1 Risk factors for lymphedema

Treatment factors Patient factors Disease-related factors
Sentinel node biopsy Older age Worse pathologic
nodal status
Axillary lymph node Obesity and/or high BMI Worse T stage
dissection
Post-operative axillary History of infection/soft tissue Advanced stages of
radiation infection (i.e., recurrent cellulitis) disease
in arm/hand
Upper extremity injury
Excessive use of arm/hand/hand
dominance
8 Symptoms: Lymphedema 103

more in total healthcare costs (e.g., cancer treatments, outpatient visits unrelated to
cancer treatment, complications of lymphedema, physical therapy, etc.) than their
counterparts with no diagnosis of breast cancer-related lymphedema (BCRL) (Shih
et al. 2009), and women diagnosed with late-stage BCRL had yearly healthcare
costs of $3,124.92, whereas early stage-BCRL patients had yearly costs of $636.19
(Stout et al. 2012). Costs are due to mental health care, diagnostic imaging for
BCRL and complex, treatment-related visits. Women with lymphedema also report
a greater frequency of infections, such as cellulitis, again increasing costs (eco-
nomic and other types) (Shih et al. 2009).
Disparities in both diagnosis and treatment of lymphedema have also been noted
for minority women. In particular, African American women are more likely than
White women to have undiagnosed lymphedema, and if they are diagnosed with
lymphedema by a physician, they are more likely to receive only bandaging and
compression treatments as opposed to complete decongestive therapy (Sayko et al.
2013). No studies have explored the impact of costs of treatment among low-income
and under/uninsured women on receiving prompt and proper treatment.

Areas of Current Investigation

Areas of investigation for lymphedema have included prevention/risk reduction

strategies, diagnosis, and treatment.
Prevention and Risk Reduction Strategies Prevention has focused on taking what
we know causes lymphedema and developing risk reduction strategies. Most impor-
tantly, sentinel lymph node dissection (SLND) has now replaced full axillary lymph
node dissection (ALND) where possible, reducing the risk of lymphedema. Infection
prevention and education about precautionary guidelines (Armer et al. 2013; Paskett
et al. 2012; Bernas 2013; Bernas et al. 2010; Erickson et al. 2001; Golshan and
Smith 2006; Shah and Vicini 2011; Shah et al. 2012a; Soran et al. 2012; Stout et al.
2013) have not been tested as risk reducing strategies, although risk and prevention
messages have been targeted to both providers—in terms of risk and how to reduce
it, minimize risk of infection (i.e., draw blood only from untreated side) (Armer
et al. 2013; Bernas 2013; Bernas et al. 2010; Shah and Vicini 2011; Soran et al.
2012; Shah et al. 2012b; Cassileth et al. 2013; O’Toole et al. 2013; Rourke et al.
2010; Schwartz 2012; Stout Gergich et al. 2008; Tam et al. 2012; Fu et al. 2012)—
and survivors—to recognize early signs, and understand methods of risk reduction
(Soran et al. 2012; Schwartz 2012; McLaughlin et al. 2013; Meneses et al. 2007;
Sherman and Koelmeyer 2011). More recently, physical activity (Ahmed et al.
2006; Brennan and Miller 1998; Jammallo et al. 2013; Jonsson and Johansson 2009;
Katz et al. 2010; McNeely et al. 2010; Schmitz 2010; Schmitz et al. 2009, 2010) and
weight reduction have been explored as prevention options with results still pend-
ing; however, some studies show no harm with physical activity (Ahmed et al. 2006;
Cormie et al. 2013; Courneya et al. 2007). The use of compression garments for air
104 E.D. Paskett

travel is still controversial (Graham 2002; Kilbreath et al. 2010) and has yet to be
evaluated.
Diagnosis Uncertainties about diagnostic measures for lymphedema exist because
current methods vary greatly in their validity, reliability and acceptability to both
women and providers/clinics. Methods studied include: water displacement (Sagen
et al. 2009), lymphoscintigraphy (Moshiri et al. 2002; Szuba et al. 2002), high-
frequency ultrasound (Adriaenssens et al. 2012), bioimpedance (Cornish et al.
2001; Ward et al. 1992), arm circumference (Deutsch et al. 2008; Chen et al. 2008),
and self-report (Czerniec et al. 2010). Each method has strengths and weaknesses;
however, the fact that there are so many tools reduces the ability of common
estimates of lymphedema to be valid and reliable. A summary of diagnostic meth-
ods are presented in Table 8.2. In addition, because there is no commonly accepted
measurement tool, the ability of any tool to be used for early detection, when early
treatment can eliminate or cure early signs of lymphedema (Deutsch et al. 2008;
Stout et al. 2011; Johansson and Branje 2010), is limited. A new area of promise is
surveillance where all women at risk are screened, and, if diagnosed with early-
stage BCRL, they receive intervention and treatment. Significant cost savings were
found using this surveillance model vs. impairment-based care (Stout et al. 2012).

Table 8.2 Benefits and limitations of breast cancer-related lymphedema diagnostic methods
Diagnostic method Benefits Limitations
Water displacement Accurately estimates arm volume Causes discomfort for patients
Cannot be used if there are
open sores/wounds on skin
Unable to account for changes
in volume caused by muscle
tissue versus subcutaneous
tissue
Arm circumference Low cost Larger inter-rater and
measurement Easily administered intra-rater variability in
Causes minimal discomfort measurements
Measurements assume that
the limb is cylindrical
Perometry Provides precise volume Positioning some patients for
measurements accurate measurements may
Causes minimal discomfort be difficult
Minimal risk of infection Device is not portable
Dual frequency Allows for the measurement of skin Studies regarding its
ultrasound thickness, which is correlated with effectiveness as a diagnostic
degree of swelling tool are limited
Causes minimal discomfort
Bioimpedance Directly measures extracellular fluid Cost
Spectroscopy Has a high specificity and sensitivity Lower accuracy for later stage
Is able to detect small changes in lymphedema
extracellular fluid and therefore
detect early stage lymphedema
Device is portable
Causes minimal discomfort
8 Symptoms: Lymphedema 105

Table 8.3 Benefits and limitations of breast cancer-related lymphedema treatment methods
Treatment method Benefits Limitations
Complex decongestive Considered the “gold standard” Study results have shown that it is
therapy of treatment for lymphedema no more effective than standard
Significantly reduces swelling compression therapy
Issues with patient adherence
Pneumatic compression Significantly reduces swelling Issues with patient adherence
Low-level laser therapy Significantly reduces swelling Requires patients to make multiple
Increases mobility visits for treatment
Surgery May reduce swelling but study Not effective for women with mild
results have been inconsistent or severe BCRL
Exercise May increase arm function Does not reduce swelling
Stem cell transplantation Improves pain, sensitivity and Compression sleeve must be worn
mobility constantly to be effective
Extra-corporeal shock Improves angiogenesis and Cost prohibitive
wave therapy reduces inflammation
Reduces swelling
Reduces skin thickness

Treatment While there is no cure for lymphedema, there are many treatment strate-
gies, some tested and others utilized but with varying efficacy (Park et al. 2012;
Sayko et al. 2013; Norman et al. 2009; Cormier et al. 2010; Sierla et al. 2013). The
most common treatment regimens are Complete Decongestive Therapy (CDT)
(including bandaging, compression garments, and manual lymphatic drainage),
pneumatic compression, low-level laser therapy (LLLT), and surgery. Newer treat-
ments include exercise, stem cell transplant, and shock wave therapy. Recent studies
have shown that guided, gradual exercise may increase arm function (Cormie et al.
2013); however, the impact of exercise on the prevention and/or reduction of swell-
ing needs to be further investigated. Evidence from randomized controlled trials
(RCTs) shows conflicting evidence on the efficacy of CDT on both arm volume/
function and quality of life (King et al. 2012; Badger et al. 2000; Dayes et al. 2013;
Huang et al. 2013; Vignes et al. 2013). Pneumatic compression used at home has
only been tested in one study and was found to significantly reduce arm volume
(Fife et al. 2012). LLLT shows some promise, but no RCTs have been conducted for
surgery as a treatment modality. For the newer treatments, only extra-corporeal
shock wave therapy has demonstrated promise but it has only been tested in one
small study (Bae and Kim 2013). Thus, treatment modalities for lymphedema are
woefully understudied. A summary of treatment methods are presented in Table 8.3.

Future Research Opportunities and Challenges

There are many research opportunities to address the many un- and under-studied
areas related to prevention (and causation), diagnosis, treatment, surveillance and
education. Overall, the current literature in all of these areas is limited by small
106 E.D. Paskett

sample sizes, lack of comparison groups, and short follow-up times. In addition,
quality of life and costs, as well as swelling and functioning, need to be included as
outcomes within each of these areas.
Prevention and Risk Reduction Strategies While common risk factors for lymph-
edema, such as ALND, infection and obesity, have emerged, an improved under-
standing of how these risk factors interact, particularly in underserved populations
(e.g., racial/ethnic minorities, urban/rural residents, the elderly, the poor, and per-
sons with disabilities), is desperately needed (Dominick et al. 2013; Meeske et al.
2009; DiSipio et al. 2010). There is a paucity of information about disparities in
lymphedema risk and incidence, as well as treatment characteristics, among under-
served populations, but it is certainly plausible that lymphedema disparities mirror
the trend generally observed in health and health care (i.e., higher incidence and
mortality). For example, African Americans have a higher rate of obesity compared
to their white counterparts (Ogden et al. 2012), and BMI is a known risk factor for
lymphedema. Minority women, particularly African Americans and Hispanics, are
also more likely to present with later stage disease and larger tumors (Dehal et al.
2013; American Cancer Society 2013), increasing the likelihood of undergoing
ALND (Arrington et al. 2013), which increases the risk for lymphedema.
Another underserved population includes those living in non-urban areas, who
have increased odds of undergoing ALND (OR for rural area = 2.06), with non-
urban areas lagging 2 years behind urban areas with respect to the use of SLND
(Arrington et al. 2013). Not only do those living in non-urban areas undergo ALND
more often, they also have limited access to trained lymphedema specialists, who
are primarily located in urban centers.
There are very few prevention strategies being tested, thus this area is ripe for
further investigation (Armer et al. 2011, 2013; Shah et al. 2012a; Soran et al. 2012;
Stout et al. 2013; O’Toole et al. 2013; Fu et al. 2012). What makes prevention stud-
ies difficult to conduct, however, is the need for long-term follow-up of women
which can be difficult and costly. Future interventions should explore the extent to
which compression garments should be worn during exercise, the timing of exercise
after curative treatment, the varying usefulness of exercise across the clinical pro-
gression of BCRL, and the type of safety monitoring needed during exercise among
this population (Tam et al. 2012). To incorporate exercise rehabilitation into cancer
survivorship care, there is a need to inform both practitioners and patients of the
risks and benefits associated with exercise (including strength training), and to pro-
vide healthcare providers with streamlined resources to promote the integration of
physical rehabilitation into the supportive care paradigm (Meneses et al. 2007).
Another unstudied research topic is whether losing weight after breast cancer treat-
ment reduces BCRL risk. If so, post treatment weight loss could be a risk reduction
strategy for survivors.
Clinical Practice Strategies for Risk Reduction There are two areas where clinical
practice can be impacted regarding BCRL risk reduction—the provider and the
patient. Providers frequently counsel patients regarding BCRL risk based on the
8 Symptoms: Lymphedema 107

presence of previously reported risk factors like injury, infection, BMI, age, and
surgery. However, recommendations based solely on these factors are unreliable, as
evidenced by the multiple studies presenting conflicting data. This suggests that an
individualization of risk reduction strategies is needed. Barriers to this approach
include lack of time and provider training to discuss individualized risk factors and
strategies with patients. Best practice guidelines need to be updated to include base-
line measurements prior to treatment, and continued routine measurements should
be part of routine survivorship care.
Women need to be educated about lymphedema, risk factors and self-care guide-
lines. The most frequent action women reported for management of symptoms for
BCRL was no action because they did not know what to do (lack of knowledge of
helpful methods). Until the last few years, women remained hospitalized for several
days following surgical treatment for breast cancer, and in-hospital care focused on
regaining arm function. Now, hospital stays are brief (1, maybe 2 days), and the
window of opportunity to introduce lymphedema prevention is gone. Studies as to
how best to inform women about these risks and practices, and when to inform
women about the risk for lymphedema (e.g., at diagnosis or at every follow-up visit)
are needed. Integrating lymphedema prevention education into routine follow-up
care alongside regular oncology appointments may improve knowledge and aware-
ness of the condition. Training health care providers to provide lymphedema pre-
vention education involves minimal resource investment and may result in reduced
incidence and severity of lymphedema over time.
Diagnosis Diagnosis of BCRL represents a significant hurdle to understanding and
managing poor outcomes among breast cancer survivors. First, standardization of
diagnostic methods is needed, as well as consensus for measurement and diagnostic
criteria. Selected method(s) must not be cost prohibitive to providers or patients and
should provide improved estimates of the incidence and prevalence of lymphedema,
as well as ways to identify women who are at increased risk of developing
BCRL. Secondly, developing standardized measurements and surveillance guide-
lines for BCRL in patients may lead to earlier detection. Standardization of diagnos-
tic criteria will allow for direct comparison of prevention/treatment interventions.
Thus, there is a need for comparative effectiveness research to determine the most
accurate and cost-efficient diagnostic method or combination of methods.
Treatment The issues with treatment for lymphedema are many—which treatments
work best, when, and delivered by whom? Little research has been conducted,
except for evaluating CDT, thus the field is wide open. Future studies should include
many outcomes, such as reduction of limb swelling, quality of life, cost and func-
tion. Once successful treatments are identified, the timing of treatment initiation and
continuation needs to be examined. Lastly, various models of care delivery should
be explored so that all women, regardless of socioeconomic status and insurance
coverage, can receive treatment. This implies dissemination of best practices, as
well as training for lymphedema providers to provide the best comprehensive care.
108 E.D. Paskett

Future Directions

Future directions for research in lymphedema should focus in several areas.

Prevention and Risk Reduction Strategies While few areas have demonstrated
reduction in the risk of lymphedema (e.g., sentinel node biopsy), there are many
opportunities to: (1) test the dissemination of risk reduction strategies into clinical
practice (e.g., infection prevention, awareness/education); and (2) find new promis-
ing risk reduction strategies (e.g., weight reduction, physical activity, prophylactic
compression garments). Ways to financially cover effective strategies for lymph-
edema prevention also need to be implemented.
Quality of Life and Physical Function Many studies have identified the negative
effects of lymphedema on quality of life, physical function and body image. No
studies have solely addressed these endpoints in studies, i.e., among women with
lymphedema. This area is important to investigate and test interventions which,
once effective, should be disseminated in clinical practice.
Surveillance Model The prospective surveillance of BCRL had been increasingly
advocated for breast cancer patients. In 2012, the National Lymphedema Network
encouraged regular BCRL screening as a method to detect and subsequently treat
BCRL at an early, or even subclinical stage, to reverse the progression of BCRL to
a chronic, irreversible condition. However, this model of early identification has yet
to be fully evaluated for its application, cost, and efficacy. Although initial studies
are promising, more research is needed to fully investigate the feasibility, applica-
bility, and outcomes of a BCRL early surveillance program (Stout et al. 2012;
Armer et al. 2013).
Patient Education The importance of educating breast cancer patients about their
risk of BCRL is paramount. There is also a need for future studies to rigorously
evaluate the timing, method, and content of disseminating BCRL educational infor-
mation. An area that should be considered is the post-operative model of care where
patients can be informed about lymphedema, the risk factors of lymphedema, and
self-care from healthcare professionals. Limited research has been done on inter-
ventions to increase patient knowledge of lymphedema. One promising study, con-
ducted by the Cancer and Leukemia Group B (CALGB), is currently testing the
efficacy of a comprehensive program of tailored exercise, patient education, and
counseling versus patient education only in reducing the incidence of BCRL in
women with stage I–III breast cancer who are undergoing ALND. Additional rigor-
ous studies are needed to help increase patient knowledge about their risk factors,
particularly modifiable risk factors, promote behaviors that reduce BCRL risk, and
improve the quality of life for breast cancer survivors.
Diagnosis Given that there is no consistent, accepted definition for lymphedema,
one needs to be developed and accepted by the medical community, and dissemi-
nated and implemented across all relevant specialty clinics. A comparison of the
effectiveness and costs associated with different diagnostic methods also needs to
8 Symptoms: Lymphedema 109

be developed. This aim follows the surveillance and education piece as these prompt
the need for early detection. In addition, ways of assuring coverage of the costs of
diagnostic tests for lymphedema can only come from validated diagnostic modalities.
Treatment New treatments need to be developed, perhaps looking to animal models
for direction. Treatment effectiveness in the presence of comorbidities, particularly
among elderly, minority, and underserved survivors, needs to be explored. Along
with examining treatment efficacy in different population groups, personalized care
based on patient and disease characteristics needs to become standard of care. An
examination of these areas would also allow for the assessment of the cost-
effectiveness of treatments. Lastly, there would need to be expansion of workforce
capacity to provide the needed lymphedema treatment.
These areas represent a spectrum along the cancer control continuum from pre-
vention and early detection to diagnosis and treatment. This comprehensive
approach is needed as prevention and early detection (through surveillance) are the
only ways to assure quality treatment and outcomes (e.g., lymphedema, quality of
life, function, cost) for all breast cancer survivors.

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Chapter 9
Symptoms: Menopause, Infertility,
and Sexual Health

Debra L. Barton and Patricia A. Ganz

Abstract By 2022, the number of survivors is expected to grow to nearly 18

million. Therefore, addressing acute and chronic negative sequelae of a cancer
diagnosis and its treatments becomes a health imperative. For women with a history
of breast cancer, one of the common goals of treatment and prevention of recur-
rence is to reduce circulating concentrations of estradiol, especially in women with
hormone receptor positive breast cancer. Hormone deprivation after a diagnosis of
breast cancer impacts physiological targets other than in the breast tissue and can
result in unwanted side effects, all of which can negatively impact quality of life
and function and cause distress. Symptoms that are most strongly linked by evi-
dence to hormone changes after cancer diagnosis and treatment include hot flashes,
night sweats, sleep changes, fatigue, mood changes, and diminishing sexual func-
tion, including vaginal atrophy (decreased arousal, dryness and dyspareunia), infer-
tility, decreased desire and negative self-image. Weight gain and resulting body
image changes are often concomitants of the abrupt onset of treatment-induced
menopause.
The purpose of this chapter is to briefly review what is known about the
advent of premature menopause in women treated for breast cancer, menopausal
symptoms that are exacerbated by endocrine treatments for breast cancer, and
the associated concerns of hot flashes and related menopausal symptoms, sexual
health and fertility issues. We will discuss limitations in the current research and
propose strategies that address current limitations in order to move the science
forward.

Keywords Menopause • Hot flashes • Infertility • Sexual health • Breast neoplasms

D.L. Barton, R.N., Ph.D., A.O.C.N., F.A.A.N. (*)

Mary Lou Willard French Professor of Nursing, University of Michigan School of Nursing,
Ann Arbor, MI, USA
e-mail: [email protected]
P.A. Ganz, M.D.
UCLA Schools of Medicine and Public Health, Jonsson Comprehensive
Cancer Center, Los Angeles, CA, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 115

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_9
116 D.L. Barton and P.A. Ganz

The Challenge of Symptom Complexity

There are estimated to be over 13 million cancer survivors alive as of January, 2012,
more than half of whom are women; 22 % are breast cancer survivors (de Moor
et al. 2013). By 2022, the number of survivors is expected to grow to nearly 18 mil-
lion (Siegel et al. 2012). Therefore, addressing acute and chronic negative sequelae
of a cancer diagnosis and its treatments becomes a health imperative.
For women with a history of breast cancer, one of the common goals of treatment and
prevention of recurrence is to reduce circulating concentrations of estradiol, especially
in women with hormone receptor positive breast cancer. Accomplishment of this goal
can result in unwanted side effects, since there are estrogen receptors throughout a wom-
an’s body. Hence, hormone deprivation after a diagnosis of breast cancer impacts physi-
ological targets other than in the breast tissue and can result in unwanted side effects.
Symptoms in women with a history of breast cancer that are most strongly linked
by evidence to hormone changes after cancer diagnosis and treatment include hot
flashes, night sweats, sleep changes, fatigue, mood changes, and diminishing sexual
function, including vaginal atrophy (decreased arousal, dryness and dyspareunia),
decreased desire and negative self-image (Rogers and Kristjanson 2002; Ganz et al.
1998, 2003; Young-McCaughan 1996; No Authors 2005). Weight gain and result-
ing body image changes are often concomitants of the abrupt onset of treatment-
induced menopause (Goodwin et al. 1999). Many of these symptoms can persist for
long periods of time (such as hot flashes and weight gain), and some can become
more severe over time (such as vaginal atrophy). Symptoms can co-occur (e.g.,
sleep disturbance and hot flashes, or depression, pain and fatigue); they can be
related to each other and yet have distinct etiologies. Although clearly related to
estrogen deprivation, symptoms such as hot flashes, sleep disturbance and decreases
in sexual health, more often than not, have multiple causes which are conceptually
a combination of physiologic and psychosocial domains. In many cases, the precise
cause and risk factors, as well as the natural course over time are not definitively
known. These features make symptom management difficult from a clinical per-
spective and challenging from a research perspective.
The purpose of this chapter is to briefly review what is known about the advent
of premature menopause in women treated for breast cancer, menopausal symptoms
that are exacerbated by endocrine treatments for breast cancer, and the associated
concerns of hot flashes and related menopausal symptoms, sexual health and fertil-
ity issues. We will discuss limitations in the current research and propose strategies
that address current limitations in order to move the science forward.

Addressing Life Stage

One common consequence of treatment for breast cancer is hormone depletion

resulting in premature menopause for women under the mean menopause age of 51
(Gracia and Freeman 2004; Ganz et al. 2003). For women in their third or fourth
9 Symptoms: Menopause, Infertility, and Sexual Health 117

decade of life, menopause is an early intruder that can be a negative reminder of

their cancer experience. The risk of premature menopause related to chemotherapy
is greatest in women 40 and older (Murthy and Chamberlain 2012). In one study
that evaluated menstrual changes longitudinally during a treatment trial (B-30) for
premenopausal women with node positive breast cancer, investigators report the
rate of amenorrhea at 24 months in those receiving doxorubicin and cyclophospha-
mide followed by docetaxel as 54.7 % in those under 40 years of age, 89.1 % in
those 40–50 years and 96.8 % in those over 50 years (Swain et al. 2009; Ganz et al.
2011). The use of cyclophosphamide and tamoxifen, however, significantly
increased rates of amenorrhea compared to those receiving only doxorubicin and
docetaxel and no tamoxifen (Ganz et al. 2011). Interestingly, in this set of reports
from the NSABP B-30 trial, amenorrhea and tamoxifen did not significantly predict
symptom severity. Rather, the type of chemotherapy did, with those receiving doxo-
rubicin and cyclophosphamide followed by docetaxel having more prolonged
symptom severity (Ganz et al. 2011). The reason for this is not clear.
Although menopause is a well-known bridge women cross in life, going through
this event a decade or so earlier, than others in one’s age group, can cause distress
and negatively impact body image. Associated with menopause and hormone with-
drawal, due to the fact that there are hormone receptors throughout the body, are
skin changes (decreased elasticity and increased dryness), vaginal atrophy, changes
in hair consistency, and mood changes, to name a few. In short, women who con-
front breast cancer treatment in their premenopausal years can experience a more
rapid aging phenomenon due to physiologic changes from cancer treatment.
Depending on the life stage and social circumstances of the premenopausal
woman, she may accept these changes gracefully or experience tremendous disrup-
tions. Those women who are married, closer to the age of natural menopause, and
who have completed their families may be trying to do everything possible to have
extended survival. The development of early onset menopause might seem like a
small price to pay in this setting. In contrast, the younger women who may have
recently married, who now have uncertainty about their fertility when they become
transiently amenorrheic after chemotherapy, may have considerable anger about
this additional burden of the cancer diagnosis. Paradoxically, post-treatment amen-
orrhea has an important survival benefit for women with hormone receptor positive
breast cancers (Swain et al. 2010); however, younger women may or may not appre-
ciate the value of this therapeutic advantage and, instead, have anger related to their
daily symptoms and loss of potential fertility (see discussion later).
Another group of women who are important to consider are those who are post-
menopausal at breast cancer diagnosis and who have been on long-term hormone
therapy (HT), often started at the perimenopause or natural menopause stage to
manage vasomotor symptoms, mood, insomnia, and general well-being, or for what
was assumed to be cardiovascular or cognitive benefit. Since we have now learned
that the potential harms outweigh the benefits of postmenopausal HT, those women
who persisted in this therapy have done so in spite of the medical evidence, and may
suffer substantially when HT is withdrawn at the time of the breast cancer diagno-
sis. These women may experience vasomotor symptoms from the sudden withdrawal
118 D.L. Barton and P.A. Ganz

of HT and then this can be exacerbated by the use of aromatase inhibitors, which
decrease endogenous levels of estrogen even further. Other psychological and phys-
ical effects from the withdrawal of HT include concerns about skin, body image,
vaginal dryness (see below), joint aches and pains, which add to the distress associ-
ated with the cancer diagnosis. These women may have difficulties adhering to
endocrine directed breast cancer treatment, and sometimes resume their HT.

Challenges of Managing Menopausal Symptoms

There are several challenges in managing symptoms related to hormone deprivation

such as hot flashes, decreased sexual desire, and difficulties with sexual arousal.
One challenge is that there is a dearth of research that describes the physiologic
etiology and biologic mechanisms of these types of symptoms. For example, animal
models for hot flashes use ovariectomized rats. This is not a sufficient model for
either natural menopause or chemotherapy induced menopause. Non-human pri-
mates offer more relevant insights, but studies with these animals are lacking and
translation to women is still largely untested (Appt and Ethun 2010). While what is
known about hot flash physiology is currently based on limited laboratory studies in
women (Freedman 2001) and points to estrogen withdrawal resulting in a loss of
regulation of the thermoregulatory zone and a rising core body temperature
(Freedman 2001), there is a newer hypothesis that proposes an imbalance in para-
sympathetic/sympathetic activity and this is not fully explored, nor are the nuances
of the hypothesis proven (Thurston et al. 2012; Freedman et al. 2011).
Another challenge of managing symptoms related to menopause, including fer-
tility, is that though there is undoubtedly a physiologic etiology (despite it being not
clearly described), there are also important psychosocial contributors that add to the
symptom burden. Insight from studies done in the general population can help
inform hypotheses to test in women with breast cancer. In a cross sectional study of
494 women, investigators evaluated attitudes and menopausal symptoms. Lower
levels of education, lack of insurance and more negative relationships with children
were associated with more severe menopausal symptoms. Negative attitudes toward
menopause were also a factor in greater symptom burden (Yanikkerem et al. 2012).
A second study in 182 women with dyspareunia revealed that rather than estrogen
concentrations, pain was associated with cognitive, affective and dyadic variables
(Kao et al. 2012). In research to date, studies generally address one or the other of
these types of etiologies, but rarely examine how biologic and psychosocial factors
may be additive or synergistic. Interventions are rarely multi-faceted to address
more than one focal cause of a symptom, and when they use multiple intervention
strategies, there can be a “kitchen sink” approach rather than a rational development
of a complex intervention that addresses specific unique and overlapping etiologic
variables. In short, research has been reductionist which has limited the ability to
fully understand the phenomenon of interest and approach it with strategies that can
move the science forward by leaps instead of the current baby steps.
9 Symptoms: Menopause, Infertility, and Sexual Health 119

The information contained in this chapter will include examples and thoughts
about how research in symptom management requires an informed, multi-
component strategy, and we hope to provide food for thought that will help our
fellow researchers develop innovative studies that will advance the science in the
area of infertility, menopause and sexual health.

Menopause: More than Estrogen

Defining the menopausal state in research has not been consistent and has focused
primarily on physiology since there are wide variations in symptoms related to
menopause. Although this inconsistency may not have led to erroneous or mislead-
ing information (Phipps et al. 2010), readers of the literature could benefit from
standardization of definitions. Clearly defining menopause may be particularly
important in studies with populations of women with breast cancer due to the some-
times late resumption of menses after treatment. Some interventions may only work
at certain stages of the transition, therefore, a clear and accurate definition would
facilitate this research. Table 9.1 defines menopause according to the Stages of
Reproductive Aging Workshop (STRAW) (Soules et al. 2001) enhanced with addi-
tional data regarding broader hormonal changes, behavioral correlates and known
predictors to date (Ganz et al. 2011; Soules et al. 2001; Hale and Burger 2009;
Freeman et al. 2008; Gracia et al. 2007; Nappi et al. 2010; Buijs et al. 2008; Cohen
et al. 2002; Gibbs et al. 2013; Sigmon et al. 2004; Stone et al. 2013). Most of the
data are drawn from the general population with a sprinkling of data from the popu-
lation with breast cancer. Despite that, researchers can derive testable hypotheses
from related populations. It is interesting to note that early postmenopause is defined
as the period through 4 years after the last menses and late postmenopause begins
after 4 years of amenorrhea. Exploring differences in factors between those two
postmenopausal periods and how those factors may influence response to various
interventions or the severity and frequency of menopause related symptoms, par-
ticularly in women post treatment for breast cancer, would be an interesting endeavor.
Physiologic changes in menopause, including chemotherapy-induced, surgical,
and natural, primarily focus on the withdrawal and gradual depletion of estradiol
(Hale and Burger 2009; Yoo et al. 2013). As the follicles become depleted, anti-
mullerian hormone decreases and follicle stimulating hormone concentrations rise
resultant from decreases in estradiol (Hunter and Rendall 2007; Harlow et al. 2013).
Although estrogens post-menopause are still produced from conversion of
dehydroepiandosterone from the adrenal gland, androstenedione in fat cells, and
from ovarian androgens (if ovaries are present), the amount of estrogen is vastly and
sharply decreased (Hunter and Rendall 2007). Estrogen depletion is directly associ-
ated with hot flashes, vaginal atrophy and the loss of fertility; however, specific estro-
gen concentrations have not been highly correlated with symptom severity (Gracia
and Freeman 2004). Less is known about the other sex steroid hormones and their
relationship to the symptoms experienced during the post-menopausal state; related
hormones in chemotherapy induced menopause have been largely unexplored.
 120

Table 9.1 Definitions, correlates and predictors of reproductive stages

Known predictors of menopause
Reproductive stage (STRAW) Known physiology Behavioral correlates transition or behavioral correlates
Reproductive early to late Normal to elevated FSH Mood swings, headaches, water History of depression, smoking, lower
Menstrual cycles obtain regularity; retention varies with cycle education, not employed outside the
later AMH drops home, copying style
Early menopause transition Increased FSH, estradiol levels are Hot flashes, night sweats, depression or Smoking, tamoxifen
maintained, AMH and inhibin B negative mood increases, irritability,
decrease, irregular menstrual cycles sleep dysregulation
occur
Late menopause transition Increased FSH, estradiol begins to Hot flashes, night sweats, depression or Smoking, physical symptoms during
decline, more irregular menstrual negative mood increases, irritability, pregnancy, history of premenstrual
cycles sleep dysregulation dysphoric disorder, tamoxifen
Early post menopause (first 4 Increased FSH, decreased estradiol, Hot flashes, night sweats, depression or Age, BMI, chemotherapy, mood/attitude,
years after menses cease) amenorrhea negative mood increases, irritability, smoking, BMI, age, tamoxifen, DHEA-S,
sleep dysregulation, fatigue, vaginal FSH, anxiety, history of PMS
dryness
Late post menopause (after 4 Increased FSH, increased LH, Hot flashes, night sweats, depression or Aromatase inhibitors, age, chemotherapy,
years of amenorrhea) undetectable inhibin B, decreased negative mood increases, irritability, mood/attitude, anxiety, DHEA-S, FSH,
estradiol, amenorrhea sleep dysregulation, vaginal atrophy, perceived stress, BMI, history of
dyspareunia premenstrual dysphoric disorder,
tamoxifen
Abbreviations: AMH antimullerian hormone, FSH follicle stimulating hormone, LH luteinizing hormone
D.L. Barton and P.A. Ganz
9 Symptoms: Menopause, Infertility, and Sexual Health 121

Recent research indicates that, in addition to follicular senescence due to

chemotherapy, there may also be stromal degradation as well, leading to decreases
in androgens (Barton et al. 2007a, 2012). Evidence for this hypothesis is demon-
strated by translational data collected for a study done, by the North Central Cancer
Treatment Group, evaluating transdermal testosterone for libido in women with a
history of breast or gynecologic cancer. At baseline and after 4 weeks of testoster-
one use, blood was collected to analyze changes in sex steroid hormone concentra-
tions. At baseline, the mean bioavailable testosterone concentration was 3.18 %
(normal range 8–10 %), mean free testosterone was .56 ng/dl (norms 0.3–1.9 ng/dl)
with 53 % of the women having free testosterone at 0.3 ng/dl and below (Barton
et al. 2007a). A longitudinal study, following 20 premenopausal women through
chemotherapy and 6 months beyond. demonstrated that women 40 and over years of
age who remained amenorrheic at 6 months after chemotherapy had significantly
lower androgen levels (in addition to estrogen) compared to the other women who
had resumed menses (Barton et al. 2012). Concentrations of DHEA-S were not dif-
ferent between those who ceased versus continued their menses suggesting that the
adrenal function was not impacted. Therefore, chemotherapy induced amenorrhea/
menopause may be more like surgical menopause than natural menopause, with
broad decreases in sex steroid hormones possibly accounting for the more severe
experience of symptoms. This hypothesis needs to be explored further and put into
context with the life stage and psychosocial factors surrounding menopause.

Interrelatedness and Co-occurrence of Symptoms

Symptom clusters have become a popular concept in oncology, however, this con-
cept can be misunderstood. One definition of a symptom cluster is a group of two ,
three or more concurrent symptoms that are related to each other (Miaskowski et al.
2007). This relationship can constitute several different things; there can be some
shared mechanisms, correlations in severity, synergistic or additive burden or emo-
tional distress. However, it does not generally mean that all of the symptoms have
the same origin and/or can be ameliorated with the same treatment. One example of
the potential heterogeneity of symptom clusters is demonstrated by a study from
Freedman and Roehrs (2007), who sought to uncover the source of sleep problems
in healthy peri and post menopausal women. These investigators found a significant
sleep disturbance in 102 women, whose mean age was 50. Overall the women slept
only 6½ hours per night. They were awake over an hour sometime during the night
and took longer than half an hour to fall asleep. Some elements of their sleep distur-
bance were due to periodic limb movements and sleep apnea while others were
related to mood and hot flash issues. Different etiologies call for different approaches
to management, and often, both physiologic and psychosocial variables are contrib-
uting to the symptom experience.
Symptom clusters can change throughout the trajectory of the cancer experience
and the symptoms within a cluster can vary in severity and prevalence over time
122 D.L. Barton and P.A. Ganz

(Kim et al. 2009; Dodd et al. 2005). Therefore, the phenomenon of symptom clusters
contributes to the complexity inherent in symptom management research. The com-
plexity of symptom relationships is further exemplified by a study in 69 women
with early stage breast cancer. Data were collected at seven points from pre chemo-
therapy through cycle 4 of chemotherapy. Sleep, menopausal symptoms and depres-
sion were evaluated in the context of menopausal status based on self-reported
menses, or absence thereof. Overall, women experienced a combination of depres-
sive symptoms, poor sleep and vasomotor symptoms. Though those who became
perimenopausal had increased vasomotor symptoms, this symptom was not related
to sleep and moreover, in all groups, depressive symptoms did not appear to be
related to sleep (Rissling et al. 2011).

Current Research Strategies and Their Limitations

Hot Flashes

There has been limited longitudinal research in hot flashes and related menopausal
symptoms in cancer that defines when the most problematic symptoms begin, which
women experience hot flashes the longest and what the predictors of response to
various treatments are. In one cross sectional internet based survey of women who
were diagnosed with breast cancer at 40 years of age or younger, cognitive symp-
toms were more prevalent than hot flashes. Of 371 women with a mean age of 33,
81 % of the sample reported forgetfulness as a bothersome symptom, 72 % concen-
tration difficulties, 71 % distractability and 46 % reported bothersome hot flashes,
using the Breast Cancer Prevention Treatment Checklist to measure symptoms
(Leining et al. 2006). In contrast, in an earlier longitudinal European treatment trial
where women were randomized to high dose versus conventional chemotherapy
(Malinovszky et al. 2006), both groups of women reported increases in night sweats
and hot flashes throughout the first year, maintaining high levels of those symptoms
throughout the 5 years of follow up. A second longitudinal study followed women
on the NSABP B-30 trial for 24 months. Vasomotor symptoms (hot flashes, night
sweats and cold sweats) were common in both women who had stopped menses and
those who continued menstruating. As early as day 1 of cycle 4 of chemotherapy,
74 % of women reported hot flashes. At 6 months, 85 % of women who were amen-
orrheic and 89 % of those who were still menstruating, reported vasomotor symp-
toms. At 12 months, of the women who ceased menses, 90 % reported symptoms
and of those who were menstruating, 55 % reported vasomotor symptoms (Swain
et al. 2009). Research indicates that hot flashes begin during chemotherapy and
increase and continue throughout 2 years of follow up (Barton et al. 2009).
Pharmacologic treatment with estrogen has been a common treatment for healthy
women, but that may not be a safe option in women who have a history of breast
cancer. During the 1990s, in the period before the results of the Women’s Health
Initiative hormone trials, bothersome hot flashes were perceived as another trauma
9 Symptoms: Menopause, Infertility, and Sexual Health 123

of the cancer diagnosis, since women with breast cancer were being denied a therapy
that was routinely recommended in healthy mid-life women. Thus, there was a
strong sense of urgency to find alternative strategies to manage hot flashes in breast
cancer patients and survivors (Loprinzi et al. 2008). Serendipitous findings, and
rigorous placebo controlled clinical trials, demonstrated the treatment benefits of
serotonin reuptake inhibitor antidepressants and gabapentin for hot flash relief
(Loprinzi et al. 2008, 2009; Barton and Loprinzi 2004). Subsequent mechanistic
studies related to these agents have been pursued. These agents now have the stron-
gest evidence to date for non-hormonal treatment of hot flashes.
None of these non-hormonal agents, though, have reduced hot flashes beyond
about 60 %. Further, pharmacologic treatments are wrought with unwanted side
effects or unwanted stigma. Many times women do not want to take an antidepres-
sant and women who have gone through treatment for breast cancer often do not
want to take “yet another pill,” as taking medication is reminiscent of “being ill”.
Research has also not provided insight into who does or does not respond to various
antidepressant therapies. It is hypothesized that serotonin is the active ingredient in
antidepressants for the amelioration of hot flashes but this has not been proven and
there is less known about why gabapentin helps hot flashes. One thing that has been
clearly proven with the hot flash research is that neither the population (naturally
menopausal, chemotherapy induced or surgically induced) nor the hot flash etiology
(tamoxifen, aromatase inhibitors, or just menopausal status) has differentially
impacted response to the evidence-based treatments to date (Loprinzi et al. 2008;
Bardia et al. 2009).
Mind-body, psycho-educational and cognitive-behavioral interventions have
also been studied. These intervention modalities are interesting as they represent
ways for women to self-manage and also have little in the way of unwanted side
effects. Unfortunately, the evidence is mixed with regard to these behaviorally based
therapies and are plagued by small sample sizes, poor effect sizes and lack of appro-
priate control groups. Recent randomized trials have evaluated cognitive behavioral
therapy (CBT) for hot flashes, and at least three have been done in women with
breast cancer. Most of these interventions have utilized a combination of cognitive
and behavioral approaches, most commonly, paced breathing and relaxation, educa-
tion about menopause, cognitive strategies to address negative thinking or attitudes
and catastrophizing, and behaviors to improve sleep and manage stress and anxiety
(Ayers et al. 2012; Duijts et al. 2012; Mann et al. 2012; Tremblay et al. 2008;
Balabanovic et al. 2012). Many of the studies have used usual care or “no treat-
ment” control groups. In addition, some of the studies used a support group approach
to deliver the intervention, while others used one on one time with clinical psy-
chologists and/or social workers. The intervention time was often 90 min for 6
weeks. Most of these studies have demonstrated improvements in the distress and
bother related to hot flashes , but not the number or severity of hot flashes them-
selves (Ayers et al. 2012; Duijts et al. 2012; Mann et al. 2012; Tremblay et al. 2008;
Balabanovic et al. 2012). One study, using a cognitive behavioral intervention for
hot flashes in women with breast cancer, included a qualitative interview to learn
about women’s perception of the effect of the intervention on their symptoms
124 D.L. Barton and P.A. Ganz

(Balabanovic et al. 2012). Women talked about having a different attitude toward
their symptoms, coping better, feeling distracted from their symptoms, and gaining
control over their lives. They also talked about the importance of the group support.
This study provides some insight into the elements of a cognitive behavioral inter-
vention that may be more important in achieving wanted results. Interestingly, to
date, there has been little research done to capitalize upon the potential synergy or
additive effect of non-pharmacologic and pharmacologic therapies in such a way as
to essentially eliminate side effects while improving effects.
Pharmacologic research for hot flash control has demonstrated a placebo effect
of about 25–30 %, but this varies across studies (Loprinzi et al. 2008; Bardia et al.
2009). The mechanism by which the placebo improves hot flashes has not been
investigated and would provide insight. It is important, though, to include an appro-
priate control group when evaluating interventions for hot flashes and related meno-
pausal symptoms. It could be said that there is a placebo effect in much of symptom
research, which makes appropriate control groups necessary, even in behavioral
research, in order to understand the benefit of the intervention evaluated.
In summary, much of the research in hot flashes has been narrowly focused and has
neither addressed menopausal symptoms broadly nor incorporated complementary
mechanistic approaches (pharmacologic with behavioral). Research is needed to address
relationships between symptoms and respective responses to tailored treatment.

Sexual Health

There is a surprising amount of research in sexual health that encompasses descrip-

tive studies, psychological interventions for overall sexual health and pharmaco-
logic interventions for vaginal symptoms. Much of the research in this area, however,
suffers from small sample sizes, small effect sizes and a lack of control groups to
account for non-specific effects of group and provider interactions. Most studies
focus on three groups of survivors, breast, gynecologic and prostate cancer (Brotto
et al. 2010; Taylor et al. 2011). In cancer survivors, sexual health research is largely
represented by cross-sectional studies or very small longitudinal research. What is
known about sexual health in women with breast cancer is that, in age matched stud-
ies, women with breast cancer report worse functioning (Howard-Anderson et al.
2012; Basson 2010; Speer et al. 2005) and that women who have undergone treat-
ment for breast cancer (including surgery, tamoxifen or chemotherapy) report more
sexual concerns than those women with breast cancer who have not had these treat-
ments (Gilbert et al. 2010). Women who are younger and those with more advanced
disease may experience the most disruption of their sexual health (Andersen et al.
2007). Though sexual health may decline during treatment, there is some improve-
ment gradually when treatment ends, but data do not support that function returns to
baseline levels (Krychman and Millheiser 2013). However, it is not known in which
individuals function returns to baseline and for whom concerns persist or even
increase. The prevalence of sexual health concerns in published data ranges from 30
9 Symptoms: Menopause, Infertility, and Sexual Health 125

to 100 % (Speer et al. 2005; Gilbert et al. 2010; Andersen et al. 2007; Burwell et al.
2006; Krychman and Millheiser 2013; Biglia et al. 2010) and generally consists of
problems with lubrication, dyspareunia, desire, body image and relationship con-
cerns (Burwell et al. 2006). Like other symptoms, such as fatigue where research is
growing to provide new insights, sexual health concerns may be more pervasive,
start earlier, and last longer than we currently know.
One source of evidence is a longitudinal study in 35 premenopausal women
diagnosed with breast cancer (Biglia et al. 2010). These women reported below
normal sexual activity on the McCoy Female Sexual Questionnaire, as early as their
first post-surgical visit. Sexual scores decreased further during chemotherapy and
even further one year later. Specific areas which were negatively impacted included
activity, desire, arousability, quality of partner relationship and body image (Biglia
et al. 2010). On the other end of the spectrum of study sizes, a survey study of breast
cancer survivors (N = 1,134) had participants complete self-report questionnaires to
identify variables that predicted sexual health (Ganz et al. 1999). Predictors of sex-
ual interest included body image and mental health, as well as having a new partner
since being diagnosed, and predictors of decreased sexual function included vaginal
dryness, past chemotherapy, and having a new partner since being diagnosed (Ganz
et al. 1999).
A comprehensive review of the literature between 1998 and 2010 summarizes
the breadth and complexity of the issues surrounding sexual health in women after
a diagnosis of breast cancer. The list includes sexual function disturbances (arousal,
lubrication, orgasm, desire and pleasure), but also lists psychological issues of nega-
tive body image, feeling sexually unattractive, loss of femininity, anxiety, depres-
sion and changes in one’s sense of sexual self (Gilbert et al. 2010). Likewise, a
meta-synthesis of 30 qualitative studies, representing 795 women, supports the con-
cepts of “redefining self” in terms of body image and womanhood/femaleness as a
pervasive, critical issue in sexual health and functioning in women with breast can-
cer (Bertero and Chamberlain Wilmoth 2007). Estimates of the prevalence of body
image concerns range from 31 to 67 %, and the prevalence of those reporting arousal
or interest issues is 46 to 56 %, respectively (Fobair and Spiegel 2009).
Thought provoking results emanate from one European longitudinal study
(Malinovszky et al. 2006). Three hundred ninety women randomized to conven-
tional or high dose chemotherapy for high risk, node positive breast cancer com-
pleted the sexual activity questionnaire at baseline, after surgery but before
treatment, at 6 and 12 months and yearly out to 5 years. Despite the findings that
vaginal dryness and dyspareunia occurred during the first year and persisted
throughout the 5 years and significantly increased compared to baseline, the num-
bers of women who engaged in sexual activity and the frequency of sexual activity
did not significantly change from 12 months and beyond. Pleasure was also signifi-
cantly lower at every time point, when compared to baseline. This was not signifi-
cantly different based on high dose or conventional dose chemotherapy (Malinovszky
et al. 2006). Therefore, women in this study were engaging in behavior that was
increasingly difficult and unpleasant, suggesting a critical need for research to
address this unmet need.
126 D.L. Barton and P.A. Ganz

It is important to note that intervention research in sexual health in the general

population cannot likely be extrapolated to the cancer population, which is admit-
tedly different than the research on hot flashes. This lesson is demonstrated by the
fact that there are 11 positive randomized controlled trials of transdermal testoster-
one in various non-cancer populations of women for improving libido (Davis et al.
2006, 2008a, b; Goldstat et al. 2003; Shifren et al. 2000, 2006; Simon et al. 2005;
Braunstein et al. 2005; Buster et al. 2005; Nathorst-Boos et al. 2006; Chudakov
et al. 2007) while the one large study that evaluated transdermal testosterone in
female cancer survivors was decidedly negative (Barton et al. 2007b). Interestingly,
the lack of benefit was seen despite similar testosterone doses and improvement in
testosterone concentrations for the intervention group (Barton et al. 2007b). This
may be because women who have chemotherapy induced menopause are hormon-
ally depleted more severely and more broadly than the women on these positive
trials. In fact, in one subanalysis, women who had had bilateral oophorectomies did
not experience the same benefit in the primary outcome of sexually satisfying events
as women who had were naturally postmenopausal (Davis et al. 2008b), thus sup-
porting the idea that the degree to which hormones are depleted makes a difference
in outcomes.
Though there are studies that provide evidence of the areas of sexual health that
are negatively impacted as a result of the cancer experience, there is little research
that teases out specific predictors in subgroups of women longitudinally. There is
even less research evaluating comprehensive interventions to address the com-
plexities of sexual health. One early and important study in this area, that was
clearly ahead of its time, was (Ganz et al. 2000; Zibecchi et al. 2003) a compre-
hensive menopausal assessment intervention. The intervention was developed to
address three symptoms (hot flashes, vaginal dryness and urinary incontinence).
An advanced practice nurse assessed each woman’s needs and developed a tai-
lored intervention, including pharmacologic and behavioral interventions for
these three main issues. At the time of the study, there were not extremely effec-
tive interventions for any of these problems. Despite this, the investigators
reported significant improvements in sexual health as measured by the sexual
summary scale from the Cancer Rehabilitation Evaluation System (CARES) over
the usual care control group. This significant improvement was still present at the
2 month follow up.
There is a fair amount of research on psychological interventions for sexual
health (Brotto et al. 2010; Taylor et al. 2011). These studies are designed to deliver
the interventions mostly in person, but at least one tested a telephone intervention
(Salonen et al. 2009). The content of the psychological interventions included edu-
cation about managing symptoms and distress related to symptoms and body image
changes, behaviors to improve sexual response, communication skills and, where
couples were involved, how to cope as a couple (Brotto et al. 2010; Taylor et al.
2011). Physical exercise was also often included (Taylor et al. 2011). Yet, research
has not been done to identify and build on the most effective strategies for sexual
health, nor has much of this research been appropriately controlled for non-specific,
provider or group effects.
9 Symptoms: Menopause, Infertility, and Sexual Health 127

For vaginal symptoms, some research has focused on evaluating the lowest dose
of estrogen that has the potential to improve symptoms of dryness and dyspareunia
without impacting systemic estradiol concentrations (Krychman and Millheiser
2013; Tan et al. 2012; Goldfarb et al. 2013). There has been little research that has
taken a systematic approach to addressing the multiple etiologies that contribute to
decreases in sexual health. In addition, the research in this area appears disparate,
without evidence of an attempt to build on and expand on previous findings. Hence,
more research is needed to clarify the etiologies of various aspects of sexual health
changes after cancer and intervention research should be individualized to target
more than one aspect of this problem.

Fertility Preservation: Practice and Research

Among a substantial number of younger women with breast cancer, the likelihood
of infertility after chemotherapy treatment, and/or the delay in potential attempts at
pregnancy due to 5 years of tamoxifen therapy is a significant concern (Senkus et al.
2014; Partridge et al. 2004). Young women’s attitudes are most influenced by
whether or not they have already had children, as well as their desire to have future
children. There appears to be considerable variability in the frequency with which
physicians discuss fertility issues with premenopausal women before initiating can-
cer treatments (Duffy et al. 2005; Quinn et al. 2007, 2009). To some extent, this may
relate to lack of knowledge by the oncologist, but also the lack of access to repro-
ductive endocrinology specialists to assist in the care of these patients. In addition,
there are substantial financial barriers to receiving these medical services, as they
may not be covered through health insurance. Embryo storage may also be costly.
In addition, women who do not have a partner may not perceive that it is feasible,
and methods of storing oocytes or ovarian tissue may not be as successful (Waimey
et al. 2013). The American Society of Clinical Oncology has published fertility
preservation guidelines emphasizing the importance of these pre-treatment discus-
sions and the offering of fertility preservation services (Loren et al. 2013).
Organizations such as LIVESTRONG and the Oncofertility Consortium (http://
www.fertilehope.org/tool-bar/referral-guide.cfm; http://oncofertility.northwestern.
edu/) can provide some financial and professional assistance for patients who wish
to pursue these options, as well as providing extensive educational and resource
information.
The technical and logistical aspects of fertility preservation in the setting of
breast cancer has become somewhat easier in large institutions where dedicated
teams exist to make this happen (Reinecke et al. 2012). This often includes having
a nurse or other professional on call to facilitate the pre-treatment counseling with
the patient and the prompt referral to the reproductive endocrinology service
(Lambertini et al. 2013). Currently, it may take a few weeks to do preoperative
evaluation and consultation for breast surgery (especially with reconstructive sur-
geons and radiation oncologists), and in this time the reproductive endocrinologist
128 D.L. Barton and P.A. Ganz

can be consulted and ovarian stimulation started so that in some cases oocyte
retrieval can coincide with definitive breast cancer surgery or before the initiation of
chemotherapy (Westphal and Wapnir 2012; Baynosa et al. 2009).
While historically there has been some concern about the safety of pregnancy after
a breast cancer diagnosis, recent studies have not supported adverse outcomes (Azim
et al. 2011, 2013; Kroman et al. 2008), and thus younger women should be given the
opportunity to pursue this as a future option, by having pre-treatment counseling.

Moving the Science Forward

Using a Theoretical Framework

The use of a theoretical framework to guide research is a helpful tool that provides
a lens through which the investigative team can focus their research strategy. Two
theories that have been instructive in symptom research include the Theory of
Unpleasant Symptoms by Elizabeth Lenz (Lenz et al. 1997) and the Revised
Symptom Management Conceptual Model developed by nurse scientists at the
University of California San Francisco (Dodd et al. 2001).
Both of these frameworks provide for psychosocial as well as physiologic influ-
ences on the symptom experience. Importantly, they also clearly articulate that
people experience symptoms in a situation specific context (age, life stage, develop-
mental stage) and bring to the perception of their symptoms their own history of
experiences, self-management, and coping strategies. These variables are not trivial
and need to be considered when developing studies to improve or prevent unwanted
symptoms related to cancer. These theoretical frameworks can assist the investiga-
tor in thinking through potential mediators and moderators of a comprehensive
intervention and, in this way, can facilitate a more realistic approach to symptom
management research.

Comprehensive Interventions

In intervention research, it is common for investigators to define the problem nar-

rowly, target a narrow population, apply a single intervention and measure one main
outcome. Further, studies have often been relatively small and been in single institu-
tions. This approach results in effect sizes that are small and the inability to define
characteristics of populations that benefit most from the intervention. Important
intervention components are generally not identified and long term outcomes are
unknown. While comprehensiveness is critical, it is also important that investiga-
tors not develop intervention studies that include “everything but the kitchen sink”
because they don’t know what will and won’t impact their desired outcomes.
9 Symptoms: Menopause, Infertility, and Sexual Health 129

Intervention research requires clearly-articulated rationale and etiologically-based

components that can address more than one factor that contributes to the symptom
experience at hand. Examples of implementing this strategy are provided for hot
flash related symptoms and sexual health below.

Specific Strategies
Hot Flash Related Symptoms

Research in menopause needs to focus on developing interventions that can address

both the physiologic and psychosocial correlates of menopausal symptoms. Hot
flashes have been shown to contribute to many other issues such as mood, sleep and
fatigue. As such, interventions targeting hot flashes need to measure effects on this
symptom cluster to determine what components are helpful in addressing the
breadth of the menopausal symptom experience.
One promising mind body therapy is hypnosis. Collaboration with a clinical psy-
chologist and hypnotherapist from Baylor University, Dr. Gary Elkins, has provided
the opportunity to build and evaluate multi-component interventions centered on
hypnosis for menopausal symptoms of hot flashes, mood, sleep and fatigue. Dr.
Elkins has demonstrated the ability for a hypnotic relaxation intervention alone to
decrease hot flashes by about 70 %, in post menopausal women (not breast cancer
survivors). The study was a randomized controlled trial using an attention control
group that received equal interactions in terms of number and time with study per-
sonnel. This 70 % reduction is greater than that seen with other non-hormonal
approaches. Importantly, hypnosis, if done by an appropriately trained provider in a
person without psychotic risk factors, is safe and without side effects (Elkins et al.
2013). In addition, Dr. Elkins’ randomized trial demonstrated significant improve-
ments in sleep quality as measured by the Pittsburgh Sleep Quality Index.
Building on Dr. Elkin’s success, a study combining venlafaxine (an effective
antidepressant for hot flash relief) with hypnosis in a four arm randomized pilot trial
was sponsored by National Center for Complementary and Alternative Medicine
(NCCAM) and the National Cancer Institute (NCI) (Barton et al. 2013). This pilot
study accomplished some important things. First, it confirmed the development of a
viable and believable control for hypnosis (a sham hypnosis condition) and second,
led to the knowledge that combining venlafaxine with hypnosis was not better than
either intervention alone. Another important lesson from this pilot study was that
nurses could efficiently be taught to provide hypnosis and the outcomes from the
hypnosis intervention alone were similar to venlafaxine alone. Unlike the other
mind-body interventions mentioned earlier, such as paced breathing and psycho-
educational programs, hypnosis was able to reduce both the actual severity and
frequency of hot flashes as well as the bother/distress associated with this symptom.
A follow up study is in development that builds on the findings of this pilot study
and expands the outcomes of interest.
130 D.L. Barton and P.A. Ganz

Sexual Health

The ability to develop interventions that target related areas in sexual health such as
partner communication, vaginal atrophy, self-image and desire, would be an impor-
tant contribution to the science and, more importantly, to women. To date, interven-
tion research has followed a similar strategy to that of hot flashes, evaluating either
behavioral interventions for general sexual improvement or pharmacologic agents
for targeted problems such as vaginal dryness or libido. It is time to build on the
many positive psychological intervention trials and examine what the strongest
effects from this type of approach are, and to evaluate what the critical and neces-
sary components are that need to be brought forward into future research.
For example, one fairly large study randomized women who were distressed
about intimacy and/or sexuality to receive a group delivered psychoeducational
intervention or to receive printed information on sexual health (control group)
(Rowland et al. 2009). Initially, 284 women were randomized to receive the interven-
tion, with 83 agreeing and 72 attending at least one of the 6 two-hour sessions. The
psychoeducational sessions addressed body image, sexual anatomy, sexual attitudes
and behaviors, menopause, communication and incorporated self-directed future
goals. The main outcome, the Mental Health Index, which measures emotional vari-
ables, was not significantly impacted by the intervention. However, there were some
positive effects on marital and sexual satisfaction for the intervention group com-
pared to the control group (Rowland et al. 2009). It is notable that less than half of
the women who were eligible and randomized to the intervention agreed to partici-
pate. Reasons for declining were mostly due to convenience of sessions and lack of
time. It is not clear what elements of this intervention were most closely aligned with
the improvement in sexual satisfaction, but future work to identify critical elements
and target elements of the intervention to specific sexual health needs could be pur-
sued. Importantly, simplification in the delivery of the intervention to reduce the time
commitment and increase the flexibility of how the intervention is received would be
needed. There are many options today for how people access information and care,
paving the way for true innovation in the delivery of interventions.
Continuing to evaluate pharmacologic interventions where cognitive behavioral
interventions would not be sufficient, such as in vaginal atrophy, is also needed. A
large multi-site trial in the cooperative group system has recently been completed
evaluating vaginal dehydroepiandosterone for symptoms of dryness and dyspareu-
nia. This study included 364 women who reported moderate or greater severity and
bother related to either vaginal dryness or dyspareunia (Clinical Trials.gov identi-
fier NCT01376349). Several measures of sexual health were collected at baseline
and at 12 weeks to explore mediators and moderators of sexual function and body
image. Variables that are being addressed in this study include relationships as
measured with the Revised Dyadic Adjustment Scale (Busby et al. 1995), stress as
measured with the Perceived Stress Scale (Cohen et al. 1983), mood as measured
with the Profile of Mood States (Curran et al. 1995), energy as measured by the
vitality subscale of the SF-36 (Ware 2000), and several outcomes that include func-
tion, physical and cognitive aspects as measured with the Female Sexual Function
9 Symptoms: Menopause, Infertility, and Sexual Health 131

Physiological
Psychological factors Situational Factors
factors

Variable Variable Measured Variable Measured by

by
Past and current Mood POMS Fatigue Vitality
Tx Subscale
Age Stress PSS Partner RDAS
Duration of vaginal
sxs
Presence of
ovaries

Vaginal atrophy (VSQQ) :

Vaginal dryness and/or
dyspareunia (VSM)

Severity (VSM) Distress/Bother (VSM) Quality (VSQQ)

Numeric analogue Numeric analogue scale Incidence of itching,
scale questions questions burning, discharge,
irritation, dry, etc.

Performance

Functional Cognitive
&
Physical

Sexual Intrusive
Function Thoughts/
Negative
Urologic Image
symptoms Adapted from Lenz, ANS, 1997

Fig. 9.1 Framework for the development of a complex sexual health intervention. Theory base is
the Theory of Unpleasant Symptoms, Lenz, Adv. Nursing Science, 1997

Index (Rosen et al. 2000), Urogenital Atrophy Scale (Lester et al. 2012) and the
Impact of Treatment Scale (Frierson et al. 2006). The model guiding this work that
is based on Lenz and is depicted above (Fig. 9.1). Current analyses are ongoing to
explore relationships between the variables in the model and to identify critical
variables that predict body image stress, relationship issues, and sexual function.
This information will add to the already published data on predictors and will
guide future research.
132 D.L. Barton and P.A. Ganz

Fertility Work

To have greater impact on fertility preservation we must focus our efforts on the
delivery of high quality cancer care for breast cancer patients and survivors, who have
a right to be counseled about the likelihood of infertility associated with breast cancer
treatments and to take actions should they wish to do so. In a recent report from the
ASCO Quality Oncology Practice Initiative (QOPI) conducted between 2006 and
2010, adherence to the quality measure of discussing infertility risk of chemotherapy
and discussing fertility preservation, documentation of these conversations in the
medical record was very infrequent and did not improve over several rounds of
assessment, suggesting the QOPI practices did not act on their poor performance
(Neuss et al. 2013). Ensuring that this is a key element of breast cancer survivorship
care, as measured through various accrediting bodies, will be very important.
In addition, to be able to deliver this care prospectively will take investment in
the organizational structures within health systems to provide services in a timely
fashion. For those women who cannot preserve either embryos or oocytes prior to
cancer treatment, it may be possible to address this in the post-treatment period.
Thus, addressing these issues, in much the same way as breast reconstruction may
be handled—either immediately or delayed—may at least give women who missed
the pre-treatment setting an opportunity to engage with reproductive specialists at a
later time. All of this will be facilitated if some of the costs of these services could
be considered as part of cancer rehabilitation. The absolute numbers of individuals
(including men who participate in cryopreservation of sperm) is likely to be very
small, and would add little to insurance benefit plans. This will be an important
policy issue in the future, especially if demand increases as a result of greater pre-
treatment counseling.

Looking into the Future

Key strategies for moving the research forward include the need to (a) individualize
interventions, (b) develop a better understanding of who responds to what interven-
tions and why, (c) understand better the breadth and consequences of premature
aging based on cancer treatment and (d) better understand the role that prevention
can play in preserving fertility, maximizing sexual health and preventing bother-
some symptoms related to menopause.

Individualizing Interventions

Building and evaluating multi-component interventions can occur from two

directions. They can be built, one at a time, with focused interventions being evaluated
in rigorously designed trials; then those demonstrating efficacy, based on a prede-
termined effect sizes, could be added together. Alternatively, several components
9 Symptoms: Menopause, Infertility, and Sexual Health 133

can be evaluated together and if effective, steps could be taken to deconstruct the
intervention to determine whether there are any unneeded elements. Either way,
once a multi-component intervention is determined to be helpful, efforts could be
made to individualize the intervention, based on specific issues. For example, in a
multi-component intervention being built for sexual health, the intervention can
have components (already tested and found effective) to address vaginal atrophy,
sexual energy, relationships, partner communication, and self-image. The specific
intervention for a particular woman, however, would be built from the menu based
on relevant concerns, so that the intervention can be tailored accordingly.

Predicting Response

The ability to understand characteristics of people who respond to an intervention

or parts of an intervention is critical in order to both individualize the intervention
but also to allow others to build on, and apply, the research to other similar popula-
tions. In order to do this effectively, studies would likely need to be large, with
sample sizes over 100, requiring multi-site networks. If studies in symptom man-
agement insist on being powered to only detect large effect sizes and evaluate only
one focused intervention on one narrowly defined outcome, it will not be possible to
either build effective multi-component interventions or do sub group analyses, as it
is unlikely that one single intervention will be strong enough to sufficiently impact
a symptom that has multiple etiologies and is highly influenced by personal charac-
teristics. The reductionist strategy is likely the reason for the many negative trials in
symptom management.
In the research on hypnosis for hot flashes, investigators are evaluating modera-
tors such as hypnotizability and expectancy to understand their influence on the
ability of the intervention to impact the outcomes. In the trial evaluating vaginal
DHEA for dyspareunia and/or dryness, the study design controls for the effect of the
strength of the relationship with the significant other as measured with the
Relationship Dyadic Adjustment Scale to see whether that variable “trumps” the
ability of the intervention to impact sexual health (Clinical Trials.gov identifier
NCT01376349). These types of explorations are important if we are to advance the
science in symptom management in a meaningful way.

Understanding Premature Aging

Although cancer treatments, in particular chemotherapy and radiation, may acceler-

ate the aging process (see especially young adults with cancer), and lead to serious
organ damage that my influence comorbid conditions and competing causes of
death, relatively little is known about premature ovarian failure in this setting.
Studies done by investigators with regard to surgical oophorectomy have shown
134 D.L. Barton and P.A. Ganz

deleterious health outcomes in such women (Rocca et al. 2006; Shuster et al. 2010).
To what extent there may be parallel adverse effects in younger women who become
prematurely menopausal with breast cancer treatments is uncertain. Currently, the
NSABP B-47 trial that is focused on use of trastuzumab or not in the adjuvant set-
ting of women with HER2 low expressing tumors has an embedded host factor
study that is looking at the incidence and prevalence of comorbid conditions, as well
as amenorrhea, in the prospective monitoring of outcomes, and this study should
provide some insight into the added burden that premature ovarian failure may play
in subsequent survivorship outcomes (see ClinicalTrials.gov NCT01275677).

The Role of Prevention

Reducing the untoward effects of cancer treatment on the reproductive health of

breast cancer survivors is the ultimate goal. Two possible prime strategies are to (1)
prevent the overtreatment of women who are not in need of gonadotoxic therapy
with genomic or other prognostic tools, and (2) tailor therapy to meet the prefer-
ences of women who may wish to preserve fertility. For example, in the NSABP
B-30 trial, investigators found that the patients in the treatment arm that did not have
cyclophosphamide had a much lower rate of post-treatment amenorrhea, compared
to the two treatment arms that contained this therapy. The differences in disease-free
survival outcomes between the treatment arms were very small, and thus this alter-
native treatment should be discussed with patients who wish to reduce their risk for
premature ovarian failure (Swain et al. 2010). Similarly, there are encouraging data
that GnRH analogs may offer protection against premature ovarian failure, with a
new large trial from SWOG whose results are pending. Should this be proven effec-
tive, then patient’s should be offered such therapy if they are concerned about future
fertility. The primary prevention assumption we must make at diagnosis is that the
patient will be a survivor, and anticipating this as part of treatment planning is
essential.

Summary/Conclusion

Menopause related to breast cancer, whether prematurely initiated or exacerbated

by the treatment, presents important challenges for women related to daily function,
personal relationships and overall feelings of well-being. Menopause can have con-
sequences that can interfere with usual life/developmental stage goals and that is
perhaps one of the most difficult issues with which cancer survivors cope with in the
long term.
While there is a fair amount of research in the areas of hot flashes, sexual health
and fertility, large, rigorous longitudinal descriptive studies and intervention
research specifically in the breast cancer population are lacking. If research would
9 Symptoms: Menopause, Infertility, and Sexual Health 135

definitively identify physiologic and/or psychosocial targets for treatment, the

evaluation of interventions likely to be beneficial could increase. Further, studies in
the general population can inform testable hypotheses for breast cancer survivors,
but extrapolation is not evidence based.
Symptoms and side effects from breast cancer and its treatment are complex in
that there are numerous physiologic and psychologic effects that overlap, but are
also distinct. Studies to date that have approached the problem from a reductionist
perspective have resulted in less than satisfactory solutions with no or small effects
on outcomes.
From a scientific perspective, it is time to change, (not merely tweak), the
research paradigm. We must be willing to embrace the complexity of the human
condition with our research designs and consider social, psychologic, physiologic,
and environmental influences on the concept of interest (ie: hot flashes, sexual
health, fertility). We must be willing to target more than one etiology and evaluate
complex interventions. It is time to move into study designs that allow for individu-
alization of treatment. More research is needed to provide information on under-
standing response. Perhaps pooled and/or meta-analyses can begin to look at the
question of who responds and why, instead of simply being a means to improve
power to add statistical significance to small or unclear effect sizes. There needs to
be increased research from a systems perspective to define what effect hormone
deprivation has on a woman’s overall physiology, neurology and psychology long
term and understand premature aging effects. Finally, we must think about prevent-
ing unwanted long term sequelae of treatment. Sometimes, that may mean a better
understanding of individual risk/benefit perceptions and decisions at the outset to
avoid treatment that will unnecessarily decrease a woman’s quality of survivorship.
It is in this way that we will be able to make clinically meaningful strides in breast
cancer treatment as we keep an eye on the quality of a woman’s life as a long term
survivor.

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Chapter 10
Host Factors and Risk of Breast Cancer
Recurrence: Genetic, Epigenetic and Biologic
Factors and Breast Cancer Outcomes

Christine B. Ambrosone, Chi-Chen Hong, and Pamela J. Goodwin

Abstract Among women with breast cancer, there is wide variability in outcomes,
both in treatment-related toxicities and disease-free survival (DFS). Primary predic-
tors of DFS are those related to the extent of the disease and tumor characteristics,
associated not only with tumor aggressiveness, but also responsiveness to targeted
therapies. Inherited germline variation may also play a role in cancer treatment out-
comes, and there have been studies targeting drug metabolism and other candidate
pathways as well as genome-wide association studies (GWAS), which take a more
agnostic approach and interrogate hundreds of thousands single nucleotide poly-
morphisms (SNPs) to determine those that modify response to breast cancer treat-
ment. While this field of pharmacogenetics and pharmacogenomics has held exciting
promise for personalized medicine, the results have not been as consistent, or the
effects as profound, as first hoped. An emerging field in studies of cancer prognosis
is epigenetics, which regulates DNA expression and can be influenced by numerous
biologic processes as well as environmental exposures. Although young, this field of
research likely holds promise for understanding of epigenetic mechanisms driving
cancer and cancer outcomes, with a potential to modify these factors through drugs
or other approaches. Finally, circulating markers in blood that reflect some lifestyle
factors have also been studies in relation to cancer outcomes, particularly Vitamin
D. In this chapter, we highlight advances in the areas noted above, and comment on
factors that can impact interpretation of results from observational studies. We also
discuss future directions, and avenues necessary to move the field forward.

Keywords Breast cancer • Prognosis • Tumor heterogeneity • Pharmacogenetics •

Epigenetics • Vitamin D

C.B. Ambrosone, Ph.D. (*) • C.-C. Hong, Ph.D.

Department of Cancer Prevention and Control, Roswell Park Cancer Institute,
Elm & Carlton Streets, Buffalo, NY 14263, USA
e-mail: [email protected]; [email protected]
P.J. Goodwin, M.D., M.Sc., F.R.C.P.C.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital,
1284-600 University Avenue, Toronto, ON, Canada, M5G 1X5
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 143

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_10
144 C.B. Ambrosone et al.

Tumor characteristics impact cancer prognosis, and also indicate treatments to be

given. However, efficacy, as well as side effects of treatment, may be affected by
genetic, epigenetic, and non-genetic factors, as shown in Fig. 10.1.

Breast Cancer Is Not One Disease

Over the last two decades, breast cancer research at the cellular and molecular level
has allowed for better understanding of the extensive heterogeneity of breast cancer,
with wide differences identified between tumors among populations, and also
molecular heterogeneity within tumors. Molecular characterization of tumors has
informed likely prognostic outcomes, and also led to targeted therapies. Tumor
characteristics indicate treatments to be given, but efficacy, as well as side effects of
treatment, may be affected by genetic, epigenetic, and non-genetic factors, as shown
in Fig. 10.1.
Investigations of the estrogen receptor (ER) began in the early 1970s (McGuire
1975; Jensen 1975), and within less than a decade, the anti-estrogen, tamoxifen, was
being used to treat ER positive breast cancer (Fisher et al. 1981). Discovery of the
HER2/neu proto-oncogene in the 1980s and identification of its important role in

Tumor Characteristics
ER, PR, HER2 Modifiable and lifestyle
a Stage, Grade
c
factors Recurrence-free survival
Genetic changes

Treatments Received b Genomic variation

Surgery Pharmacogenetics
Radiation Genes affecting tumor growth and metastases
Chemotherapy Other genetic pathways affecting prognosis
Hormonal therapy
Epigenetics
Methylation of loci affecting cancer outcomes

Fig. 10.1 Factors affecting breast cancer prognosis. (a) Characteristics of the tumor will affect
likelihood of recurrence and metastasis, and will also determine treatments to be given. (b) The
effects of treatments on outcomes may be modified by genomic variation in drug metabolism and
other pathways, as well as epigenetic silencing our activation of important pathways. (c) Treatment
outcomes may also be modified by numerous lifestyle factors, including physical activity, body
size, and dietary factors
10 Host Factors and Risk of Breast Cancer Recurrence… 145

breast cancer prognosis then led to development of trastuzumab, a monoclonal

antibody directed against HER2 (Slamon and Pegram 2001), which has greatly
improved survival for women with HER2 positive breast cancer (Baselga et al.
2006). For many years, testing for ER, progesterone receptor (PR) and HER2 has
guided breast cancer treatments, in addition to standard chemotherapy regimens.
Even with ER+ breast cancer, however, there are notable differences in treatment
outcomes, and additional molecular tests, such as Oncotype Dx recurrence score,
have been used to further stratify patients for adjuvant chemotherapy treatments
(Paik et al. 2004).
Finer classifications of breast cancer subtypes were identified with the advent of
multi-gene arrays and expression analyses (van de Vijver et al. 2002; Perou et al.
2000), and the intrinsic subtypes have been shown to be associated with breast can-
cer prognosis (Carey et al. 2006). Importantly, classifications obtained using these
arrays can be approximated using immunohistochemical (IHC) markers to classify
ER+ breast cancer into Luminal A and Luminal B, with the latter having more pro-
liferative indices and associated with poorer prognosis than Luminal A. Further
refinement of ‘triple negative’ breast cancer (ER−, PR−, HER2−) into basal-like
cancers (ER−, PR−, HER−, ck5/6+, EGFR+) with poorer prognosis is also possible
using IHC markers. More recently, the PAM50 assay, which can now be performed
using formalin-fixed paraffin-embedded tissue, builds upon classifications based on
IHC markers, with reassignment of a fair proportion of tumors to other intrinsic
subtype groups based upon the more detailed analyses, further refining prognostic
estimates (Nielsen et al. 2010; Cheang et al. 2012; Caan et al. 2014).
Recent research from the Molecular Taxonomy of Breast Cancer International
Consortium (METABRIC) in the United Kingdom and Canada, and the NCI-led
Tumor Cancer Genome Atlas (TCGA) Network has provided more comprehensive
portraits of breast cancer, with classifications into subgroups. With fresh frozen
tumor samples from more than 2,000 women with breast cancer, METABRIC
examined copy number and gene expression in discovery and validation sets (Curtis
et al. 2012). Analyzing paired DNA and RNA samples, they identified novel sub-
groups with different clinical outcomes, including a high-risk ER+ subgroup, and a
group with better prognosis whose tumors had no copy number variants. Their work
highlighted a limited number of gene regions that likely harbor ‘driver’ genes. The
next step recommended by the authors is to follow up with sequencing efforts for
mutational profiles, particularly in cancers with no copy number aberrations.
In the TCGA, breast tumor and germline samples were available from 825
patients, and were analyzed on a number of platforms for assessment of copy num-
ber variants, DNA methylation, exome sequencing, messenger RNA arrays, and
analysis of microRNAs and proteins (Cancer Genome Atlas Network 2012).
Combining data from several platforms, tumors were classified into four main
classes, although there was extensive heterogeneity within these groups. In fact,
mutations were more diverse and recurrent in luminal A and luminal B tumors than
within basal-like and HER2 enriched. The most frequently mutated genes in lumi-
nal A tumors were PIK3CA (45 %) and others including MAP2K4, which was also
identified as a key cancer gene in the METABRIC analysis (Curtis et al. 2012). In
146 C.B. Ambrosone et al.

basal-like tumors, 80 % of the cases had p53 mutations. These projects have
provided a wealth of data and information which helps to elucidate breast cancer
subtypes and may also provide clues for therapeutic targets to be followed. The
TCGA study also showed a number of similarities between basal-like tumors and
serous ovarian cancer, suggesting common therapeutic approaches.
This advanced molecular work using a number of platforms supports the initial
classification of the intrinsic breast cancer subgroups, but also points to the signifi-
cant heterogeneity within classes. Further research along these lines will hopefully
not only inform our understanding of etiologic pathways, but perhaps lend guidance
for development of targeted therapeutics. For cancer prevention and control, how-
ever, it is unclear how fine-grained classification of tumors needs to be to categorize
for studies of lifestyle or other interventions. There are a growing number of studies
showing, for example, that PAM50 classifications better predict treatment outcomes
in breast cancer patients than IHC subgroups alone. Would this more refined clas-
sification also better inform studies evaluating the effects of, for example, physical
activity and recurrence? These are studies that will likely need to be done to be able
to best target those most likely to benefit from interventions.

Does Genetic Make-up Influence Recurrence and Survival?

For many years, scientists focused on characteristics of breast tumors as predictors

of cancer outcomes. Although there had been awareness of the concept of pharma-
cogenetics, genetic variability in drug metabolism, from before the 1950s, it was
primarily in relation to adverse outcomes for subsets of the population when being
treated with drugs, such as isoniazid (Weber and Cohen 1968). It is only within the
last two decades that there has been growing interest in the role of genetic variabil-
ity in relation to breast cancer treatment outcomes. Initial studies investigating the
role of genetic variability in relation to treatment outcomes focused on specific drug
regimens and their metabolic pathways, taking a candidate gene approach in path-
ways for cyclophosphamide, anthracyclines and taxanes, with few consistent results
[reviewed in Yao et al. (2012); Westbrook and Stearns (2013)].
The anti-estrogen tamoxifen is metabolized by cytochrome p450 enzymes, with
CYP2D6 primarily investigated because it produces endoxifen, considered to be the
primary activity metabolite responsible for the anti-estrogen activity of tamoxifen
(Hoskins et al. 2009). Initially, there was enthusiastic interest and recommendations
for genotyping for CYP2D6 variants in the clinic to predict drug efficacy and side
effects, with the goal to be able to titrate doses based upon genotypes to enhance
efficacy while reducing adverse outcomes, or for selection of alternate agents. This
may be particularly important when using tamoxifen in a prevention setting among
high risk patients. However, numerous studies have resulted in inconsistent results,
leading to some controversy. In commenting on results from two trials showing null
results, the accompanying editorial stated that “this matter has likely been laid to
rest” (Kelly and Pritchard 2012), but other researchers believe that the lack of
10 Host Factors and Risk of Breast Cancer Recurrence… 147

replication may be due to a number of methodological issues, including use of

tumor DNA and problems with genotyping (Pharoah et al. 2012), as well as poten-
tial confounding by use of other medications that may induce or inhibit CYP2D6,
or other differences in study populations (Stearns et al. 2003). In particular, a num-
ber of serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors
(SNRIs) used to treat depression and hot flashes also inhibit CYP2D6 activity (Jin
et al. 2005; Borges et al. 2006). In breast cancer patients, CYP2D6 inhibition by
co-medication with these drugs results in lower levels of the active metabolite
endoxifen and potentially, reduction of efficacy of treatment with tamoxifen (Goetz
et al. 2007). Although there is drug label information regarding the potential for
drug interactions between tamoxifen and SSRIs and SNRIs, it is likely that these
medications are still prescribed together, and may contribute, in part, to the incon-
sistency in study results regarding CYP2D6 genotypes, tamoxifen, and breast can-
cer outcomes (Binkhorst et al. 2013).
This example (tamoxifen and CYP2D6) illustrates the challenges faced when
hoping to apply pharmacogenetics in a clinical setting to prediction of treatment
outcomes. Here was a drug where there was bountiful data showing the functional
activity of genotype variants and direct associations between genotypes and levels of
the active metabolite. It seemed relatively straightforward to then extrapolate that
there would be associations between genotypes and tamoxifen-related side effects as
well as outcomes. However, results have been disappointing, perhaps due to the com-
plexity of drug metabolic pathways, interactions between tamoxifen and CYP2D6
inhibitors, issues with study design, and heterogeneity of study populations.
Although investigations of drug metabolism pathways and breast cancer out-
comes have not yielded definitive results with direct relevance for the clinic, there
has been great anticipation for the use of genome wide association studies (GWAS)
to identify key genes and/or gene variants that are associated with treatment side
effects and recurrence and survival. Using an agnostic approach, genomic DNA from
patients is genotyped for thousands of single nucleotide polymorphisms (SNPs), and
genomic profiles compared between patients with and without the outcomes of inter-
est. It is clear that not all patients respond similarly to cancer therapy, and it is likely
that genetic variability, in part, plays a role in these differential responses.
GWAS have been used with some success for identification of susceptibility loci
for etiology of a number of cancers, many of which are multifactorial and likely
caused by numerous exposures and genetic variants. Thus, the thinking has been
that genetic factors likely play a large role in differences in experience of grade 3
and 4 toxicities among patients receiving specific chemotherapy agents. Unlike
using a candidate gene approach, GWAS may reveal pathways involved in side
effects and outcomes that may not have been previously hypothesized. For exam-
ple, Ingle and colleagues performed a GWAS to identify SNPs that were associated
with musculoskeletal adverse events (AEs) among breast cancer patients treated
with aromatase inhibitors (AIs) (Ingle et al. 2010). The SNPs identified were near
the T-cell leukemia 1A (TCL1A) gene; follow-up with functional studies revealed
effects of differential TCL1A expression on cytokine receptor genes and on tran-
scription of NF-kB, indicating that the musculoskeletal AEs are related to an
148 C.B. Ambrosone et al.

inflammatory response (Liu et al. 2012). Genetic variability in this pathway had not
been previously hypothesized to be associated with AI-related side effects, and
opens doors for new approaches for prevention of these AEs.
GWAS has also been used to investigate the basis for neurotoxicities often experi-
enced among breast cancer patients treated with taxanes. In a Cancer and Leukemia
Group B clinical trial, the loci identified that were associated with paclitaxel-induced
neuropathy were in genes involved in axon outgrowth (Baldwin et al. 2012; Chhibber
et al. 2014). Although, in retrospect, these findings make sense, they provide a new
perspective or paradigm for pharmacogenetics. Previously, pathways that could mod-
ify the treatment agent effects were investigated, such as drug activation, detoxifica-
tion, and DNA repair. These findings regarding neurotoxicity and SNPs in genes in
axonal outgrowth, as well as the finding for AIs and musculoskeletal AEs, illustrate
the value of GWAS in relation to treatment outcomes. By revealing pathways that
were previously not hypothesized, new targets can be identified for prevention efforts.

The Interface Between Genomics and the Environment

Genomic DNA sequences are inherited, are in every cell in the human body, and
account for a large portion of variations in phenotypes and conditions. Unlike DNA
sequences, however, epigenetics, defined as covalent modifications of DNA base
and chromatic alterations, affect DNA function without altering sequence. The most
commonly studied epigenetic mechanism is DNA methylation, which is known for
its plasticity, and is influenced by genetics as well as external exposures (Bernstein
et al. 2007). DNA methylation is tissue specific, undergoing dynamic changes and
influenced by factors such as aging, smoking, alcohol, and dietary intake (Rakyan
et al. 2011; Langevin and Kelsey 2013; Langevin et al. 2011). There have been a
number of studies of DNA methylation in breast tumors in relation to breast cancer
characteristics, risk factors and prognosis, the majority of which have been per-
formed targeting genes known to be commonly mutated in breast cancer, such as
p16, ER, cyclin D2, RASSF1A, TWIST, RATB and HiN1 (Fackler et al. 2004;
Swift-Scanlan et al. 2011; Tao et al. 2009). More recently, platforms have been used
to examine thousands of loci for methylation. In the Sister Study, using a 27K plat-
form, 250 differentially methylated loci were identified from blood samples that
distinguished women who later developed breast cancer from those who did not (Xu
et al. 2013). Using the same platform, Fackler and colleagues found that DNA
methylation classified tumors into ER positive and ER negative, with 100 methyl-
ated loci significantly associated with disease progression (Fackler et al. 2011). We
recently used the Illumina 450K platform and DNA from African-American and
European American women, and found that methylation classified tumors accord-
ing to ER status (Ambrosone et al. 2014), similar to Fackler et al. We also noted that
there were more differentially methylated loci by race among women with ER nega-
tive breast cancer than those with ER positive disease, suggesting that etiologic
pathways of ER negative breast cancer could differ between racial groups
(Ambrosone et al. 2014).
10 Host Factors and Risk of Breast Cancer Recurrence… 149

With the refinement of approaches to conducting Epi-Genome Wide Associations

Studies (EWAS), it is likely that this biomarker, which incorporates genetic and
biologic factors with environmental exposures, will be used increasingly to estab-
lish risk prediction models and to identify genes that impact the disease process
when altered through methylation. Although still in the early stages, there are also
groups who are studying changes in methylation over time with cancer therapies
and in response to interventions. Because methylation has been shown to differ
between current, ex- and never smokers (Harlid et al. 2014), as well as between
obese and non-obese individuals (Almén et al. 2014), there are hopes that it may
eventually be used to monitor efficacy of interventions to reduce risk of breast can-
cer recurrence. In fact, in a 6 months exercise intervention, DNA from adipose tis-
sue showed distinct methylation differences before and after the exercise intervention
(Rönn et al. 2013). Of interest, the exercise intervention resulted in differential
methylation of 39 candidate genes for obesity and type 2 diabetes. Thus, this marker
holds promise for prognostic studies among breast cancer survivors, particularly to
monitor efficacy of interventions.

Blood Levels of Vitamin D

Host factors that influence prognosis, particularly tumor characteristics and inher-
ited genetic make-up, cannot be modified, but may be used to better understand
survival outcomes. As discussed in other chapters, there are a number of behavioral/
lifestyle factors that may be relevant for prognosis, and could be undertaken among
patients diagnosed with breast cancer to reduce the likelihood of breast cancer
recurrence and poorer survival. Blood levels of 25-hydroxyvitamin D (25(OH)D)
reflect uptake from diet, supplements, sun exposure, and biologic processes, and
may therefore be a better measure for studies of prognosis than assessment of intake.
Goodwin et al. were the first to report an association of Vitamin D blood levels with
breast cancer outcomes (Goodwin et al. 2009); there have been a number of subse-
quent studies examining serum 25(OH)D and breast cancer survival, with somewhat
inconsistent results. Studies conducted outside of clinical trial settings have fairly
consistently identified significant associations of low vitamin D with poor disease-
free or overall survival [reviewed in Rose et al. (2013)], while studies conducted in
the setting of a clinical trial have failed to identify associations of vitamin D with
outcomes (Lohmann et al. 2014; Pritchard et al. 2011). A recent systematic review
concluded that circulating 25-OHD levels “may be associated with better prognosis
in patients with breast cancer,” but the included studies had mixed results (Toriola
et al. 2014). One important issue for assessment of serum vitamin D and breast
cancer outcomes in observational studies, however, is the time during the clinical
course of the disease at which blood samples were drawn. For example, prospective
studies may use blood samples that were drawn prior to the occurrence of breast
cancer, others have used samples that were drawn after surgery but before adjuvant
therapy (Goodwin et al. 2009), and some studies were from well past breast cancer
150 C.B. Ambrosone et al.

diagnosis and treatment, such as in the Health, Eating, Activity and Lifestyle Study
(Villaseñor et al. 2013). The latter design does not allow for examination of associa-
tions of Vitamin D with early breast cancer events (as they have already occurred
before patients are enrolled); this may be of greatest relevance for triple negative
breast cancers that are most likely to recur early. Recently, we examined serum
25-OHD levels in relation to prognosis in a subset of the Pathways Study, a prospec-
tive cohort of breast cancer patients enrolled through Kaiser Permanente Northern
California (Yao et al. 2014). The vast majority of samples were drawn prior to adju-
vant therapy, but after surgery. In these analyses, all women in quartiles above the
lowest had improved overall survival, with the greatest risk reduction among
women in the highest quartile (adjusted HR = 0.57, 95 % CI, 0.37–0.87). Although
there were suggestions of reduced risk of disease-free survival, the point estimate
was weaker and the confidence interval included unity. Another important consider-
ation in interpretation of the Vitamin D—breast cancer prognosis literature is the
differentiation of association from causality. Higher blood levels of Vitamin D may
reflect other factors that impact breast cancer outcomes, including normal body size
and adoption of healthy behaviors (such as outdoor physical activity, balanced diet
and use of supplements) that are the causal basis for the observed association.
Although preclinical evidence supports a potential biologic effect of Vitamin D in
breast cancer, it cannot be concluded that any association of Vitamin D with out-
comes is causal, or that breast cancer patients should take Vitamin D supplements
in the hopes of improving their outcomes.

Conclusion

Research is advancing at a rapid pace to better understand host factors that may
impact risk of recurrence and mortality from breast cancer. With accelerating
knowledge and newer technologies to examine both tumor and host genomes at
the molecular level, the promise of personalized medicine becomes further within
the reach of the breast cancer research and clinical community. With genomic
profiles of tumors, therapies targeting specific mutations may lead to better prog-
nosis, and discoveries of GWAS studies may lead to the right drugs, at the proper
doses, for the right patients, to minimize side effects and enhance treatment effi-
cacy. Use of intermediate biomarkers that reflect both genomic and environmen-
tal exposures will hopefully lead to further understanding of the role of lifestyle,
genetic and non-genetic factors in determination of treatment outcomes among
breast cancer patients. With the growing body of research showing associations
between non-genetic factors, such as body size and physical activity and breast
cancer outcomes, we may be able to incorporate these factors with information on
tumor mutations and inherited genetics to provide a more comprehensive picture
of prognostic factors, and better recommendations for enhancing breast cancer
outcomes.
10 Host Factors and Risk of Breast Cancer Recurrence… 151

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Chapter 11
Comorbidities and Their Management:
Potential Impact on Breast Cancer Outcomes

Chi-Chen Hong, Christine B. Ambrosone, and Pamela J. Goodwin

Abstract Pre-existing comorbidities negatively impacts overall breast cancer

prognosis, increasing both breast cancer specific deaths as well as death from com-
peting causes. Improvements in breast cancer survival in recent decades, however,
have primarily been experienced among cancer patients without comorbidities, and
less so among those with moderate or severe comorbidities. As guidelines for the
treatment of breast cancer are mostly based on studies excluding patients with mod-
erate and severe comorbidities with under-representation of older women with
comorbid conditions, information regarding treatment effectiveness in breast cancer
patients with comorbidities is currently lacking. This chapter describes the impact
of comorbidities on breast cancer treatment and outcomes, previous research
approaches taken, and specific populations that may be most susceptible to the
effects of comorbidities on breast cancer outcomes. Future research directions are
suggested that may help to improve understanding of comorbidity-related factors
that underlie disparities in breast cancer outcomes, and to examine the potential role
of effective management of comorbidities among breast cancer patients as a strat-
egy to help close gaps in disease prognosis.

Keywords Comorbidities • Medications • Breast cancer survival • Competing

cause mortality

C.-C. Hong, Ph.D. (*) • C.B. Ambrosone, Ph.D.

Department of Cancer Prevention and Control, Roswell Park Cancer Institute,
Elm & Carlton Streets, Buffalo, NY 14263, USA
e-mail: [email protected]; [email protected]
P.J. Goodwin, M.D., M.Sc., F.R.C.P.C.
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital,
1284-600 University Avenue, Toronto, ON, Canada, M5G 1X5
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 155

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_11
156 C.-C. Hong et al.

Introduction

Pre-existing comorbidities are increasingly recognized to negatively impact overall

survival in breast cancer patients (Ording et al. 2013; Sogaard et al. 2013; Patnaik et al.
2011a; Ring et al. 2011) and was highlighted as a pressing issue in the most recent
Annual Report to the Nation on the Status of Cancer (Edwards et al. 2013). The nega-
tive impact of comorbidities on breast cancer outcomes is substantial and can be as
important as stage in predicting survival (Patnaik et al. 2011b). Breast cancer patients
with comorbidities are less likely to receive definitive treatment (Louwman et al. 2005;
Griffiths et al. 2014), and have higher overall mortality compared to those without
comorbidities. Similar to the rest of the US population, breast cancer patients bear
substantial comorbidity burdens, particularly as they age, with rates of severe comor-
bidities rising to over 30 % among women age 65 and older (Edwards et al. 2013; Cho
et al. 2013). Rising rates of breast cancer risk factors, such as obesity, metabolic syn-
drome, and reduced levels of physical activity may further contribute to high rates of
comorbidity in breast cancer patients (Guh et al. 2009; Berrino et al. 2014; Hair et al.
2014). Improvements in breast cancer survival in recent decades, however, have pri-
marily been experienced among cancer patients without comorbidities, and less so
among those with moderate or severe comorbidities (Cronin-Fenton et al. 2007; Land
et al. 2012a). As guidelines for the treatment of breast cancer are mostly based on stud-
ies excluding patients with moderate and severe comorbidities with under-representa-
tion of older women, who are more likely to have comorbid conditions (Hutchins et al.
1999), information regarding treatment effectiveness in breast cancer patients with
comorbidities is currently lacking and the potential role that effective management and
control of comorbidities play on breast cancer treatment and outcomes are largely
unknown. This has fueled increasing research attention in the past decade on the impact
of comorbidities on cancer outcomes, and going forward, how these relationships
might be modified to improve disease prognosis among women with comorbid condi-
tions. The goals of this chapter will be to highlight the impact of comorbidities on
breast cancer treatment and outcomes, discuss how comorbidities are being researched
and how this might be expanded, point out specific populations that may be most sus-
ceptible to the effects of comorbidities on breast cancer outcomes, and suggest future
research directions that may improve our understanding of factors that underlie the
disparities in breast cancer outcomes experienced by women with comorbidities and
provide insights into strategies needed to close these gaps in disease prognosis. The
conceptual outline and key points raised in this chapter are presented in Fig. 11.1.

Current Research

Comorbidities and Survival Outcomes

There is ample evidence indicating that breast cancer patients with comorbidities have
poorer overall disease prognosis, which includes increased breast cancer specific
deaths as well as death from other causes (Sogaard et al. 2013; Edwards et al. 2013;
11 Comorbidities and Their Management… 157

Non-cancer Comparison Groups

Breast Cancer
Treatment Quality of Life

Comorbid Control Management

Racial, SES, Age Disparities Conditions Adherence Racial, SES, Age Disparities

Medications

Breast Cancer Competing Cause

Prognosis Mortality

Fig. 11.1 Relationships between comorbidities, breast cancer treatment and breast cancer out-
comes. Comorbid conditions among breast cancer survivors can negatively influence breast cancer
treatment and patient quality of life, increasing breast cancer mortality by 20–50 %, and competing
cause mortality by up to sixfold. The large influence of comorbidities on competing cause mortality
suggests that early stage breast cancer patients are more likely to die from competing causes than
from breast cancer, and that addressing comorbid conditions effectively will be important to further
gains in improving breast cancer prognosis. Research is needed to understand how effective control
of comorbid conditions, as an interplay of management approach, choice of medications used, and
patient adherence to treatment of comorbid conditions, affects breast cancer treatment, quality of
life, breast cancer prognosis, and competing cause mortality, and reciprocally, how a diagnosis of
breast cancer affects comorbid conditions, their management, and control. The influence of specific
comorbidities and various management approaches used to treat these conditions, including choice
of medications used, also needs to be evaluated. These questions are particularly important for
African Americans, older women, and women of lower socioeconomic status (SES) who bear
higher comorbidity burdens, experience worse breast cancer prognosis, and potentially utilize
health care differently compared to the general population. Studies aimed at understanding the pat-
tern of comorbid conditions among breast cancer patients, the larger set of lifestyle and biological
risk factors contributing to these conditions, and their impact on quality-of-life and competing
cause mortality in these women will be strengthened by including comparison samples of women
without a history of breast cancer with similar burdens of comorbidity. This knowledge, particularly
the interplay of factors that contribute to the various breast cancer outcomes, and how relationships
between breast cancer treatment, quality-of-life, breast cancer prognosis, and competing risk mor-
tality are potentially modified by comorbidity and their management will be instrumental in reduc-
ing disparities in disease prognosis experienced by breast cancer patients with comorbidities
158 C.-C. Hong et al.

Patnaik et al. 2011b; Land et al. 2012a, b; Berglund et al. 2012; Bush et al. 2011). In a
US population of older breast cancer patients, women with stage 1 tumor and a comor-
bid condition had similar or poorer overall survival compared with patients with stage
2 cancer and no comorbid conditions (Patnaik et al. 2011a). In a cohort of ~125,000
breast cancer patients aged 65 years of age or older, diagnosed between 1992 and
2005 residing in 11 Surveillance, Epidemiology, and End Results (SEER) areas, the
prevalence of 16 comorbidities that contribute to the Charlson Comorbidity Index
was considerable with 32.2 % of women having 1 or more conditions, similar to the
prevalence (31.8 %) observed among women without breast cancer receiving
Medicare benefits (Edwards et al. 2013). Most women with 1 or more comorbid
condition fell into the severe comorbidity group, which referred to illnesses, such as
congestive heart failure and chronic renal failure that often led to organ failure or
systemic dysfunction requiring adjustments in cancer treatment. Moderate comor-
bidity referred to conditions such as diabetes and vascular disease that sometimes
required modifying cancer treatment, while low comorbidity referred to conditions
that usually did not require adjustments to cancer treatment. Among women aged
66–74 years in this cohort, the probability of dying from breast cancer among those
with severe comorbidities was twofold higher (6 % vs 3 %) than in women without
any comorbidities if diagnosed with local cancer, and 37 % higher (20.2 % vs
14.7 %) if diagnosed with regional cancer. The probability of dying from other
causes in this same group of women was substantially raised, with probabilities of
dying from other causes observed at 23.3 %, 10.6 %, and 5.1 % among women
with severe, low/moderate, and no comorbidities, respectively. As expected,
women diagnosed with distant stage disease were most likely to die of their breast
cancers (≥69 %) regardless of their comorbidity status, although non-breast can-
cer related deaths still accounted for 5 to 20 % of deaths in this group. These find-
ings reported in the 2014 Annual Report to the Nation on the Status of Cancer
(Edwards et al. 2013) underscore previous findings that breast cancer patients with
one or more comorbidities are at substantially increased risk of death from com-
peting causes and at modestly increased risk of breast cancer specific death
(Sogaard et al. 2013; Patnaik et al. 2011b; Land et al. 2012a, b; Berglund et al.
2012; Bush et al. 2011), and that breast cancer survivors who are most likely to be
impacted by comorbidities are women with early stage breast cancer who have
high other cause mortality, who have shown little or modest improvements in
breast cancer specific mortality over time (Edwards et al. 2013; Cronin-Fenton
et al. 2007; Land et al. 2012a; Izano et al. 2014). Findings from over 15 retrospec-
tive cohort studies (Cronin-Fenton et al. 2007; Tammemagi et al. 2005; Yancik
et al. 2001a; Schonberg et al. 2010; Carlsen et al. 2008; Dalton et al. 2007; Janssen-
Heijnen et al. 2005; Louwman et al. 2005, Houterman et al. 2004; Nagel et al.
2004; Maskarinec et al. 2003; Du et al. 2008; Harris et al. 2008; McPherson et al.
2002; Siegelmann-Danieli et al. 2006) suggest that comorbidity increases risk of
competing cause mortality by up to sixfold, while breast cancer specific mortality
is increased by 20–50 % (Patnaik et al. 2011a; Berglund et al. 2012; Schonberg
et al. 2010; Dalton et al. 2007; Du et al. 2008), although some studies have failed
11 Comorbidities and Their Management… 159

to observe differences in breast cancer recurrence or survival (Tammemagi et al.

2005; Braithwaite et al. 2012; Field et al. 2011).
The larger influence of comorbidities on competing cause mortality compared
to breast cancer mortality suggests that most early stage breast cancer patients
with comorbidities will die from competing causes before they die of breast can-
cer, and that the former is a larger contributor to the disparities in overall mortal-
ity observed among these women (Ring et al. 2011). This understanding points to
the overall importance of addressing comorbid conditions appropriately if further
gains are to be made in improving overall survival among breast cancer patients.
To date, most studies examining breast cancer outcomes have focused on breast
cancer related deaths to the exclusion of competing causes of deaths. Given that
most breast cancer patients are diagnosed at an early stage disease due to better
screening efforts, and are expected to have good disease prognosis due to advance-
ments in breast cancer treatments, greater understanding of factors contributing to
high competing-cause mortality in breast cancer patients needs to become an
important research priority (Cho et al. 2013). It should be noted, however, that
although comorbidities in early stage breast cancer patients contributes to higher
mortality rates among breast cancer survivors, these women are no more likely
than the general United States population to die from other conditions (Cho et al.
2013). This comparison, however, may mask the true impact of comorbidities
among early stage breast cancer patients (who often find their cancers through
screening), since these women may be more likely to engage in healthy behav-
iors, have higher socioeconomic status, and show greater access to health care,
including routine physician monitoring for existing comorbid conditions com-
pared to the general population (Cho et al. 2013; Bush et al. 2011). Even among
older women in the SEER-Medicare database, women diagnosed with DCIS or
stage 1 breast cancer have slightly lower mortality than non-cancer controls
(Schonberg et al. 2011). Early stage breast cancer patients should instead be com-
pared to patients without breast cancer who participate in breast cancer screening
programs to determine if early stage breast cancer patients are more likely to die
from other conditions compared to a similar group of women without breast can-
cer. If death rates are found to be higher, this might suggest that further improve-
ments to overall mortality in these patients can be made by reducing deaths due to
other causes among women with early stage disease.
The potential long-term impact of comorbidities in combination with a diagno-
sis of breast cancer on non-breast cancer deaths are also not well understood in
relation to the general population. Very few prior studies include comparisons to
women without a history of breast cancer (Ording et al. 2013; Cho et al. 2013;
Schonberg et al. 2011; Snyder et al. 2013; Hanchate et al. 2010), and virtually
none have matched on comorbidity status to help understand potential differences
in the long-term impact of comorbidities in combination with a diagnosis of
breast cancer in comparison to women in the general population with the same
comorbidity (Ording et al. 2013). Studies including a well-characterized com-
parison group with extended follow-up will help to elucidate key groups at excess
risk for poor outcomes among breast cancer survivors.
160 C.-C. Hong et al.

Effect of Comorbidities During and After Breast Cancer Treatment

Comorbidities may reduce breast cancer specific survival, in part, by reducing the
likelihood that these patients receive guideline recommended treatment (Land et al.
2012b, c; Vulto et al. 2006; Jagsi et al. 2009, 2010; Bouchardy et al. 2007; Harlan
et al. 2009; Ring 2010; Kimmick et al. 2014; Sabatino et al. 2014; Shayne et al.
2006), which in turn, is linked to higher rates of breast cancer recurrence (Lash et al.
2000). The impact is likely to be strongest among those with early stage breast can-
cer since the likelihood of a cure is highest in these women and more dependent on
treatment decisions. Generally, as comorbidity increases, treatment intensity
decreases, including decreased ability to complete prescribed chemotherapy treat-
ments (Lee et al. 2011). Findings from previous studies show that breast cancer
patients with comorbidities are less likely to receive surgery, axillary dissections if
undergoing breast-conserving surgery, radiotherapy, and adjuvant chemotherapy
(Louwman et al. 2005; Griffiths et al. 2014; Vulto et al. 2006; Jagsi et al. 2009,
2010; Harlan et al. 2009; Ring 2010; Kimmick et al. 2014; Sabatino et al. 2014;
Land et al. 2012c; Shayne et al. 2006; Bouchardy et al. 2007; Velanovich et al. 2002;
Stavrou et al. 2012; Dialla et al. 2012; Garg et al. 2009; Ballard-Barbash et al.
1996). Comorbidities have also been shown to predict nonadherence to tamoxifen
and aromatase inhibitors (Hershman et al. 2010), although not in all studies (Hadji
et al. 2013). Certain comorbidities, including congestive heart failure, chronic
obstructive pulmonary disease, osteoarthritis, autoimmune disease, liver dysfunc-
tion, renal disease, and thyroid disorder can elevate risk of developing chemotherapy-
induced febrile neutropenia (Chia et al. 2013; Chao et al. 2014; Hosmer et al. 2011),
which can lead to chemotherapy dose delays and dose reductions (Shayne et al.
2006; Garg et al. 2009). Pre-existing comorbidities can also increase risk of treat-
ment associated comorbidities. For instance, cardiac dysfunction, diabetes, and
hypertension are all associated with greater risk of anthracycline cardiotoxicity
(Lotrionte et al. 2013). An important unanswered research question is whether treat-
ment intensity can be safely increased in those with comorbidities and by how
much, and whether variations exist according to the type of comorbidity.
Guidelines for the treatment of breast cancer are mostly developed on the basis
of findings from clinical trials that exclude patients with moderate and severe
comorbidities, to examine the impact of breast cancer treatments without the effect
of other health conditions that may interfere with treatment or increase the risk of
death. These exclusions mean that participants in randomized controlled trials are
generally healthier than the general population. As a result, there are limited data
available on the impact of comorbidities on treatment complications among breast
cancer patients and the underlying reasons for failure to complete treatment. A
recent study, for instance, that evaluated the impact of self-reported comorbidities
among older women receiving adjuvant chemotherapy for breast cancer while in the
CALGB 49907 and CALGB 361004 clinical trials found comorbidity to be associ-
ated with shorter overall survival, but not with toxicity or time to relapse (Klepin
et al. 2014), possibly because these women all had good functional status with less
11 Comorbidities and Their Management… 161

severe comorbidity at the time of enrollment since eligible patients could not have a
medical condition that would make the protocol hazardous (Klepin et al. 2014).
Greater understanding of the degree to which various comorbidities affect breast
cancer treatment and ultimately breast cancer survival is a research priority, and can
be addressed through both observational studies as well as randomized trials
designed to more broadly examine the potential impact of new breast cancer treat-
ments across the entire targeted patient population.
There are very limited data on the effect of breast cancer and its treatment on the
development of newly diagnosed comorbidities, and whether these incident comor-
bidities are associated with poorer outcomes than in a comparable population with-
out a history of breast cancer. Only a few studies have followed breast cancer patients
longitudinally and assessed comorbidities at more than one time point. Harlan and
colleagues (Harlan et al. 2009) reported that breast cancer patients who received
chemotherapy alone, chemotherapy plus radiation or radiation plus tamoxifen were
2–3 times more likely to develop newly diagnosed comorbidities after breast cancer
diagnosis than women who did not receive radiation, chemotherapy, or tamoxifen,
with arthritis, hypertension and osteoporosis being among those commonly reported
(Harlan et al. 2009). A study of 1,361 five year breast cancer survivors aged 65 and
older compared to women without breast cancer for a 10 year follow-up period,
found that comorbidities included in the Charlson Comorbidity Index were not more
likely to develop in breast cancer patients compared to age-matched women free of
breast cancer, although breast cancer patients were slightly more likely to die in the
10 year follow-up period beginning 5 years after diagnosis (Jordan et al. 2014), sug-
gesting perhaps for a role for more common comorbidities not represented in the
Charlson Comorbidity Index. These findings point to a need to examine the impact
of comorbidities on breast cancer treatment and outcomes more broadly, beyond
those represented in the commonly used Charlson Comorbidity Index.

Impact of Type of Comorbidities

To date most studies examining the link between comorbidities and breast cancer
outcomes have been based on population-based cancer registry data linked with
administrative health insurance claims data, with many studies taking advantage of
data from the SEER-Medicare database. While these studies have been instrumental
for determining the prevalence of comorbidity among older women and their impact
on survival outcomes, they have largely focused on the impact of a few select
comorbidities available in these databases. The most widely used of these indices is
the Charlson Comorbidity Index, along with several adaptations of the Charlson
Comorbidity Index, including the National Cancer Institute Comorbidity Index
(Klabunde et al. 2007). A few studies have also used the Adult Comorbidities
Evaluation Index (ACE-27) (Kimmick et al. 2014; Fleming et al. 2011), which con-
siders a greater number of comorbidities than the Charlson Comorbidity Index and
unlike most measures of comorbidity, considers the severity of each condition with
162 C.-C. Hong et al.

three grades of decompensation (Kallogjeri et al. 2014). The ACE-27 method also
captures obesity comorbidity, hypertension, and a wider range of cardiovascular
diseases not captured by Charlson that may be particularly relevant to breast cancer
outcomes. Despite differences in the number, type, and severity of comorbid condi-
tions captured, however, the Charlson and ACE-27 indices perform similarly in
predicting 2 year overall survival in cancer patients, and models including both
indices produced better predictive models (Kallogjeri et al. 2014). Direct compari-
sons between the Charlson Comorbidity Index and ACE-27, however, have not been
made for breast cancer patients and future research can be directed at testing the
predictive ability of these comorbidity measures individually and together on vari-
ous breast cancer outcomes.
The Charlson score was originally developed in 1987 using medical records to
predict 1 year mortality among hospitalized patients, and was later shown to predict
risk of death from comorbid disease in a 10 year follow-up study (Charlson et al.
1987). Reflecting the original intent of the index to predict short-term mortality, the
16 comorbidities that contribute to the Charlson Comorbidity Score tend to be more
severe, requiring hospitalization, and include myocardial infarction, congestive heart
failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic
obstructive pulmonary disease, connective tissue disease, peptic ulcer disease, type
2 diabetes, chronic renal disease, paralysis, malignant lymphoma, solid tumor, liver
disease and acquired immunodeficiency syndrome (AIDS). Comorbidities are
assigned a weight between 1 and 6, reflecting likelihood of dying from the disease.
This was later expanded to incorporate physician claims in addition to inpatient data
from Medicare files since most individuals will have comorbidities that do not
require hospitalization. This allowed improved prediction of non-cancer mortality
and treatment choice for breast cancer patients after development of condition
weights specific for breast cancer (Klabunde et al. 2000). While the Charlson
Comorbidity Index has been repeatedly shown to be a valid prognostic predictor
among breast cancer patients, the index is based on underlying assumptions more
relevant to short term mortality risk, with very few patients actually having a high
Charlson Index score in most early stage breast cancer populations. Consequently, an
important limitation of the Charlson Index is that the score tends to classify a large
proportion of breast cancer patients as having no comorbid conditions. Nevertheless,
the hypertension-augmented comorbidity index, an extension of the Charlson index,
has been shown to be a significant predictor of overall survival, breast cancer spe-
cific, and competing cause survival in breast cancer patients (Braithwaite et al. 2009).
Also, given dramatic improvements in the prognosis of individuals with AIDS in the
past 20 years, the need for reappraising how AIDS is weighted in the Charlson
Comorbidity Index has been raised (Zavascki and Fuchs 2007). This reassessment
may be particularly important in breast cancer studies focused on women with higher
relative incidence of positive HIV status and AIDS, such as young African Americans
(Center for Disease Control, HIV surveillance report 2010).
Conceivably, certain comorbidities may have different effects on breast cancer
treatment, quality-of-life, and survival outcomes (Louwman et al. 2005; Braithwaite
et al. 2009). Very little research to date has assessed associations between individual
11 Comorbidities and Their Management… 163

comorbid conditions and their impact on breast cancer prognosis (Patnaik et al.
2011a, b; Yancik et al. 2001b), and whether these relationships might be modified
by other prognostic factors such as estrogen receptor status or tumor subtypes.
Studies that have examined specific comorbidities have largely focused on comor-
bidities contributing to the Charlson Comorbidity Index (Patnaik et al. 2011a, b;
Yancik et al. 2001b). Patnaik et al. (2011a) showed in a large cohort of >63,000
breast cancer cases, using SEER-Medicare linked data, that breast cancer patients
with any of the comorbidities comprising the Charlson Comorbidity Index had
lower survival rates compared to patients with no comorbidities, and that liver dis-
ease, chronic renal failure, dementia, and congestive heart failure were associated
with the highest all-cause mortality, while cardiovascular disease, COPD, and dia-
betes, specifically raised breast cancer deaths by 10–25 % (Patnaik et al. 2011a, b),
presumably due to less intensive treatment and/or to direct biologic effects, e.g.
diabetes is associated with reduced likelihood of receiving chemotherapy and
increased glucose and insulin which have been associated with poorer outcomes
(Goodwin et al. 2012; Gold et al. 2014; Peairs et al. 2011).
Generally, cancer patients who report more comorbid conditions report lower
quality of life, including poorer physical and mental health (Smith et al. 2008).
Specific comorbidities have been shown to increase adverse effects of breast cancer
therapy although most of this research has focused on the effects of obesity and
related cardiovascular risk factors (Schmitz et al. 2013). Diabetes for instance is a
risk factor for paclitaxel neuropathy and increased risk of neuropathic pain follow-
ing breast surgery (Lee and Swain 2006; Wilson et al. 2013). Hypertension and
obesity are risk factors for development of heart failure with trastuzumab, and
development of postoperative lymphedema, fatigue and worse functional health
(Schmitz et al. 2013; Helyer et al. 2010; Perez et al. 2008).
The effects of specific comorbid conditions on various breast cancer endpoints,
including quality of life, needs to be further examined, although, going forward,
comorbidities considered should be expanded beyond those in the Charlson
Comorbidity Index to include major chronic health conditions that are highly preva-
lent in the United States’ population (US Burden of Disease Collaborators 2013)
and among breast cancer patients (Piccirillo et al. 2008; Sarfati et al. 2013), includ-
ing obesity, high blood pressure, diabetes, metabolic syndrome, cardiovascular dis-
ease, respiratory disease, and psychiatric diseases. Such research may be aided by
recent development of the Chronic Condition Warehouse (Centers for Medicare and
Medicaid Services, Chronic Condition Warehouse, accessed 10/11/14), which com-
bines Medicare, Medicaid, and Part D Prescription Drug Events data and makes
these datasets available for research. The Chronic Conditions Warehouse was
designed to support studies on improving care for chronically ill beneficiaries and
contains 27 annual chronic condition flags indicating the presence of specific diag-
nostic codes on Medicare claims. These include chronic conditions such as asthma,
anemia, depression, Alzheimer’s, hyperlipidemia, osteoporosis, arthritis, and diabe-
tes. Understanding which comorbid conditions have the greatest impact on breast
cancer specific outcomes may provide insights into common etiological risk factors
shared between the comorbidity and breast cancer, and suggest improved manage-
ment strategies that offer the best gains in disease outcomes.
164 C.-C. Hong et al.

Use of Cancer Registry and Administrative Claims Data

to Study Comorbidities

While use of cancer registry and administrative claims data has helped to define the
link between comorbidities and breast cancer outcomes at the population level, the
scope of questions that can be posed in studying the effects of comorbidity on breast
cancer is constrained by a number of limitations inherent in these databases (Riley
2009). Presently cancer registries do not routinely collect data on comorbidities,
although for some populations, these data can be obtained by linking with Medicare
or Medicaid data, hence the popularity of using linked SEER-Medicare data.
Secondly, as discussed above, a very limited number of comorbid conditions are
usually considered and many of the more common, minor, chronic conditions are
not assessed. Development of the Chronic Condition Warehouse linking Medicare
and Medicaid data, however, can help facilitate the study of how common chronic
conditions impact cancer outcomes. Other challenges include examining the impact
of disease duration and severity, which is difficult to gauge because changes in
claims for a specific comorbidity may be a function of payment rules rather than
variability of the comorbidity over time. Incident disease in claims databases are
hard to identify, and limited availability of clinical information in these databases
means that the underlying reason for service and outcomes are unavailable. Some
conditions, particularly less severe ones, tend to be under-diagnosed and under-
reported in insurance claim data, and comorbidities might be missed if only inpa-
tient care is considered. These include conditions such as osteoporosis, dementia,
arthritis, and low back pain, which are usually treated in outpatient settings, are not
associated with short-term mortality, and often do not require hospitalization.
Patient movement in and out of insurance claims databases may also limit the utility
of these data for prospective comorbidity studies, making populations who do not
have continuous health coverage difficult to study.
If using Medicare data, one problem with studying women close to age 65 will
be that these women have less “at risk” time to appear in Medicare claims. One
study found that 12 % of people enrolled in Medicare at age 65 waited more than 2
years before making their first use of Part B services, which includes medically
necessary services and preventive services (Sloan et al. 2012). Use of SEER-
Medicare data also excludes examination of comorbidities among women who are
diagnosed with breast cancer at younger ages, who are more likely to have aggres-
sive estrogen receptor negative breast cancers. SEER areas are also known to have
lower proportions of Caucasians, to be more urbanized, and to have fewer people
living in poverty, which may make findings less generalizable (Warren et al. 2002).
Future studies on the impact of comorbidities on breast cancer treatment and
outcomes will need to use study approaches that complement findings obtained by
studying large administrative databases, which have not been able to provide data
on the impact of comorbidities on treatment delivery, complications, toxicities, and
patient tolerance of treatments, nor on quality-of-life in these women. Some of these
questions can only be answered with prospective studies of breast cancer patients.
11 Comorbidities and Their Management… 165

Findings from these studies will be able to provide information on the duration and
severity of comorbidities that affect cancer treatment and outcomes, and how these
relationships are potentially modified by management and control of coexisting
conditions. Such studies will also be able to address potential confounders, includ-
ing functional status and lifestyle factors such as smoking, diet, and physical activ-
ity that are not available in most administrative databases. Thus to improve research
on the impact of comorbidity on breast cancer outcomes, an expansion of study
approach is needed along with collection of information from a greater number of
data sources. This includes the use of survey data, administrative data, detailed clin-
ical data, prescription records, and patient medical records from all health care
providers.

Research Priorities

Management and Control of Comorbidities and Impact

on Breast Cancer Outcomes

The majority of breast cancer patients have at least one chronic disease condition at
the time of diagnosis, but management of these conditions may be overlooked dur-
ing survivorship care, leading to poorer outcomes (Weaver et al. 2013). Consequently,
an important research priority will be to determine whether adequate management
and control of comorbid conditions among breast cancer patients is associated with
greater likelihood of receiving guideline-recommended breast cancer treatment,
better quality-of-life, and better survival outcomes, including better breast cancer
survival as well as competing cause survival. Studies, including those using a ran-
domized clinical trial design, are needed to assess the importance of primary care
physician involvement in the care of breast cancer patients with co-morbidities to
ensure that co-morbidities are optimally diagnosed and managed, and to facilitate
collaborative care between the oncologist and primary care provider (Oeffinger and
McCabe 2006) as an essential component of survivorship planning identified in the
2005 Institute of Medicine report From Cancer Patient to Cancer Survivor: Lost in
Transition (Hewitt et al. 2005). Studies using administrative data suggest that breast
cancer survivors who see both their oncologist and primary care providers are more
likely to receive preventive health services such as cholesterol screening, mammo-
grams, and flu vaccination (Snyder et al. 2009), and breast cancer patients who have
5–10 primary care physician visits in the 2 year period prior to their breast cancer
diagnosis have lower breast cancer mortality and all-cause mortality compared to
those who had 0 or 1 primary care physician visit, which was only partly explained
by greater use of screening mammography (Fisher et al. 2013).
The management and control of traditional risk factors for cardiovascular disease
and their impact on breast cancer outcomes will be particularly important to under-
stand since individuals diagnosed with early stage breast cancer will more often die
166 C.-C. Hong et al.

of cardiovascular disease than from breast cancer recurrence (Patnaik et al. 2011b;
Weaver et al. 2013), and cardiovascular risk factors, including obesity, hyperten-
sion, and diabetes are more common among breast cancer survivors than the general
population (Weaver et al. 2013). These comorbidities may be particularly important
among African American women, who have high rates of obesity, hypertension and
diabetes, and may account for some of the survival disparity observed between
African American and Caucasian women (Tammemagi et al. 2005; Braithwaite
et al. 2009; Polednak 2004).
A related research priority will be to understand how breast cancer impacts the
care and control of comorbid conditions, which may include increasing non-
adherence to chronic disease medications. In a study of 1,393 women with breast
cancers who were also statin users (Calip et al. 2013), the percent of women who
were adherent with statin use was 67 % prior to breast cancer diagnosis, fell to 52 %
during the breast cancer treatment period, and remained low in the years that fol-
lowed breast cancer treatment. Similarly, the percent of women adherent with use of
oral type 2 diabetes medications declined from 75 % prior to breast cancer diagnosis
to 25 % during breast cancer treatment, and rose up to 32 % three years post treat-
ment, but never returned to baseline levels. This coincided with declines in glyce-
mic control, with the proportion of women with percent glycosylated hemoglobin
levels (HbA1C) ≤ 7 dropping from 65 % in the year prior to diagnosis to 52 % dur-
ing treatment and 45 % three years post-treatment (Calip et al. 2014). Compared to
adherent users during the breast cancer treatment period, non-adherent users of oral
diabetes medications tended to have higher stage breast cancers, were more likely
to have been treated with chemotherapy, and were more likely to have ≤1 visit to
their primary care provider within the year following breast cancer diagnosis.
A few studies have examined whether breast cancer modifies management of
comorbid conditions among older adults. A recent study found no differences
between breast cancer survivors and age-matched controls, with breast cancer sur-
vivors appearing to have similar or better quality of care (Hanchate et al. 2010).
Snyder and colleagues using the national SEER-Medicare database found that
breast cancer survivors received care comparable to non-cancer controls for both
chronic and acute conditions using indicators of care quality (Snyder et al. 2013).
The study, however, using administrative data was only able to look at the frequency
of visits to health care providers and could not simultaneously assess the degree to
which the condition was medically controlled. Less is understood of the impact of
breast cancer on management of comorbid condition in more disadvantaged groups,
who tend to have higher burdens of comorbidities and simultaneously less access to
health care. Also, whether breast cancer survivors receive comparable chronic dis-
ease care compared to women with similar disease burdens is not clear because
comorbidity has not been consistently used as a matching variable in most studies
(Earle et al. 2003). A large study of >23,000 breast cancer survivors compared to
comorbidity controls (i.e. Chronic obstructive pulmonary disease, congestive heart
failure, diabetes) using SEER-Medicare data, did find that survivors were more
likely to receive preventive care, which included cholesterol screening and influ-
enza vaccination (Snyder et al. 2009). Generally breast cancer survivors as a group
11 Comorbidities and Their Management… 167

receive high-quality health care, at least among older adults with Medicare, with
breast cancer patients displaying enhanced participation in the health care system.
Nevertheless, inequities still exist according to race and socioeconomic status and it
is not clear if breast cancer impacts health care utilization differently in these
groups, and in younger breast cancer survivors, who may have more limited access
to health care compared to older adults with Medicare.

Potential Independent Effects of Medications

An important research priority will be to delineate the mechanism through which

better medication adherence for chronic conditions might improve breast cancer
outcomes, i.e. whether through better control of the comorbid condition, direct
effects of these medications on pathways implicated in breast cancer progression,
and/or better compliance with breast cancer medications/treatment as an extension
of good medication adherence for pre-existing chronic conditions. This is particu-
larly important given emerging evidence that a number of commonly prescribed
medications for chronic conditions may have direct beneficial effects on breast can-
cer outcomes, possibly by modulating pathways necessary for breast cancer pro-
gression (Holmes and Chen 2012; Vaklavas et al. 2011; Vendramini-Costa and
Carvalho 2012; Vinayak and Kurian 2009; Bo et al. 2012). For example, metformin
for treatment of type II diabetes may improve insulin and other metabolic parame-
ters that have been associated with poor breast cancer outcomes (Goodwin et al.
2012); the effect of metformin on breast cancer outcomes and on co-morbidities is
being examined in a fully accrued Phase III trial of 3,649 women with early stage
breast cancer (Goodwin et al. 2011), and has been associated with reduced breast
cancer mortality in population-based studies (Zhang et al. 2013; Hou et al. 2013).
Other medications that may improve breast cancer outcomes include angiotensin-
converting-enzyme (ACE) inhibitors and angiotensin receptor blockers for the
treatment of hypertension and diabetic nephropathy (Mc Menamin et al. 2012;
Barron et al. 2011), statins for the management of dyslipidemia (Holmes and Chen
2012; Ahern et al. 2011; Kwan et al. 2008; Nickels et al. 2013), and aspirin and
NSAIDs for treatment of inflammatory conditions (Holmes and Chen 2012; Kwan
et al. 2007; Blair et al. 2007). This raises the possibility that use of these medica-
tions for management of comorbidities may have direct beneficial effects on breast
cancer outcomes. Thus, comprehensive assessments are needed to simultaneously
evaluate the potential beneficial effects of specific medications against the benefits
of achieving good control of the comorbid condition to determine their relative
importance in improving breast cancer outcomes. To minimize the possibility that
specific medications are erroneously identified as potentially benefiting breast can-
cer outcomes, it may be necessary in future studies to include adjustments for
guideline-concordant breast cancer treatment as a potential confounder (Kimmick
et al. 2014). For some conditions, such as hypertension, better guideline concor-
dance for breast cancer treatment is observed, possibly because these individuals
168 C.-C. Hong et al.

have better access to health care rather than because they achieved better control of
their condition, and this in turn may confound associations suggesting that antihy-
pertensive use improves breast cancer diagnosis (Kimmick et al. 2014).

Comorbidities Among Susceptible Populations

The role of comorbidities on breast cancer outcomes is likely to be most important

for older patients, minorities, particularly African Americans, and women of lower
socioeconomic status, because these women have greater comorbidity burdens than
the general population, are least likely to receive guideline concordant treatment for
their breast cancer (Kimmick et al. 2014), and have poorer disease prognosis (Albain
et al. 2009; Aizer et al. 2014). Hence, improvements to breast cancer outcomes
potentially achieved by better management of comorbid conditions will likely be
greatest among these women, making them a research priority.
The potential impact of comorbidities on breast cancer outcomes is important for
older women since comorbidities become more common with increasing age,
resulting in reduced life expectancy. At the same time, older women are at increased
risk of recurrence from breast cancer, which may be due in part to the larger tumor
sizes found in older women and greater probability of undertreatment due in part to
comorbid conditions (Ring et al. 2011; Bouchardy et al. 2007). While a number of
studies have examined the impact of comorbidity on breast cancer outcomes in
older women, relatively few have examined the role of comorbidity as a mediator
for the survival disparity between younger and older breast cancer survivors. A
recent study of 553 women with metastatic breast cancer found that both hyperten-
sion and higher Charlson Comorbidity Scores were related to worse overall sur-
vival, with hypertension explaining much of the survival disparities observed
between young and older women (Jung et al. 2012). If better comorbidity control is
indeed linked to better breast cancer outcomes in future studies, older breast cancer
patients might be more likely to make positive changes in health behaviors com-
pared to younger women, and may be most likely to benefit from improved care as
younger patients may survive many years regardless of health behavior and adher-
ence to comorbidity treatment (Bush et al. 2011).
African American women may be another group that is strongly impacted by
comorbidities since these women are more likely to have sub-optimally managed
comorbidities because of low medication adherence (Kyanko et al. 2013; Bosworth
et al. 2008), which may decline further during breast cancer treatment (Calip et al.
2013, 2014). African American breast cancer patients have more breast cancer
recurrence/progression and worse all-cause, breast cancer specific and competing
cause survival. A cohort study from the Henry Ford Health System (Tammemagi
et al. 2005) that followed women for a median of 10 years found that over 85 % of
African American had one or more comorbidities at the time of breast cancer diag-
nosis, and several studies have found that comorbidity explains 25–50 % of the
overall survival disparity observed between African Americans and Caucasian
11 Comorbidities and Their Management… 169

breast cancer patients (Tammemagi et al. 2005; Eley et al. 1994). Among African
Americans, comorbidities related to cardiovascular disease, such as hypertension
and diabetes, seem to be particularly important in explaining racial disparities in
overall breast cancer survival (Tammemagi et al. 2005; Braithwaite et al. 2009).
This is important given recent findings that hypertension may be independently
related to overall and breast cancer specific mortality (Braithwaite et al. 2012; Jung
et al. 2012), an effect that can be attenuated when adjusted for antihypertensive
medication (Braithwaite et al. 2012) suggesting that control of comorbidities may
modify associations between comorbidities and breast cancer outcomes. Among
416 African-American and 838 White women diagnosed with breast cancer in the
Kaiser Permanente Northern California Medical Care Program, Braithwaite and
colleagues (2009) found that even after accounting for the effects of age, tumor
characteristics and breast cancer treatment, high blood pressure was associated with
60 % increased risk of recurrence and 49 % increased risk of breast cancer specific
deaths among African Americans with non-significant effects among Whites, and
that this single comorbidity explained 30 % of racial disparities in all-cause mortal-
ity and 20 % of racial disparities in breast cancer specific survival. While these
findings were adjusted for breast cancer treatment, future studies will need to deter-
mine if reductions in treatment intensity, such as chemotherapy dose delays and
dose reductions, can explain these survival disparities.

Summary

Over the past decade the use of cancer registry and administrative claims data has
helped to establish and define links between comorbidities and poorer breast cancer
survival at the population level. Comorbidities have been associated with lower
treatment intensities for breast cancer, and increases in overall, breast cancer spe-
cific, and competing cause mortality. Based on this knowledge, we are now poised
to design comprehensive longitudinal studies to assess the clinical importance of
adequate management and control of comorbid conditions on breast cancer treat-
ment, quality-of-life, and breast cancer outcomes. A comprehensive assessment of
the role of comorbidities before, during and after breast cancer diagnosis and treat-
ment will be critical for developing strategies to improve breast cancer survival.
Findings from such studies will fill current gaps in understanding of how comor-
bidities and their management affect breast cancer treatments and outcomes, and
how relationships between breast cancer treatment, quality-of-life, breast cancer
prognosis, and competing risk mortality are potentially modified by comorbidities.
This understanding could have a major impact on advancing clinical approaches to
breast cancer treatment and survivorship care, with the goal of further improving
breast cancer and overall outcomes. Greater understanding of these relationships
may be particularly relevant among older women, African Americans, and women
of lower socioeconomic status since these women generally have poorer disease
prognosis and higher rates of comorbid conditions.
170 C.-C. Hong et al.

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Chapter 12
Modifiable Lifestyle Factors and Breast
Cancer Outcomes: Current Controversies
and Research Recommendations

Pamela J. Goodwin, Christine B. Ambrosone, and Chi-Chen Hong

Abstract Lifestyle factors, particularly obesity, have been associated with poor
breast cancer outcomes in a large number of observational studies. Despite a grow-
ing body of research, controversy exists regarding obesity associations across
breast cancer subtypes and the importance of obesity versus physical activity and
dietary composition in determining breast cancer outcome. These controversies
are reviewed and the complex biologic nature of the association of obesity with
breast cancer addressed. Potential mediators, including insulin, estrogens, adipo-
kines and inflammation markers are identified. Relevant prognostic findings of
previous research involving dietary, physical activity and weight loss interven-
tions are summarized. A broad-based program of research is outlined, highlighting
the need for a randomized trial of weight loss that is adequately powered to exam-
ine survival effects, as well as correlative and preclinical research to investigate
mediators and mechanisms of obesity effects on breast cancer outcomes. Finally,
potential contributions of alcohol intake and tobacco use in breast cancer survivors
are discussed.

Keywords Breast cancer • Obesity • Subtype • Prognosis • Diet • Exercise •

Research priorities • Biologic mediators

P.J. Goodwin, M.D., M.Sc., F.R.C.P.C. (*)

Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto,
1284-600 University Avenue, Toronto, ON M5G 1X5, Canada
e-mail: [email protected]
C.B. Ambrosone, Ph.D. • C.-C. Hong, Ph.D.
Department of Cancer Prevention and Control, Division of Cancer Prevention and Population
Sciences, Roswell Park Cancer Institute, Elm St, Buffalo, NY 14263, USA
e-mail: [email protected]; [email protected]

© Breast Cancer Research Foundation 2015 177

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_12
178 P.J. Goodwin et al.

Introduction

Women diagnosed with breast cancer often ask whether there are any lifestyle
changes they can make that will improve their breast cancer outcomes, over and
above the benefits of standard medical therapy. There is increasing evidence that
patients who have a healthier lifestyle, notably those who maintain a normal weight
and are more physically active, may have better outcomes than those who have less
healthy lifestyles. Breast cancer diagnosis and treatment has been considered a
“teachable moment,” (Demark-Wahnefried et al. 2005) a time when women are
more receptive to lifestyle change; if outcomes could be improved as a result of
these changes, this may represent an untapped opportunity for clinically significant
benefit. In this article, our primary focus will be on obesity-associated variables
(BMI, physical activity, diet), however, we will also briefly discuss two additional
lifestyle attributes (alcohol intake and tobacco exposure) that are of interest to
breast cancer survivors; tobacco exposure is of particular concern as it can increase
risk of second primary cancers.
A key scientific issue in the area of lifestyle and breast cancer outcome relates
to the tension between the modest prognostic associations of lifestyle factors
that have been seen in observational studies and the paucity of data from ran-
domized trials supporting beneficial effects of adoption of a healthier lifestyle
post-diagnosis. The modestly better outcomes associated with healthier life-
styles (typically a relative improvement of 25–50 %) (Protani et al. 2010) are in
a range that could reflect bias and/or confounding; as a result it cannot be con-
cluded that the observed associations are causal. Even if causal, it is not clear
whether adoption of a healthier lifestyle post diagnosis will improve outcomes,
or whether effects of unhealthy lifestyles are reflected in more aggressive tumor
characteristics at diagnosis that have fixed effects on outcome. Data from well-
designed and conducted, adequately powered, randomized trials that test whether
adoption of a healthier lifestyle improves outcome, would overcome this ten-
sion. Such trials present serious challenges in term of feasibility, cost and dura-
tion but their conduct would generate sufficiently rigorous evidence that lifestyle
change can be recommended to patients. These trials may also identify improve-
ments in non-cancer outcomes, such as cardiovascular disease (the commonest
cause of death in breast cancer survivors beyond 10 years post-diagnosis), or in
quality of life. The latter may be sufficient for some survivors to adopt a health-
ier lifestyle in the absence of effects on breast cancer outcomes. Inclusion of a
spectrum of outcomes, including overall survival, will be important in any
planned trials.
In this article, we briefly review the evidence linking these traditional lifestyle
factors to outcome in breast cancer survivors, highlighting areas of controversy. We
focus on key research priorities and challenges in this area, outlining potential strat-
egies for moving forward.
12 Modifiable Lifestyle Factors and Breast Cancer Outcomes… 179

Current Controversies Relating to Body Size

and Breast Cancer Outcome

Obesity was first reported to be associated with poor breast cancer outcomes in 1976
(Abe et al. 1976). Since then, over 50 studies have examined this association and
obesity has become a recognized adverse prognostic factor. Recent meta-analyses
(Protani et al. 2010; Chan et al. 2014; Niraula et al. 2012) that included studies pub-
lished up to 2011 have provided evidence that the risk of breast cancer specific or
overall mortality is increased by one-third or more in women who are obese com-
pared to those who are normal weight. BMI measured 1 year after diagnosis may be
more strongly associated with outcomes that BMI measured closer to diagnosis (HR
1.29, HR 1.17 respectively per 5 kg/m2) (Chan et al. 2014). Obesity at diagnosis has
been associated with poor outcomes regardless of menopausal status or hormone
receptor status in these meta-analyses (Niraula et al. 2012). Results of some studies
have provided evidence that the association of body mass index (BMI) with progno-
sis may be curvilinear (Goodwin et al. 2002; Suissa et al. 1989). The greatest increase
in mortality is seen in women with BMI ≥ 30 kg/m2; there is a more modest increase
in mortality in those with BMI under 18–20 kg/m2. The basis for an adverse associa-
tion of underweight is poorly understood; it is possible that it may reflect subclinical
metastatic disease, although there is no evidence to support this contention.
Although the associations of BMI with breast cancer outcomes were similar in
the observational studies and randomized trials included in these meta-analyses,
recent post hoc analyses conducted in large, cooperative group randomized clinical
trials (RCTs), have yielded inconsistent results (see Table 12.1), and some investi-
gators have suggested that obesity associations may be present only in women with
hormone receptor positive breast cancer (Pan et al. 2014; Sparano et al. 2012). If
correct, this would have implications for potential weight loss intervention trials in
breast cancer survivors and for the selection of participants and identification of
subgroup hypotheses to be tested in such trials.
Recent RCT based analyses of prognostic associations of BMI in ER+ breast
cancer include reports that high BMI was associated with poor outcome in the
ATAC and BIG 1-98 trials (Sestak et al. 2010; Ewertz et al. 2012) which involved
only women with ER+ breast cancer receiving tamoxifen or aromatase inhibitors.
Analysis of completed ECOG (E1199, E5188) (Sparano et al. 2012) and NSABP
studies (B30, B38) (Cecchini et al. 2013) as well as a recent meta-analysis con-
ducted by the Early Breast Cancer Clinical Trialists Collaborative Group (Pan et al.
2014) also identified an increased risk of recurrence or death in obese (vs. non-
obese) women with hormone receptor positive breast cancer (premenopausal only
in the latter). A meta-analysis involving 8,874 women enrolled onto seven German
adjuvant trials identified adverse prognostic associations of BMI in hormone recep-
tor positive cases (Pajares et al. 2013). These results are consistent with results of
earlier meta-analyses (Niraula et al. 2012).
Results of similar post hoc RCT analyses in women with hormone receptor
negative, triple negative or HER2 positive breast cancer have been less consistent.
North American investigators, using data from both ECOG (Sparano et al. 2012)
180 P.J. Goodwin et al.

Table 12.1 Recent inconsistent results of BMI—prognostic associations

Citations Setting n Results
HR-
Pajares et al. (2013) 2013 GEICAM RCTS 1,502 Worse OS, BCS if BMI > 35
(all anthracycline)
Cecchini et al. 2013 NSABP RCTs Not stated No difference in recurrence,
(2013) OS by BMI
Pan et al. (2014) 2014 EBCTCG 19,618 No difference in BCS
TN
Turkoz et al. (2013) 2013 Non RCT 193 Worse DFS, OS in obese
(Turkey)
Sparano et al. (2012) 2012 ECOG RCTs 878 No difference in DFS, OS by
(all anthracycline) BMI
Fontanella et al. 2013 Neoadjuvant RCTs 1,570 Lower pCR, worse DFS, OS
(2013) (Germany) in obese
(BSA capped at 2.0 m2 in 3 of
7 trials)
HER2+
Turkoz et al. (2013) 2013 Non RCT 238 No difference in DFS, OS by
(Turkey) BMI
Pajares et al. (2013) 2013 GEICAM RCTs 830 Worse OS if BMI > 35
n/s Worse BCS if BMI > 35
Crozier et al. (2013) 2013 RCT 3,017 DFS worse in OW, OB
(N9031)
Mazzarella et al. 2013 Non RCT 1,250 ER neg: OS, DFS worse in OB
(2013) (Italy) ER pos: No difference in OS,
DFS
Sparano et al. (2012) 2012 ECOG RCTS 940 No difference in DFS, OS
Abbreviations: RCT = randomized clinical trial; OS = overall survival; BCS = breast cancer sur-
vival; pCR = pathologic complete response; DFS = disease free survival; BSA = body surface area;
n/s = non significant; ER = estrogen receptor; neg = negative; pos = positive; BMI = body mass
index; ECOG = Eastern Oncology Co-operative Group; GEICAM = Spanish Breast Cancer
Research Group; EBCTCG = Early Breast Cancer Trialists Co-operative Group; NSABP =
National Surgical Adjuvant Breast and Bowel Project

and NSABP (Cecchini et al. 2013) RCTs (E3189, B30, B31, B34, B38) failed to
identify significant prognostic associations of BMI in those with hormone receptor
negative breast cancer. In contrast, Fontanella et al. (2013) identified adverse prog-
nostic associations of obesity in women with triple negative breast cancers partici-
pating in a group of German neoadjuvant RCTs (chemotherapy dose was capped at
2.0 m2 in three of these trials; this may have contributed to adverse obesity associa-
tions) while Pajares et al. (2013) identified worse overall and breast cancer specific
survival in triple negative breast cancer patients with BMI > 35 kg/m2 enrolled in a
series of GEICAM RCTs. In HER2 positive patients, a significantly worse outcome
in heavier women with HER2+ breast cancer was identified in two RCTs; (Pajares
et al. 2013; Crozier et al. 2013) in an observational study, Mazzarella et al. (2013)
identified a similar association that was present only when cancers were also estro-
gen receptor negative. In contrast, Sparano et al. (2012) and Turkoz et al. (2013)
12 Modifiable Lifestyle Factors and Breast Cancer Outcomes… 181

identified no associations of BMI with disease-free or overall survival in women

with HER2+ breast cancer enrolled onto RCTs or an observational study.
In summary, adverse associations of BMI with breast cancer outcomes have been
repeatedly reported in all breast cancer subtypes. It is not clear whether the incon-
sistency of recent data may relate to differences in study design (discussed below)
or to true biologic differences in BMI associations across breast cancer subtypes.
The latter should be explored in preclinical studies and in adequately powered clini-
cal datasets that include a full, and representative, spectrum of breast cancer patients.
The more consistent results reported in ER+ breast cancer may reflect, at least in
part, higher estrogen levels in obese postmenopausal women, leading to enhanced
signaling through estrogen pathways in obese women. Because BMI is associated
with prognosis in women receiving tamoxifen and aromatase inhibitors (Sestak
et al. 2010; Ewertz et al. 2012), these treatments do not appear to fully overcome
effects of higher BMI, suggesting that other obesity associated factors, such as insu-
lin or inflammatory mediators, contribute to the BMI-prognosis association in these
patients.
The less consistent results in triple negative breast cancer in particular may
reflect capping of BMI at arbitrary levels (e.g. 2.0 m2, 2.2 m2) when calculating
chemotherapy doses [a practice that has been less common in recent years and
avoided in modern RCTs and advised against in a recent American Society of
Clinical Oncology guideline (Lyman and Sparreboom 2013)], leading to BMI asso-
ciations that reflect under-treatment rather than biologic effects in earlier studies.
This practice may have had the greatest impact in triple negative breast cancer in
which chemotherapy is the primary adjuvant approach, and targeted treatments,
which may overcome effects of under-dosing to some extent, are not available. The
observation that BMI is associated with prognosis in recent cohorts and RCTs that
avoided dose capping suggest these factors do not fully account for BMI associa-
tions. One alternative explanation is that the underlying aggressiveness of advanced
triple negative breast cancers in some studies, leading to poor outcomes, may be
associated with reduced prognostic impact of obesity.
Different temporal patterns of relapse of ER+, triple negative and HER2+ breast
cancers and differing durations of follow-up in reported studies are unlikely to be
the primary cause of inconsistent results—for example, our group has demonstrated
that obesity effects are constant in periods up to 5 years, and 5–10 years and beyond
in a long-term prospective study (Goodwin et al. 2012).
Inclusion of locoregional events (which contribute a greater proportion of events
in the modern era of breast conserving therapy and effective systemic adjuvant ther-
apies) in outcome measures in recent trials may have introduced noise and led to
reduced power in some studies as these events have not been associated with BMI
(Ewertz et al. 2012). The analysis of BMI as a categorical (vs. continuous) variable
in statistical analyses, or the modelling of associations as linear (vs. quadratic which
allows a curvilinear association which has been demonstrated in several studies)
may also have reduced power. Importantly, power to detect associations may have
been lower in subsets of receptor negative, triple negative and HER2+ breast cancer,
due to smaller numbers of these cancers in some RCTs.
182 P.J. Goodwin et al.

It is also possible that unappreciated differences in the study populations contrib-

uted to inconsistencies. Many of the earlier observational studies were population or
institution based and included all women diagnosed with breast cancer, regardless
of the presence or absence of associated medical conditions. Many recent RCTs
involved cardiotoxic medications (e.g. anthracyclines, HER-2 targeted agents) and
women with cardiac morbidity (or cardiac risk factors such as hypertension, dyslip-
idemia, diabetes) were commonly excluded, either explicitly through entry criteria
or as a safety precaution by physicians (and patients) wanting to avoid cardiotoxic-
ity of unproven treatments. In trials involving taxanes, women with diabetes were
often excluded because of the need for steroid pre-medications; they may also have
been less likely to be enrolled because of concerns about neurotoxicity. Cardiovascular
disease, dysglycemia, hyperlipidemia and hypertension are components of the insu-
lin resistance (or metabolic) syndrome; (Alberti et al. 2009) physiologic compo-
nents of this syndrome (e.g. insulin, glucose, inflammation) may mediate the
association of obesity with breast cancer outcomes (see below) and it is possible
these recent trials preferentially enrolled metabolically healthy women who do not
have the physiologic attributes that mediate obesity-breast cancer associations. This
selection process has not been investigated in a breast cancer population, however,
Kramer et al. (2013) have shown that obese individuals in the general population
with any one of hypertension, abnormal lipids, central obesity, abnormal glucose/
diabetes or high C-reactive protein (CRP—a marker of inflammation) have signifi-
cantly higher greater levels of insulin resistance [reflected by homeostasis model
assessment (HOMA) scores] than those who do not have any of these attributes.
This issue is of relevance not only to understanding the inconsistency of recent
reports; it could also impact the design of weight loss intervention trials in breast
cancer survivors. If adverse associations of BMI are present only in metabolically
unhealthy women, such trials should be designed to enrich for this population.
Thus, although the associations of obesity with outcome may truly differ
across breast cancer subtypes, adverse associations have been repeatedly identi-
fied in all subtypes. Design differences across studies may have contributed to the
identified inconsistencies.

Obesity Versus Physical Activity

Body size reflects the net balance of energy intake vs. energy expenditure. Energy
expenditure occurs as a result of resting metabolism, dietary thermogenesis and
physical activity—changes in the latter (occupational and/or recreational) can help
to regulate body size. Understanding the relative contribution of obesity vs. physical
activity has potential implications for intervention research and patient care—for
example, is physical activity in the presence of overweight or obesity sufficient to
improve breast cancer outcomes? Overweight women who are physically active
have cardiovascular outcomes similar to normal weight women—is the same true
for breast cancer prognosis?
12 Modifiable Lifestyle Factors and Breast Cancer Outcomes… 183

The association of physical activity, undertaken either before or after breast

cancer diagnosis, with breast cancer specific or overall mortality has been examined
in over 15 studies. Ballard-Barbash et al. (2012) recently reviewed this evidence.
Modest, largely non-significant associations of pre-diagnosis physical activity with
reduced breast cancer specific or overall mortality were identified (the point esti-
mate of the HR of death was between 0.5 and 1 in virtually all studies). A somewhat
larger proportion of studies reported greater physical activity post-diagnosis to be
associated with reduced overall mortality; again, HRs were in the range of 0.5–1
and were not always significantly different from 1. There was little evidence that
physical activity associations differed by menopausal status, tumor stage, hormone
receptor status, comorbidity, race or ethnicity, or BMI (although variable BMI sub-
group effects have been reported, with stronger and weaker effects seen in obese
women in different studies). The available data are not sufficient to conclude a
causal association exists. They may reflect (1) greater physical activity in otherwise
healthy women (reverse causation bias), (2) a recall bias when physical activity is
reported years after breast cancer diagnosis, or (3) adverse effects of more toxic
therapy given to women with higher risk of recurrence leading to lower levels of
physical activity, rather than a causal effect of physical activity on breast cancer
outcomes.
Small randomized trials of physical activity in breast cancer survivors have dem-
onstrated beneficial effects of physical activity on quality of life, treatment toxicity
and fitness. Some have examined effects of physical activity on a number of bio-
markers. Consistent improvements (significant or marginally significant) have been
seen in biomarkers of the insulin pathway (including insulin-like growth factor-1)
after physical activity interventions; these improvements may be greatest in obese
and/or sedentary women. Weaker effects have been seen on markers of inflamma-
tion (CRP or interleukin-6) and circulating levels of markers of cell mediated immu-
nity. In one trial that compared effects of physical activity alone versus dietary
restriction with or without physical activity in healthy women, changes in key bio-
markers postulated to mediate the obesity-breast cancer prognosis association
(insulin, hsCRP, estrogens) were significantly greater in either dietary intervention
arm were greater than in the physical activity only arms (e.g. insulin and estrogen
decreased >20 vs. <5 %), suggesting dietary restriction leading to weight loss may
be key to the link with breast cancer outcomes (Mason et al. 2011; Imayama et al.
2012; Campbell et al. 2012; Abbenhardt et al. 2013).
These observations suggest that physical activity may be most relevant as a con-
tributor to weight management (where it may be most important in maintenance of
weight loss) rather than as an independent predictor of outcome, however, they do not
preclude an independent effect, particularly in women who are metabolically healthy
but overweight, in whom changes in the metabolic factors discussed above may not
be key mediators of a physical activity-prognosis association. Future observational
and intervention research into physical activity associations with breast cancer out-
comes should be prospective, use validated comprehensive assessments of physical
activity, and should examine potential contributions of different types (e.g. aerobic,
resistance), intensity and duration of physical activity. This research should include
184 P.J. Goodwin et al.

embedded correlative studies that prospectively examine effects of physical activity

on key biomarkers (discussed below), notably insulin related factors (Ballard-Barbash
et al. 2012; Lof et al. 2012), that may mediate physical activity associations with
obesity and breast cancer outcomes. Finally, although sedentary behavior, indepen-
dent of physical activity, may be associated with risk of some cancers (e.g. colorectal)
sedentary behavior has not been examined in relation to breast cancer prognosis; this
issue could also be addressed in prospective studies of physical activity.

Does Dietary Composition Contribute to Breast Cancer

Outcomes?

Caloric intake exceeding energy expenditure contributes to obesity; reduction in

caloric intake is a key component of weight loss interventions. It has also been sug-
gested that dietary composition, particularly dietary fat content, may be linked to
breast cancer outcomes, independent of total caloric intake. Two randomized trials
(Chlebowski et al. 1992; Pierce et al. 2007) conducted in the mid to late 1990s
examined the effects of (1) dietary fat reduction in isolation or (2) a complex dietary
intervention that included reduction in fat intake, increases in fruits, vegetable and
grains (See Table 12.2).
The Women’s Intervention Nutrition Study (WINS) (Chlebowski et al. 1992)
randomized 2,437 postmenopausal women within 1 year of breast cancer diagnosis
to a 15 % fat diet or a control arm. At 12 months, intervention subjects lowered fat
intake significantly and lost a mean of 2.1 kg (2.8 %) while control subjects gained

Table 12.2 Differing designs and results of the WINS vs. WHEL RCTs
WINS (Chlebowski et al. 1992) WHEL (Pierce et al. 2007)
Population
Number 2,437 3,088
Enrollment period Up to 1 year post diagnosis Up to 4 years post diagnosis
Menopausal status Post Pre and post
Age 48–79 18–70
Intervention group
Fat intake Reduction maintained Transient reduction
Weight change 2.3 kg (3.2 %) relative loss Modest weight gain
DFS All HR 0.76 (0.60–0.98) HR 0.96 (0.80–1.14)
ER- HR 0.58 (0.37–0.91)
ER+ HR 0.85 (0.63–1.14)
BMI < 25 kg/m2 HR 0.83 (0.54–1.27)
BMI 25–30 kg/m2 HR 0.77 (0.51–1.18)
BMI > 30 kg/m2 HR 0.66 (0.41–1.0)
Abbreviations: WINS = Women’s Intervention Nutrition Study; WHEL = Women’s Healthy Eating
and Living Study; DFS = disease free survival; ER = estrogen receptor; BMI = body mass index;
HR = hazard ratio
12 Modifiable Lifestyle Factors and Breast Cancer Outcomes… 185

a mean of 0.2 kg (0.3 %). At 60 months, a significant improvement in relapse-free

survival was identified (HR 0.76, 95 % CI 0.6–0.98, 2-tailed p = 0.034) in women
randomized to the reduced fat diet. In unplanned subset analyses, this effect appeared
to be greatest in patients with ER- cancer (HR 0.58, 95 % CI 0.37–0.91, p = 0.018
vs. HR 0.85, 95 % CI 0.63–1.14, p = 0.277 in ER+ women) and in those with the
highest BMI (HR 0.83, 95 % CI 0.54–1.27; HR 0.77, 95 % CI 0.51–1.18; HR 0.66,
95 % CI 0.41–1.0 for BMI < 25, 25–30 and ≥30 kg/m2, respectively). In contrast, the
Women’s Healthy Eating and Living Study (WHEL) (Pierce et al. 2007) random-
ized 3,088 pre- and postmenopausal women up to 4 years post-diagnosis to a com-
plex dietary intervention that included reduced intake of fat and increased intake of
fruit, vegetables and grains. Effects of the intervention on diet were greater at 12
months than at 72 months. There was no evidence of weight loss in the intervention
group and there was no effect of the intervention on disease-free (HR 0.96, 95 % CI
0.81–1.14) or overall survival (HR 0.91, 95 % CI 0.72–1.15) at 5 years.
Although there were multiple differences between these two studies, including
the nature of the intervention and interval post diagnosis allowed for enrolment,
both involved reduction in dietary fat and only the WINS study identified a signifi-
cant benefit. It has been postulated that this may reflect the weight loss observed in
women in the WINS study; it is also possible that early recurrences in ER negative
women were missed in the WHEL study. The WINS intervention has not been
incorporated into clinical practice; total caloric intake rather than fat intake has been
the focus of more recent intervention research.
Observational research has failed to identify consistent associations of specific
dietary composition (e.g. saturated vs. unsaturated fats, protein sources, types of
carbohydrates and fiber) with breast cancer outcomes (Kampman et al. 2012). A
recent analysis of diet quality in women participating in the Women’s Health
Initiative who developed breast cancer provided evidence that better diet quality
was associated with reduced overall mortality and non-breast cancer related mortal-
ity; it was not associated with reduced breast cancer mortality (George et al. 2014).
These results underscore the importance of differentiation of associations with
breast cancer vs. non-breast cancer deaths is essential in lifestyle studies. Although
improvement in overall survival in breast cancer survivors is clearly of interest, it is
unlikely that the impact of diet composition on non-breast cancer related outcomes
differs in these survivors compared to the general population. Confirmation of this
would allow data generated in the general population to be applied to breast cancer
survivors, at least in relation to non-breast cancer outcomes.

Biologic Mediators of the Obesity-Prognosis Association

The biologic basis for the obesity-cancer relationship is likely multifactorial, with
inter-related contributions of multiple factors whose individual contributions may
vary across breast cancer subtypes (Goodwin and Stambolic 2015). Enhanced
insight into the biology of this association would advance understanding of the
186 P.J. Goodwin et al.

differential contributions of obesity, physical activity and excess caloric intake to

breast cancer outcomes and it would contribute to resolution of controversies regard-
ing differential effects in breast cancer subtypes. This insight will come from pre-
clinical as well as clinical research, including RCTs of weight loss interventions.
Obesity is a complex physiologic state that is commonly associated with the meta-
bolic syndrome (particularly when the obesity is centrally located). The metabolic
syndrome (Alberti et al. 2009), also known as the insulin resistance syndrome, is
characterized by high levels of insulin due to insulin resistance (insulin levels may fall
after diagnosis of diabetes as the pancreas fails), dysglycemia (with frank hyperglyce-
mia when diabetes is present), dyslipidemia (high total and LDL cholesterol, low
HDL cholesterol), hypertension and a chronic inflammatory state (which is commonly
evaluated using hsCRP, a systemic marker of chronic inflammation), however, these
patterns are not present to the same extent in all overweight or obese individuals.
Obesity is also associated with inflammation within adipose tissue (including in the
breast) which may lead to high local levels of cytokines, adipokines (such as leptin)
and other inflammatory factors (e.g., TNF-alpha), resulting in a pro-carcinogenic
state; these factors may also be elevated systemically. Together, these factors activate
many biologic processes associated with cancer progression (Goodwin and Stambolic
2015; Gilbert and Slingerland 2013), including growth pathways (e.g. PI3K, ras-raf-
MAPK, JAK-STAT) and cell metabolism (e.g. shunt from oxidative phosphorylation
to aerobic glycolysis, the Warburg effect). Many of these biologic correlates of obe-
sity (e.g. insulin, glucose, insulin resistance reflected by HOMA, leptin, hsCRP) have
been associated with poor breast cancer outcomes (Hazard Ratios for risk or recur-
rence or death of 1.5–3 after adjustment for traditional prognostic factors) and it is
possible they interact to mediate the association of obesity with poor outcomes.
Higher circulating estrogen levels present in obese postmenopausal women may also
contribute to poor outcomes although their effects may be reduced by the administra-
tion of hormonal interventions such as tamoxifen and aromatase inhibitors.

Putting It All Together: Weight Loss Through Lifestyle Change

Recent focus has shifted from isolated dietary or physical activity interventions to
more comprehensive interventions designed to promote weight loss through reduc-
tion in caloric intake, increases in physical activity and behavioral counselling to
promote adherence to lifestyle change. Small intervention trials have demonstrated
the feasibility of weight loss in breast cancer patients; face to face and remotely
delivered (telephone, mail) interventions have been tested (Reeves et al. 2014;
Goodwin et al. 2014; Rock et al. 2013). Both approaches lead to weight loss that is
comparable to similar interventions in other populations (Pi-Sunyer et al. 2007)—
the degree of weight loss is approximately 5 % using older approaches and up to
7–10 % using more intensive approaches developed in the last 5 years. A key con-
cern in all of these interventions is maintenance of weight loss; in most studies there
is modest regain beginning after the first year, although differences between inter-
vention and control groups persist to 2 years and longer.
12 Modifiable Lifestyle Factors and Breast Cancer Outcomes… 187

There is major interest in the conduct of well-designed and adequately powered

trials that will formally test the impact of lifestyle based weight loss after breast
cancer diagnosis on breast cancer outcomes. Two such trials are underway in Europe,
one testing a lifestyle based approach to weight loss (Rack et al. 2010) and the other
a Mediterranean diet (Villarini et al. 2012), however it is unclear whether they are
adequately powered for breast cancer outcomes. Key issues in the design of such
trials include the expected magnitude of weight loss given currently validated inter-
vention approaches (and whether it is sufficient to impact breast cancer outcomes),
the target population (e.g. inclusion of overweight vs. obese women only, incorpora-
tion of an attribute of poor metabolic health into inclusion criteria), the potential for
differential effects in breast cancer subtypes as well as the optimal method of deliv-
ery of the intervention (in person, remote, web-based) and the intervention intensity
and duration needed to achieve lasting weight loss (2 years is considered a mini-
mum). Available data suggest that the degree of weight loss seen with intensive
lifestyle interventions will result in changes in potential biologic mediators that
could yield clinically relevant improvements in breast cancer outcomes. For exam-
ple, a weight loss of 10 % has been associated with a reduction in insulin of 20–22 %;
(Mason et al. 2011) if this proportionately reversed the reported association of insu-
lin with breast cancer outcome (Goodwin et al. 2002) a clinically important 24 %
reduction in relative risk of distant recurrence (HR 0.76) could be seen.
It is essential that weight loss intervention trials powered to examine effects on
breast cancer outcomes include measurement of a full range of tumor characteristics
including breast cancer subtype and evidence of activation of signaling pathways
that may be targets of the altered physiology resulting from a weight loss interven-
tion (e.g. PI3K pathway activation may reflect high insulin levels that can be reduced
by weight loss) as well as obesity associated physiologic mediators. The resulting
information would greatly enhance our understanding of the obesity—prognosis
relationship. It might also facilitate the development of targeted therapies. Metformin
is one such therapy that is being tested in the breast cancer adjuvant setting (Goodwin
et al. 2011), based in part on its ability to lower insulin and other components of the
insulin resistance syndrome that have been associated with poor breast cancer
outcomes.
Despite the many challenges, it is essential that these trials be conducted in order
to obtain high quality evidence for (or against) the benefits of weight loss in breast
cancer patients that will lead to clear recommendations for breast cancer survivors
and, ideally, to funding of effective lifestyle interventions by third party payers.

Obesity: Breast Cancer Research Priorities

Major research priorities include a range of observational, interventional, transla-

tional and preclinical research studies that would ideally be conducted in parallel,
with the primary goal being to develop strategies that will improve breast cancer
outcomes (see Table 12.3). The available evidence is sufficiently strong that the
188 P.J. Goodwin et al.

Table 12.3 Obesity and breast cancer outcomes: five top research priorities
1. Association of obesity with prognosis across breast cancer subtypes/treatments
a. Modern prospective population/registry based studies that include subjects regardless of
metabolic health—adequately powered across subtypes, with full data on key co-variates
(tumor, treatment including BMI used for dosing, objectively measured height and weight),
reliable data on outcomes (locoregional, distant recurrence, death including cause) and
potential to examine associations over time post-diagnosis
b. Investigation of impact of RCT entry criteria related to cardiac disease, diabetes on
metabolic profiles of selected individuals
2. Relative contributions of obesity and physical activity to breast cancer prognosis
a. Prospective prognostic studies including (i) serial, objective measurement of BMI, diet and
physical activity (e.g. using accelerometers) in patients recruited at breast cancer diagnosis,
(ii) full co-variate, treatment and outcome data (see #1) and (iii) inclusion of translational
research into mediators/predictors of associations (collection of tumour tissue and serial
blood samples)
b. Intervention research to examine effects of weight loss (diet with or without physical
activity) versus physical activity alone (overall, aerobic, resistance) on potential prognostic
mediators in the presence/absence of standard breast cancer therapies
3. Definitive RCT of impact of an optimal weight loss intervention on breast cancer outcome
a. Adequately powered to identify clinically relevant HR, rigorous weight loss intervention
using optimal weight loss approaches
b. Serial measurement of changes in weight, diet, physical activity
c. Embedded correlative research—serial blood specimens, tumor tissue designed to elucidate
biologic processes and to identify predictors of weight loss benefit
4. Identification of biomarkers of obesity—prognosis association
a. Host markers—blood and adipose tissue factors associated with obesity that may mediate
prognostic associations (e.g. insulin, glucose, HOMA, adipokines, inflammatory factors),
DNA methylation patterns; focus on joint/interacting effects
b. Tumor markers—pathways that may be impacted by prognostic mediators, traditional
breast cancer characteristics
5. Pre-clinical investigation of obesity-breast cancer association
a. Development of clinically relevant models of host and cellular metabolism that include the
range of breast cancer subtypes
b. Identification of potential host and tumor markers of prognostic effects, including
evaluation of potential differences across racial/ethnic groups
c. In vivo modelling of weight loss, physical activity and dietary interventions
Abbreviations: BMI = body mass index; RCT = randomized controlled trial; HOMA = Homeostasis
Model Assessment

initiation of definitive RCTs testing the impact of weight loss interventions is high
priority; such trials should not be delayed while other research priorities are
addressed. These RCTs are expected to contribute key data that will inform the
questions raised in other research priorities.
Key priorities include (1) exploration of the association with obesity with prog-
nosis across breast cancer subtypes, including an examination of the impact of
selection criteria on the representativeness of women enrolled onto systemic ther-
apy trials, (2) investigation of the relative contributions of obesity and physical
activity to outcomes, (3) conduct of adequately powered RCTs (that include a full
12 Modifiable Lifestyle Factors and Breast Cancer Outcomes… 189

spectrum of embedded correlative research to identify predictors of benefit) using

an effective weight loss intervention to directly test the impact of weight loss on
breast cancer outcomes, (4) identification of host and tissue biomarkers of the
obesity-prognosis association (some of these may prove useful as intermediate end-
points in small trials of specific interventions, prior to testing in full scale trials) and
(5) a range of preclinical research that builds on correlative research in clinical set-
tings and includes the development of clinically relevant models of the breast can-
cer-obesity association and in vivo modelling of the effects of weight loss, physical
activity and dietary interventions on breast cancer biology.
This is an ambitious interdisciplinary research agenda that will be costly and
time-consuming, however, the benefits will be large if it results in clinically relevant
improvements in breast cancer outcomes. Care is needed to prioritize research to
focus on areas of potentially greatest impact.

Alcohol

Although there is clear evidence that alcohol intake, even at modest levels, is associ-
ated with increased breast cancer risk (Seitz et al. 2012), there is little evidence that
intake post diagnosis is associated with risk of breast cancer recurrence or death.
Concerns have been raised that alcohol intake after breast cancer diagnosis may
increase risk of a new breast primary, however, results of published studies have been
inconsistent (Demark-Wahnefried and Goodwin 2013; Newcomb et al. 2013; Kwan
et al. 2010). Given these observations, and the recognized benefits of modest alcohol
intake on risk of cardiovascular disease (a major source of mortality in breast cancer
survivors beyond 10 years post diagnosis), adherence to population based recom-
mendations for alcohol intake appears reasonable in breast cancer populations.

Tobacco

There is growing evidence that tobacco exposure may be associated with a modest
increased risk of mainly premenopausal breast cancer, particularly in those with slow
acetylation N-acetyl transferase 2 genotypes (Johnson et al. 2011; Land et al. 2011,
2014). There are no data available regarding the association of continued tobacco
exposure post-diagnosis and breast cancer outcomes. However, tobacco use post-
diagnosis may increase risk of lung and esophageal cancer (as well as other tobacco
associated cancers), both of which have been reported to occur with increased fre-
quency in breast cancer survivors. Concerns have been raised that tobacco exposure
may alter tamoxifen metabolism in individuals with certain CYP2D6 polymor-
phisms; it is not clear whether this impacts clinical outcomes in breast cancer patients
receiving tamoxifen (Fujita 2006). Because of the well recognized general adverse
health effects of smoking, and the excellent long-term outcomes of breast cancer,
avoidance of tobacco exposure is recommended for all breast cancer survivors.
190 P.J. Goodwin et al.

The Future

A wealth of primarily observational research over the past 35 years has identified
important associations of lifestyle with outcome in breast cancer survivors. This
research has led to the testable hypothesis that adoption of a healthier lifestyle,
through changes in diet and physical activity, will improve breast cancer outcomes.
It has also identified biologically plausible mediators of this association. Well-
designed and conducted, adequately powered RCTs, with strong embedded correla-
tive components designed to identify important biologic mediators and predictors of
benefit, are needed to provide definitive information regarding the benefits of life-
style change. Such RCTs may identify benefits that are comparable in magnitude to
those seen with drug therapies. They should be assigned a high research priority by
funders and breast cancer researchers.

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Chapter 13
Risk Reduction from Weight Management
and Physical Activity Interventions

Melinda L. Irwin, Carol Fabian, and Anne McTiernan

Abstract Obesity and low levels of physical activity are associated with a higher
risk of breast cancer recurrence and mortality. Currently, over 65 % of breast cancer
survivors are overweight or obese, and fewer than 30 % engage in recommended
levels of physical activity. The reason for low adherence to lifestyle guidelines is
likely multifactorial. Given the continuing trend of increased obesity and physical
inactivity in the United States, worldwide and in breast cancer survivors, more
research showing the direct effect of weight loss and/or exercise on breast cancer
recurrence and mortality is needed. Many exercise interventions have examined the
impact of increasing exercise on changes in quality of life, with most studies show-
ing a favorable effect of exercise on quality of life. Smaller Phase II randomized
trials using biomarkers as surrogate endpoints is likely appropriate to answer ques-
tions regarding mechanisms of action, exercise type, volume, and intensity, yet a
definitive trial of weight loss and exercise on disease-free survival is critical for
moving the field forward. Research is also necessary on how to disseminate lifestyle
interventions into the clinic and community that lead to clinically meaningful
weight losses of at least 5 % that are maintained over time, and favorable sustained
changes in physical activity levels. Changes in referrals, access, and reimbursement
of lifestyle programs may lead to favorable changes in the prevalence of obesity and
physical activity in breast cancer survivors and in turn rates of breast cancer recur-
rence and mortality.

Keywords Obesity • Weight • Physical activity • Exercise • Interventions •

Breast cancer

M.L. Irwin (*)

Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
e-mail: [email protected]
C. Fabian
Cancer Prevention, University of Kansas Cancer Center, Kansas, USA
e-mail: [email protected]
A. McTiernan
Cancer Epidemiology, Fred Hutchinson Cancer Research Center, Seatle, WA, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 193

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_13
194 M.L. Irwin et al.

Introduction

Obesity and low levels of physical activity are associated with a higher risk of breast
cancer recurrence and mortality (Chan et al. 2014; Ballard-Barbash et al. 2009).
Post-diagnosis weight gain has also been associated with a higher risk of recurrence
and mortality (Caan 2012; Bradshaw et al. 2012). Obesity, weight gain and physical
inactivity are also risk factors for cardiovascular mortality which is higher in breast
cancer survivors than those without breast cancer (Darby et al. 2005, 2013).
For achieving and maintaining a healthy weight, the American Cancer Society
recommends following a dietary pattern that is high in vegetables, fruits, and whole
grains, 150 min per week of aerobic exercise and at least two sessions of strength
training exercise per week for cancer survivors, and avoiding physical inactivity
(Rock et al. 2012). This is similar to the US Department of Health and Human
Resources Physical Activity Guidelines for healthy adults and the American College
of Sports Medicine recommendation for healthy adults which suggest 150 min per
week of moderate-intensity aerobic physical activity or 75 min/week of vigorous-
intensity aerobic physical activity plus two sessions of strength training per week
(DHHS 2008; Schmitz et al. 2010a, b). Despite these lifestyle recommendations,
over 65 % of breast cancer survivors are overweight or obese, and fewer than 30 %
engage in recommended levels of physical activity (Jiralerspong et al. 2013; Mason
et al. 2013a, b).
The reason for low adherence to lifestyle guidelines is likely multifactorial and
related to the difficulty in making lifestyle changes; lack of access and reimburse-
ment to structured weight management and exercise programs; and lack of evidence
from large-scale randomized trials of weight loss and/or exercise as to the amount
of weight which needs to be lost and/or exercise that needs to be performed to
reduce breast cancer recurrence and mortality. Given the continuing trend of
increased obesity and physical inactivity in the United States, worldwide and in
breast cancer survivors, more research showing the direct effect of weight loss and/
or exercise on breast cancer recurrence and breast cancer, cardiovascular and all-
cause mortality is needed. In this chapter we will outline research priorities for
energy balance interventions, with a specific focus on physical activity and weight
loss interventions in breast cancer survivors including the need for information on:
(1) Dose, type, volume and intensity of exercise which will result in improved
health outcomes for breast cancer survivors; (2) Amount and duration of weight loss
likely to result in reduced breast cancer recurrence; (3) Objective yet cost effective
methods for delivering energy balance interventions to general as well as targeted
populations which have been historically difficult to reach such as minorities, rural
women, and those with physical disabilities or a very limited budget; and (4)
Surrogate markers strongly associated with breast cancer recurrence and cardiovas-
cular health which might be substituted for recurrence and cardiac events and used
in smaller trials particularly to answer questions of dose, volume intensity of exer-
cise, and amount of weight loss.
13 Risk Reduction from Weight Management… 195

Physical Activity Interventions in Breast Cancer Survivors

In the last three decades, observational studies of physical activity have suggested that
physical activity is a modifiable health behavior that can play a key role in both reduc-
tion of risk and improvement of prognosis in breast cancer (Ballard-Barbash et al.
2009). However, fewer than 30 % of breast cancer survivors attain the recommended
150 min of moderate-intensity aerobic physical activity plus two sessions of strength
training per week when exercise is measured by self-report (Mason et al. 2013a, b).
Recent accelerometer data from the National Health and Nutrition Examination Survey
showed a smaller proportion of cancer survivors met physical activity guidelines when
physical activity was measured objectively, with only 13 % of cancer survivors exer-
cising for 150 min or more each week (Loprinzi et al. 2013). Further, the percentage of
women meeting exercise guidelines decreases with increasing time since diagnosis
such that at 5 or 10 years post-diagnosis, less than 10 % of survivors are meeting guide-
lines (Mason et al. 2013a, b). A high proportion of physically inactive survivors are
also overweight or obese and poorly fit. A number of questions exist about the amount
(volume), type, and intensity of exercise that is safe but effective in improving breast
cancer specific and overall health outcomes after a diagnosis of breast cancer.

Duration, Intensity and Type of Physical Activity

While most observational research shows a dose-response of more exercise being

better for lowering breast cancer risk, recurrence and mortality, we do not know if a
threshold level exists or if vigorous-intensity physical activity is beneficial or detri-
mental. Currently, trials are in progress examining the effect of different durations
and intensities of exercise on breast cancer biomarkers in healthy women and breast
cancer survivors (clinicaltrial.gov NCT01435005 and NCT01186367). Also of
importance is the impact of reducing sedentary time on breast cancer outcomes. A
growing number of studies have assessed sedentary behavior and breast cancer-
specific and all cause-mortality, with most studies not observing a significant asso-
ciation when adjusting for physical activity levels (George et al. 2013; Kim et al.
2013; Basterra-Gortari et al. 2014).
Future research should examine different types of exercise on cancer outcomes.
Trials are in progress examining the impact of resistance training vs. muscle relaxation
training on fatigue, quality of life, body composition, fitness and inflammatory bio-
markers in breast cancer survivors undergoing chemotherapy or radiation therapy
(Potthoff et al. 2013). Recently, Courneya and colleagues showed that recommended
amounts of 150 min/week of aerobic exercise had similar effects on physical function-
ing in breast cancer survivors as did a higher dose of 300 min/week of aerobic exercise
or a combined 300 min/week of aerobic exercise and resistance training, but that the
higher dose and combined exercise may be more beneficial than lower amounts of aero-
bic exercise on endocrine symptoms and other QOL endpoints (Courneya et al. 2013).
196 M.L. Irwin et al.

Different types of exercise have different physiologic effects, with aerobic

exercise enhancing cardiorespiratory function to a greater degree than resistance
exercise, and resistance training enhancing muscular function to a greater degree
than aerobic exercise (DHHS 1996). Additionally, aerobic and resistance exercise
impart different effects on body composition, with aerobic exercise leading to larger
losses in fat mass, and resistance exercise to larger increases in lean body mass
(DHHS 1996). Given these differences, it is likely that different types of exercise
impact metabolic and inflammatory biomarkers linked to breast cancer risk and
prognosis in different ways, and that these effects could differ based on individual
patient characteristics such as age, BMI and menopausal status. Future exercise tri-
als need to carefully specify the type, volume, and intensity of the exercise to allow
these characterizations to be made.

Physical Activity, Quality of Life and Side Effects of Breast

Surgery and Treatments

Many exercise interventions have examined the impact of increasing exercise on

changes in quality of life, with most studies showing a favorable effect of exercise
on quality of life (Schmitz et al. 2010a, b). Exercise does prevent weight gain
(DHHS 2008), and a recent Cochrane review suggests exercise improves sleep,
pain, fatigue, body image, sexuality, anxiety, and global quality of life measures in
breast cancer survivors (Mishra et al. 2012). Exercise has also been shown to pre-
vent or improve breast cancer-related lymphedema (Schmitz et al. 2010a, b).
However, the effect of exercise on cognition are not clear. A recent randomized trial
has shown that higher volumes and intensity of exercise during chemotherapy is
safe and associated with improved endocrine symptoms and bodily pain (Irwin et al.
2014). Irwin and colleagues recently conducted the Hormones and Physical Exercise
(HOPE) randomized trial, which enrolled 121 breast cancer survivors taking an
aromatase inhibitor (AI) and experiencing AI-associated joint pain to either a year
of aerobic and resistance training exercise or usual care group. The yearlong exer-
cise program led to a statistically significant 29 % decrease in arthralgia severity
among women randomized to exercise vs. an increase among women randomized to
usual. Exercise was also associated with an improvement in endocrine-related qual-
ity of life in this sample of breast cancer survivors taking AIs and experiencing joint
pain. Evaluating type, duration and intensity of exercise on cognition and specific
quality of life domains, especially in breast cancer survivors at higher risk of
treatment-related side effects, needs to be a priority in the future. Future research
should also possible adverse effects of exercise on cancer outcomes (Schmitz et al.
2010a, b). Jones et al. recently reported that patients with cancer randomized to
supervised exercise vs. usual care had a higher incidence of cardiovascular mortal-
ity and or hospitalization for cardiac events with aerobic exercise than usual care
(Jones et al. 2014).
13 Risk Reduction from Weight Management… 197

Improving Uptake of Exercise in Cancer Survivors

Currently, the proportion of breast cancer survivors that participate in recommended

levels of exercise is very low; and many women decrease physical activity levels
further after cancer diagnosis (Mason et al. 2013a, b). These low rates of participa-
tion in physical activity have been shown to be a strong risk factor for post-diagnosis
weight gain, which is also associated with a higher risk of breast cancer recurrence
and mortality. The reasons underlying this low uptake of exercise guidelines are
probably multifactorial but there is little third-party reimbursement for exercise pro-
grams in breast cancer survivors, and many oncologists do not address these issues
with patients. Research on the best, most cost-effective, approach for increasing
physical activity levels in breast cancer survivors is necessary; however studies have
shown in-person, telephone and use of mailed interventions have all have been asso-
ciated with increased physical activity levels (Irwin et al. 2009a, b; Cadmus et al.
2009; Demark-Wahnefried et al. 2000). Furthermore, a number of community-
based exercise programs are increasingly available to cancer survivors, such as the
LIVESTRONG® at the YMCA program, which offers free 12-week exercise pro-
grams to cancer survivors at participating YMCAs across the United States. The
effectiveness of the LIVESTRONG® at the YMCA program has been evaluated
only in Western Washington YMCAs (Rajotte et al. 2012), however a study is
underway evaluating the LIVESTRONG® at the YMCAs in MA and CT (clinicaltri-
als.gov number NCT02112149). Evaluation of exercise interventions in the co-
operative group setting was evaluated by Ligibel et al., and showed promise as a
strategy towards increases exercise particularly in breast cancer patients treated at
community practices (Ligibel et al. 2012).

Future Physical Activity Research Needs

Despite a growing body of observational evidence suggesting a strong link between

physical activity and outcomes (especially survival) following breast cancer, there
is still the potential for unknown or poorly characterized factors to confound these
associations. Women who participate in higher levels of physical activity may
engage in many other healthy behaviors that contribute to reduced risk, or they may
have higher levels of adherence with their cancer treatments. Thus, a randomized
controlled trial testing the effects of a prescribed level of physical activity on breast
cancer recurrence and mortality outcomes would, if positive, likely impact the num-
ber of oncologists recommending exercise, as well as third-party reimbursement for
exercise programs. Although a randomized trial of exercise vs. usual care with pri-
mary outcomes of disease-free and overall survival would be ideal in terms of estab-
lishing exercise as a treatment for breast cancer survivors and thus reimbursable,
such a trial would require significant resources, a challenge in the current funding
environment, yet clinically significant. Smaller Phase II randomized trials using
198 M.L. Irwin et al.

biomarkers as surrogate endpoints is likely appropriate to answer questions regard-

ing mechanisms of action, exercise type, volume, and intensity. These smaller stud-
ies should include biomarkers for both cardiovascular disease and breast cancer
recurrence. Also of great need are studies examining physical activity as a strategy
towards increasing medication adherence in breast cancer survivors, as well as ran-
domized trials of exercise vs. novel therapies for breast cancer (e.g., metformin). In
summary, physical activity may improve breast cancer and overall survival via
favorable changes in biomarkers, body composition, and/or medication adherence.
Yet, the impact of physical activity on favorable changes in quality of life, fatigue,
and depression may be considered most important by breast cancer survivors, espe-
cially in those survivors experiencing common treatment side effects. Research in
all of these areas is needed (see Table 13.1) to ultimately improve access to and
reimbursement of exercise programs by third party payers, and in turn, more survi-
vors initiating and adhering to physical activity guidelines.

Table 13.1 Top research priorities in physical activity and weight management interventions in
breast cancer survivors
Physical activity
1. Trials comparing types, intensity, and dose of exercise (including sedentary activity) on
patient-reported outcomes, biomarkers, recurrence and mortality
2. Evaluating impact of exercise on cognition and specific quality of life domains in high risk
groups based on diagnosis and/or treatment prescribed
3. Examining if there are adverse effects of exercise in breast cancer survivors
4. Trials of exercise on biomarkers for both cardiovascular disease and breast cancer recurrence
5. Studies examining physical activity as a strategy towards increasing medication adherence
in breast cancer survivors, as well as randomized trials of exercise vs. novel therapies for
breast cancer (e.g., metformin)
6. Research on the best, most cost-effective, approach for increasing physical activity levels in
breast cancer survivors
Weight management
1. Trials of weight loss on recurrence and mortality
2. Studies of weight loss medications or surgeries on breast cancer prognosis
3. Studies comparing diet alone, exercise alone, and combined diet plus exercise interventions
on health outcomes in cancer survivors
4. Examining if there are adverse effects of weight loss or dietary change interventions in
breast cancer survivors
5. Research on how to disseminate weight management interventions into the clinic and
community
6. Novel interventions approaches that are cost-effective strategies (including reimbursement)
towards losing and maintaining weight loss
7. Research on what is the most efficient way to lose weight and keep it off particularly in
underserved populations (minorities, rural Americans)
8. Research on understudied breast tissue and blood biomarkers include DNA methylation of
breast cancer genes and small molecule metabolite levels
13 Risk Reduction from Weight Management… 199

Weight Management

Obese breast cancer survivors have a poorer overall and breast cancer specific sur-
vival compared with normal-weight breast cancer survivors. A recent systematic
review and meta-analysis of 79 cohort studies including over 210,000 women with
41,477 deaths estimated that compared with normal-weight women (BMI 18.5–
24.9 kg/m2), those who were overweight (BMI 25.0–29.9 kg/m2) or obese (≥30.0 kg/
m2) before diagnosis had statistically significant 11 % and 35 % increased risks for
breast-cancer-specific mortality, respectively (Chan et al. 2014). Similar results
were observed for BMI after diagnosis. A J-shaped curve of risk was also observed:
women who were underweight (BMI < 18.5 kg/m2) within 12 months after diagno-
sis had a statistically significant 53 % increased risk of breast-cancer-specific mor-
tality (Caan et al. 2008). A similar pattern of risks was observed for overall mortality.
Little is known about weight change and prognosis, which has led experts to pro-
pose testing weight loss interventions on prognosis in randomized controlled trials
before making firm recommendations for weight loss in overweight or obese survi-
vors (Ballard-Barbash et al. 2009). No such trial has been conducted, however. This
section reviews the status of research on weight loss and diet interventions in breast
cancer survivors, with particular focus on interventions that included caloric reduc-
tion as part of the intervention because reducing caloric intake is integral to substan-
tial weight loss. There have been no studies of weight loss medications or surgeries
on breast cancer prognosis, so no conclusions of effects of these interventions in this
population can be made.

Weight Loss and Diet Interventions

Early suggestions of an association between dietary fat and breast carcinogenesis,

with evidence strongest in animal models (Rose 1997), led to the design of several
small and two large-scale randomized controlled trials focused on the effect of a diet
change intervention on intermediate or prognosis-related outcomes in breast cancer
patients (Demark-Wahnefried et al. 2012; Chlebowski et al. 2006; Pierce et al.
2007). The diet change interventions have included reduced fat (typically a goal of
less than 20 % of daily calories from fat), increased vegetables and fruits, increased
fiber, or various combinations of these components. Durations have ranged from a
few months to several years, but most have been of 6 or 12 months’ duration.
Reporting of effect size varied among studies, with some showing absolute change
in weight, others reporting relative change, and a smaller number providing data on
other body composition variables such as waist circumference or image-derived
body fat. Biological endpoints have included insulin and insulin resistance markers,
inflammation-related biomarkers, sex hormones (estrogens, androgens, sex hor-
mone binding proteins), and various adipokines (Scott et al. 2013). Few trials have
examined the effect of weight loss on important quality-of-life endpoints in breast
cancer survivors.
200 M.L. Irwin et al.

Two full-scale randomized clinical trials evaluated dietary change in the adjuvant
breast cancer setting (Chlebowski et al. 2006; Pierce et al. 2007). The WINS and
WHEL study enrolled different populations and studied different dietary patterns,
but both aimed to reduce dietary fat intake. Neither targeted weight loss nor physi-
cal activity. In the WINS trial, while weight loss was not a specific intervention
target, there was a statistically significant (P = 0.005), 6-pound lower mean body
weight in the intervention group at 5 years. There were more recurrence events in
the control (181 of 1,462, 12.4 %) compared to the intervention group (96 of 975,
9.8 %, hazard ratio (HR) 0.76, 95 % CI 0.60–0.98, p = 0.034). The WINS results
suggest that a lifestyle intervention reducing dietary fat intake and associated with
modest weight loss may improve outcome of breast cancer patients receiving con-
ventional cancer management.
Following the observations that overweight and obesity adversely affect progno-
sis, a number of randomized controlled trials have tested the effect of weight loss on
various health factors in women with breast cancer. None, however, have been spe-
cifically designed or sufficiently powered to test the effect of weight loss on sur-
vival. Several diet or diet plus exercise intervention trials have tested weight loss
interventions on health factors other than survival. Earlier studies used individual
in-person counseling to deliver guidance on caloric-restriction, while more recently,
group-based or telephone support have been used (Goodwin et al. 2014).
The Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer
(LISA) Weight Loss randomized controlled trial enrolled 338 women with early
stage estrogen receptor positive breast cancer to either a telephone-based weight
loss intervention or educational control group (Goodwin et al. 2014). The initial aim
was to assess weight loss effect on disease-free survival but the trial was stopped
due to lack of funding. Eligibility included diagnosis of Stage I-III breast cancer,
BMI ≥ 24 kg/m2, and treatment with letrozole. The weight loss intervention, based
on the Diabetes Prevention Program lifestyle change intervention (DPP 2002a, b),
focused on weight reduction through calorie restriction and increased physical
activity. The weight loss intervention arm lost significantly more weight than the
control arm, with mean reductions of 5.3 vs. 0.7 % at 6 months (p < 0.001) and 3.6
vs. 0.4 % at 24 months (p < 0.001).
A12-month trial with 48 obese stage I-II breast cancer patients, produced weight
losses of <1 % in controls, 8.4 % with individualized counseling, and 9.8 % with
individualized counseling paired with Weight Watchers® group classes (Djuric et al.
2002). Two other group-based randomized clinical trials in breast cancer survivors,
i.e., the Healthy Weight Management Study (n = 85) (Mefferd et al. 2007), and the
Survivors Health And Physical Exercise (SHAPE) trial (n = 258) tested the effect of
a cognitive-behavioral weight loss program plus telephone counseling vs. wait-list
controls (Taylor et al. 2010). The Healthy Weight Management intervention
produced an 8 % weight loss at 12 months, while the SHAPE intervention yielded a
4.5 % weight loss at 18 months. The weight loss interventions were also associated
with favorable changes in self-esteem, depression and serum concentrations of sex
hormone binding globulin, estradiol, bioavailable estradiol, insulin, leptin and total
and LDL cholesterol.
13 Risk Reduction from Weight Management… 201

The ongoing Exercise and Nutrition to Enhance Recovery and Good Health
for You (ENERGY) Trial, is a multi-site randomized controlled trial designed to
promote and sustain a 7 % weight loss over a 2-year period in 693 overweight or
obese women who have been diagnosed with early stage breast cancer (Rock et al.
2013a, b). Secondary aims are to evaluate weight loss at 24 months according to time
since diagnosis and type of tumor and therapy; to assess the impact of the intervention
on quality of life; and to prospectively collect biological samples for future biomarker
studies to help explain the mechanism and probable differential response across sub-
groups. The group-class weight loss intervention addresses breast cancer specific
issues and promotes an energy-restricted diet, plus increased physical activity, behav-
ioral strategies, cognitive restructuring, skills to facilitate and maintain good choices,
social support, self-nurturing, and body image and self-acceptance.
As in persons without cancer (Butryn et al. 2011; DPP 2002a, b), randomized
trials in breast cancer survivors indicate that optimal weight loss effects result from
multicomponent behavior change interventions that target dietary calorie reduction
to reach a deficit of 500–1,000 kcal/day, moderate or greater intensity physical
activity for at least 150 min/week, and behavior change principles including goal
setting, self-monitoring, and stimulus control. Interventions that include group
behavior change sessions have produced results equal to or greater than one-on-one
counseling, although optimal results provide for some individual contact with a
counselor/case-worker (Befort et al. 2014).
The considerable costs of delivering in-person individual or group interventions,
and the difficulties accruing participants who live at some distance from research
centers, has led to several trials testing home interventions with remote contacts
with case-workers. For cancer survivors, these remote contacts have primarily been
via telephone. Befort et al. delivered a group behavioral weight loss intervention by
conference call to obese breast cancer survivors living in remote rural locations after
first recruiting them in person with the assistance of their local caregivers (Befort
et al. 2012). The intervention included a reduced calorie diet incorporating prepack-
aged entrees and low calorie high protein shakes, advice on physical activity which
was gradually increased to 225 min/week of moderate intensity exercise, and weekly
group phone sessions which included education about breast cancer as well as
advice on how manage life on a diet. Adherence was excellent with a loss of 13.9 %
of baseline weight and significant reductions in leptin and insulin. A follow-up ran-
domized study of usual care vs. a structured weight loss and maintenance interven-
tion patterned on the above has completed accrual.
Irwin et al. 2015a, b recently completed a 6-month diet- and exercise-induced
randomized weight loss trial in overweight and obese breast cancer survivors who
had completed adjuvant treatment, entitled the Lifestyle, Exercise and Nutrition
(LEAN) Study (Irwin et al. 2014). The LEAN Study randomized 100 women to one
of three arms: an 11-session weight loss counseling program occurring over 6
months delivered in-person (Arm 1) vs. 11-session weight loss counseling over 6
months delivered via telephone (Arm 2) vs. usual care group where women received
AICR pamphlets on healthy eating and exercise (Arm 3). The weight loss counsel-
ing was adapted from the 2010 U.S. Dietary Guidelines, the Diabetes Prevention
202 M.L. Irwin et al.

Program, and American Cancer Society and AICR publications. They found statistically
significant decreases in body weight among women randomized to in-person (−6.2 %
weight loss) and telephone (−5.8 % weight loss) counseling compared to usual care, as
well as significant decreases in several biomarkers related to breast cancer including
C-reactive protein, insulin, and leptin levels. In addition to being of potential beneficial
for breast cancer survivors, the changes seen in these biomarkers could predict reduced
risk of diabetes and heart disease for those in the weight loss groups.

Possible Adverse Effects of Purposeful Weight Loss in Cancer

Survivors

Most of the previously reported randomized clinical trials of weight loss used diet
change interventions for weight loss, without addition of an exercise program.
While diet change to reduce calories and fat has been shown to be highly efficacious
in inducing relatively long-term weight loss (Foster-Schubert et al. 2012), it does so
at the expense of muscle loss (Mason et al. 2013a, b). This is a significant issue for
cancer survivors, who have a high prevalence of sarcopenia, among both obese and
non-obese survivors, and sarcopenia has been associated with poorer prognosis
(Villasenor et al. 2012). In non-cancer populations, exercise aids with weight loss
maintenance (Miller et al. 2013), and somewhat with weight loss efficacy (Foster-
Schubert et al. 2012). Yet, there are no controlled clinical trial data comparing
effects of diet alone, exercise alone, and combined diet plus exercise interventions
on health outcomes in cancer survivors. Given the findings in non-cancer popula-
tions, more recent weight loss trials in cancer survivors should include an exercise
component.
Other adverse effects of weight loss through caloric reduction have been observed
in populations without cancer, including reduced white blood cell and neutrophil
counts (Imayama et al. 2012a, b), but this have been largely unexplored in weight
loss trials in breast cancer survivors. Weight loss programs that include exercise
interventions could carry risk for musculoskeletal injuries or cardiovascular events
(Campbell et al. 2012a, b; Dahabreh and Paulus 2011). These, too, have not been
part of outcomes reporting for most weight loss trials in breast cancer survivors.

Future Weight Loss Research Needs

Ideally, resources would be available to determine effects of various weight loss,

diet, and physical activity interventions on breast cancer prognosis. An alternative
would be to launch a full-scale randomized controlled trial testing the effect of a
weight loss intervention on overall and breast-cancer-specific survival with an inter-
vention known to maximize weight loss while having high acceptability to survivors
and a favorable risk profile. The same trial could also test mediating biomarkers that
13 Risk Reduction from Weight Management… 203

could then be used as endpoints in future trials of other weight loss interventions.
Effects on health and quality of life factors relevant to breast cancer survivors should
be assessed, including lymphedema, bone density, diabetes, cardiovascular disease,
arthralgias, cognitive function, fatigue, anxiety, depression, and adverse effects
should be enumerated. Such a trial has been proposed, although resources have not
been available (Ballard-Barbash et al. 2009). While these definitive trials of weight
loss and exercise on disease-free survival are critical for moving the field forward,
dissemination and implementation of evidence-based lifestyle interventions needs
to occur. Research is necessary on how to disseminate lifestyle interventions into
the clinic and community that lead to clinically meaningful weight losses of at least
5 % that are maintained over time. Whether these interventions are more effective
when implemented in cancer hospital survivorship clinics/centers or when imple-
mented via referrals to community-based programs needs to be examined. In sum-
mary, a growing number of observational studies have consistently shown obesity to
be associated with a higher risk of breast cancer and all-cause mortality, yet no
randomized controlled trial of weight loss on disease-free survival has been con-
ducted (see Table 13.1 for future research needs). A growing number of randomized
weight loss trials on biomarkers or quality of life have been conducted, yet it is
unknown if these findings will lead to implementation and reimbursement of weight
management programs in the clinic or community. If so, then we could expect to see
decreases in obesity in breast cancer survivors, as well as prevention of weight gain
in women newly diagnosed with breast cancer.

Surrogate Endpoints for Exercise and Weight Loss Trials

for Breast Cancer Recurrence and Mortality

Increased concentrations of several obesity- and physical inactivity-related blood

proteins have been associated with increased breast-cancer-specific and all-cause
mortality in breast cancer survivors, including insulin, c-peptide, C-reactive protein,
and estrogens, making these markers ideal surrogate markers of breast cancer risk,
recurrence and mortality when those definitive endpoints cannot be assessed
(Duggan et al. 2011; Irwin et al. 2011; Goodwin et al. 2002; Pierce et al. 2009;
Villaseñor et al. 2014). Some of these endpoints are also related to risk for cardio-
vascular disease, although associations of these biomarkers with cardiovascular
mortality in breast cancer survivors have not been adequately studied. Given these
associations, it is prudent to identify interventions that can favorably change these
surrogate biomarkers. While this will not prove cause-and-effect (Fleming and
Powers 2012), it can point to types of interventions that could have biological
effects, and which would be most advantageous to test in a randomized clinical trial
with survival and recurrence endpoints.
Surrogate endpoints obtained from blood that likely impact both risk for breast
cancer and cardiovascular outcomes include: (1) inflammatory cytokines such as
TNF-α, Interleukin 1, 6, 8, 10, macrophage chemoattractant protein (MCP-1), and
204 M.L. Irwin et al.

C-reactive protein (CRP). CRP is often assessed as a general marker of inflamma-

tion as hepatic production of CRP is increased in response to IL6, and TNF-α
(Kasapis and Thompson 2005); (2) adipokines such as adiponectin and leptin; (3)
bioavailable hormones especially estrogen; (4) insulin sensitivity; (5) markers of
angiogenesis and tissue invasion such as VEGF, PAI-1, PEDF, and metalloprotein-
ases; and (6) leukocyte telomere length. Many of these markers are profoundly
affected by weight, body fat, time interval since last food intake, medications, and
recent vigorous exercise. Consequently, it is important to select a relatively homog-
enous group and perform the biomarker assessments under controlled conditions.
For example several of the plasma inflammatory markers including TNF-α, IL6,
IL10, and CRP exhibit large increases after vigorous exercise. If blood is sampled
prior to an appropriate interval after exercise, spurious increases in these cytokines
could occur, particularly in small studies (Mishra et al. 2012).
Interventional trials of exercise and diet-induced weight loss on breast cancer
outcomes have also differed by cohort characteristics in terms of initiation of inter-
vention during adjuvant chemotherapy, or later post-adjuvant treatment, homogene-
ity of the cohort in terms of BMI and physical activity levels, receipt of endocrine
therapy or anti-inflammatory drugs, type and intensity of physical activity during
the intervention, type of intervention for the control group, whether exercise was
supervised, biomarkers assessed, and specified interval since last exercise session
when biomarkers were drawn.

Estrogens

One of the most plausible mechanisms of how exercise may reduce breast cancer
risk, recurrence and mortality is by lowering estrogen concentrations through reduc-
tion in body fat and decreased estrogen production from aromatization of andro-
gens. Two randomized controlled exercise trials, conducted in healthy women have
shown an increase in sex hormone binding globulin and an ~10 % decrease in bio-
available estrogen and testosterone primarily in those women who lost body fat
(McTiernan et al. 2004; Friedenreich et al. 2010). In a 4-arm randomized controlled
trial, a far greater reduction in serum estradiol was observed with weight reduction
through caloric restriction, with or without exercise, compared with controls or with
an exercise-only intervention (Campbell et al. 2012a, b). The greater effect of
dietary weight loss on serum estrogens compared with exercise alone is not surpris-
ing, since caloric reduction of about 500–1,000 kcal/day typically produces 10 %
weight loss over 6–12 months, while exercise alone produces 1–2 % loss (DHHS
1996). The effect of weight loss on blood estrogens in women with breast cancer
has been little studied, likely because of the potential for confounding effects of
some treatments such as aromatase inhibitors and tamoxifen. One study in 220 sur-
vivors enrolled in a weight loss intervention found that postmenopausal women
who lost ≥5 % of body weight at 6 months had lower estrone (P = 0.02), estradiol
(P = 0.002), and bioavailable estradiol (P = 0.001) concentrations than women who
did not lose at least 5 % of body weight (Rock et al. 2013a, b).
13 Risk Reduction from Weight Management… 205

Insulin Sensitivity

Elevated insulin levels have been linked to an increased risk of breast cancer, and
several reports have demonstrated that women with higher levels of insulin at the
time of breast cancer diagnosis are at increased risk of cancer recurrence and death
(Duggan et al. 2011; Irwin et al. 2011; Goodwin et al. 2002). These findings showed
that a lowering of insulin levels by 25 % may be associated with a 5 % absolute
improvement in breast cancer mortality, and this strong association between fasting
insulin levels and breast cancer mortality has led a number of oncologists and sci-
entists to consider the targeting of insulin as a therapeutic modality in breast
cancer.
A number of exercise and weight loss interventions have been shown to impact
insulin in healthy women. One recent trial, conducted by Dr. McTiernan, random-
ized 439 overweight/obese, sedentary postmenopausal women to one of three
energy balance interventions (dietary weight loss alone, exercise alone or dietary
weight loss plus exercise) or to control and demonstrated that the weight loss groups
experienced the most significant changes in insulin (−22.3 % in the dietary weight
loss alone and −24 % in the combined diet and exercise group vs. −7.8 % in the
exercise alone group and −1.9 % in the control group) (Mason et al. 2011).
There are fewer data regarding the impact of energy balance interventions upon
insulin in breast cancer survivors. One study looked at the impact of three different
dietary weight loss interventions (Weight Watchers, an individualized weight loss
program or a combination of the two) vs. control on fasting insulin in 48 breast
cancer survivors and demonstrated an average 12 % reduction in insulin levels in the
three dietary intervention groups. Another study looked at the impact of a diet and
exercise weight loss program on insulin levels in 35 rural breast cancer survivors
and demonstrated a 17 % reduction in fasting insulin levels. Finally a few small
studies have looked at the impact of exercise-only interventions upon insulin levels
in breast cancer survivors. One exercise study demonstrated a 28 % reduction in
fasting insulin levels in 101 inactive, overweight breast cancer survivors participat-
ing in a mixed strength and aerobic exercise intervention (p = 0.07) (Ligibel et al.
2008). The other exercise study looked at the impact of a moderate-intensity aerobic
exercise intervention in 68 sedentary, overweight breast cancer survivors, and dem-
onstrated an 8 % decrease in insulin levels in exercisers and a 20 % between group
difference (p = 0.089) (Irwin et al. 2009a, b). Thus there is preliminary evidence in
healthy populations that weight loss may be the most important factor in reducing
insulin, but data are limited in breast cancer survivors. Metformin reduces insulin
levels by 22 % in non-diabetic breast cancer survivors (Palmirotta et al. 2009), and
a randomized trial of metformin vs. placebo is being tested in the adjuvant setting
(clinicaltrials.gov NCT01101438), as well as trials of metformin alone or with exer-
cise or with weight loss are being tested in the NCI-funded Transdisciplinary
Research on Energetics and Cancer studies (clinicaltrials.gov NCT01340300 and
NCT01302379). These findings will move the field forward in regards to the role of
lifestyle factors compared to medication upon lowering insulin levels in breast can-
cer survivors.
206 M.L. Irwin et al.

Inflammatory Cytokines

Exercise training seems to lower both resting and post exercise inflammatory cytokine
levels through reduction of circulating monocyte as well as tissue macrophage pro-
duction and release (Kasapis and Thompson 2005). Preclinical studies suggest that
exercise can have a profound effect on macrophage infiltration into adipose and mus-
cle tissue with reduction in M1 macrophage concentration associated with cytokine
production and chronic inflammation particularly in diet induced obesity (Kawanishi
et al. 2010). Most moderate volume and intensity exercise intervention studies in the
general population have found no significant change in inflammatory biomarkers
(Marcell et al. 2005; Hammett et al. 2006; Arsenault et al. 2009). Those studies in
which inflammatory markers particularly TNF-α, IL6, and/or CRP were favorably
modulated with exercise tended to be those in which: (a) individuals were obese at
baseline and thus had higher baseline levels of inflammatory cytokines (Kasapis and
Thompson 2005; Christiansen et al. 2009; Arikawa et al. 2011; Phillips et al. 2012);
(b) exercise volume and intensity were high enough to result in loss of weight and/or
body fat (Christiansen et al. 2009); and/or (c) where cytokine production (TNF-α or
IL6) was stimulated with lipopolysaccharide exposure (Phillips et al. 2012). Loss of
5–10 % of baseline weight through caloric reduction with or without an exercise pro-
gram has been shown to reduce inflammation-related biomarkers such as CRP and
IL-6 by 20–40 % (Imayama et al. 2012a, b). These effects far exceed those seen with
exercise interventions in the absence of significant weight loss. A systematic review
concluded that across lifestyle and surgical weight loss interventions, for each 1 kg of
weight loss, the mean change in CRP level was −0.13 mg/L (with a weighted Pearson
correlation of r = 0.85) (Selvin et al. 2007). Although future research in this area is
definitely warranted, investigating more sensitive circulating as well as breast and
adipose tissue based immune parameters is warranted.

Surrogate Biomarker Summary

In summary, although an exercise or weight loss threshold for reduction in risk for
breast cancer development, recurrence or mortality has yet to be defined, biomarker
studies to date in largely sedentary women suggest approximately 2.5–3.0 h per
week of moderate-intensity exercise, and weight losses of 5 % or more, are suffi-
cient to observe changes in insulin sensitivity. Changes in many inflammatory, hor-
monal, and angiogenic markers may be more dependent on both decreases in fat
mass and weight than exercise alone, although chronic exercise may reduce both
resting cytokine output in response to various stressors.
Other newer potential mechanisms of action and biomarkers from breast tissue
are largely unexplored in trials of exercise or weight loss and may help define the
optimum exercise and/or weight loss prescription. Assessing changes in proliferation
or cytomorphology in benign breast tissue is not likely to be helpful since the major-
ity of breast cancer survivors are peri or postmenopausal and on prolonged endo-
13 Risk Reduction from Weight Management… 207

crine therapy. Under these conditions ductal tissue is largely replaced by fat with
very low if any Ki-67 (Woolcott et al. 2010). Mammographic breast density is likely
to be increased not decreased with exercise particularly if there is a reduction in fat
mass (Woolcott et al. 2010). However, assessment of methylation, gene changes at
the mRNA level including microRNA, tissue cytokine changes, or changes in key
proteins in pathways such as MAP kinase and mTOR can now be performed on very
small amounts obtained inexpensively by the minimally invasive technique of ran-
dom peri-areolar fine needle aspiration (RPFNA) (Fabian et al. 2005). Fabian et al.
have performed RPFNA on women undergoing combined caloric restriction and
exercise and showed changes in a variety of blood and tissue biomarkers for women
losing 10 % or more of their initial weight (Fabian et al. 2013). Irwin et al. are cur-
rently performing needle core biopsies (which may be more appropriate for study-
ing macrophage infiltration, aromatase activity and miRNAs) in overweight breast
cancer survivors enrolled into a healthy eating and exercise (weight loss) trial (clini-
caltrials.gov NCT02110641). Some studies are exploring breast tumor tissue bio-
markers. Specifically, a study of exercise between diagnosis and surgery on breast
tumor markers (e.g., Ki-67) is being conducted (clinicaltrials.gov NCT01516190).
Other novel, understudied biomarkers include DNA methylation of breast cancer
genes and small molecule metabolite levels.
Whatever the biomarker used as a surrogate endpoint, it is important that the
subject population for these translational trials be relatively homogenous with
meticulous detail paid to other medications, sample acquisition, processing and
assessment for meaningful answers to be obtained. Sufficient funds should be allo-
cated for bio-specimen screening with the acknowledgement that the majority of
potential subjects screened may not be medically eligible or because the primary
biomarker of interest may not be measurable to advance onto the intervention.

Summary and Future Directions

Physical activity and weight management have not traditionally been a part of can-
cer treatment/survivorship programs. Given, physical activity and weight manage-
ment programs carry tremendous potential to affect length and quality of survival in
a positive manner and prevent or control morbidity associated with breast cancer or
its treatment, oncologists and primary care physicians should be encouraged to
counsel cancer survivors proactively about exercise and weight management. There
are, clearly, many questions to be answered concerning who would benefit, and
what type of intervention, duration and intensity of exercise would be most benefi-
cial. A better understanding of the effect of exercise and/or weight loss upon path-
ways linked to breast cancer risk and prognosis could lead to lifestyle prescriptions
better targeted to impact these pathways and thus more likely to improve breast
cancer prognosis. Personalized lifestyle prescriptions based on patient and treat-
ment characteristics may also lead to better compliance, given the stronger biologic
rationale for potential benefit and the parallels to modern adjuvant therapy para-
digms focusing on host and tumor biology. This may be especially true in patients
208 M.L. Irwin et al.

for whom current therapies are less effective, such as those with triple-negative
breast cancer.
Given weight loss and exercise are associated with reductions in risk for a num-
ber of diseases (including breast cancer, cardiovascular disease, diabetes, osteopo-
rosis, and mental health) and treatment side effects (including fatigue, lymphedema,
and arthralgia), knowing that weight loss and exercise could benefit many health
outcomes may have a positive effect on making favorable behavioral changes.
Future research needs to also focus on novel interventions approaches that are cost-
effective strategies (including reimbursement) towards losing and maintaining
weight loss and increasing exercise, as well as how to incorporate weight manage-
ment and exercise counseling into the clinic (and when, i.e., during or post-
treatment) (see Table 13.2). Additional research on novel measurement techniques
of body composition, exercise and sedentary behavior are also encouraged. Lastly,
research on what is the most efficient way to lose weight and keep it off particularly
in underserved populations (minorities, rural Americans) is necessary, as well as
how weight loss medications and/or bariatric surgery can best be studied in mor-
bidly obese breast cancer survivors, while also including exercise interventions?
In summary, obesity and low levels of physical activity are risk factors for poor
breast cancer outcomes, but we do not know how much weight loss or how much
exercise is necessary, and for how long, to change breast cancer outcomes. It is
unclear if being overweight or even in the lower BMI levels of obesity is a risk fac-
tor for poor breast cancer outcomes in women who are physically fit or physically
active. Biomarker studies can help with some of these questions, as can large epide-
miological observational studies, but ultimately it is likely that large-scale random-
ized trials of weight loss and exercise on breast cancer recurrence, breast cancer
mortality and all-cause mortality will be necessary to lead to significant changes in
referrals, access, and reimbursement of lifestyle programs, which in turn may lead
to favorable changes in the prevalence of obesity and physical activity in breast
cancer survivors and in turn rates of breast cancer recurrence and mortality.

Table 13.2 Approaches for improving nutrition and physical activity after a breast cancer diagnosis
• Oncologists should discuss weight management, physical activity, and healthy eating with
their patients and refer them to exercise and nutrition programs
• Cancer survivors and providers can consult
– The American College of Sports Medicine’s website (http://members.acsm.org/source/
custom/Online_locator/OnlineLocator.cfm) using the “Profinder” feature to locate a
ACSM/ACS certified cancer exercise trainer in their community
– The Academy of Nutrition and Dietetics website (www.eatright.org), using the “Find a
registered dietitian” feature and clicking “Cancer/Oncology Nutrition” in the expertise
tab to find a dietitian in their community
• Cancer survivors should contact their health insurance company to find out if post-treatment
care is covered, and if so, what lifestyle programs are covered, e.g., health club membership,
certified personal trainer, dietitian
• Cancer survivors should keep a daily diary of their nutrition and physical activity practices
to discuss with their oncologist, nutritionist, and certified cancer exercise trainer
13 Risk Reduction from Weight Management… 209

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Chapter 14
Prevention and Treatment of Cardiac
Dysfunction in Breast Cancer Survivors

Carol Fabian

Abstract As recurrence free survival following a breast cancer diagnosis continues

to improve, cardiovascular morbidity and mortality will assume greater importance
in the breast cancer survivorship research agenda particularly for women receiving
potentially cardiotoxic therapy. Development of (1) tools to readily identify pre-
diagnostic risk factors for cardiac dysfunction, (2) well-tolerated prophylactic treat-
ments to reduce the risk of cardiac injury, and (3) sensitive and affordable monitoring
techniques which can identify subclinical toxicity prior to a drop in left ventricular
ejection fraction are or should be focus areas of cardio-oncology research. Since
weight as well as cardiorespiratory fitness generally decline after a breast cancer
diagnosis, behavioral approaches which can improve energy balance and fitness are
important to optimize cardiovascular health in all breast cancer survivors not just
those undergoing cardiotoxic therapy. These goals are likely best achieved by part-
nerships between cardiologists, oncologists and internists such as those initiated
with the formation of the International CardiOncology Society (ICOS) and the NCI
Community Cardiotoxicity Task Force.

Keyword Risk factors and prevention of cardiac toxicity with breast cancer
treatment

Introduction

Cardiovascular disease is the most common cause of death for women with Stage I
breast cancer who are 67 years of age or older (van de Water et al. 2012) and the
third most common cause of death in women undergoing adjuvant treatment irre-
spective of age and type of treatment (Schonberg et al. 2011) behind breast cancer

C. Fabian, M.D. (*)

Director Breast Cancer Prevention and Survivorship Center,
University of Kansas Cancer Center, 2330 Shawnee Mission
Parkway Suite 1102, Westwood, KS 66205, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 213

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_14
214 C. Fabian

recurrence and second primary tumor. Treatment can increase the risk of cardiovas-
cular morbidity and mortality through (1) damage to cardiac myocytes (anthracy-
clines and HER-2 targeted agents) (Swain et al. 2003; Naumann et al. 2013); (2)
damage to blood vessels (radiation) (Darby et al. 2013); (3) induction of hyperten-
sion (VEGF inhibitors, platinum) (Steingart et al. 2012; Cameron et al. 2013); (4)
reduction in tissue estrogen levels with premature menopause or antihormonal ther-
apies (Rivera et al. 2009; Ewer and Glück 2009); (5) weight gain (Rock et al. 1999);
and (6) reduction in cardiorespiratory fitness (Darby et al. 2013; Bowles et al. 2012;
Barlow et al. 2012) due to a decrease in physical activity after diagnosis (Irwin et al.
2003; Lakoski et al. 2013). As the proportion of women surviving a breast cancer
diagnosis continues to increase, the prevalence of cardiovascular disease and car-
diac dysfunction due to the combination of pre-existing risk factors and cancer
treatment is also likely to rise (Carver et al. 2007). A major thrust of survivorship
research needs to be the identification of those at highest risk for developing cardiac
dysfunction and development of pathways and treatment protocols to reduce dys-
function. The National Cancer Institute has formed a work group called the NCI
Community Cardiotoxicity Task Force in an effort to standardize terminology and
to help refine and prioritize clinical cardio-oncology research. In this chapter we
will focus primarily on cardiac dysfunction and heart failure as opposed to, coro-
nary artery and peripheral artery disease although these may be important pre-
existing factors or in some cases induced by treatment such as radiation therapy
(Darby et al. 2013).

Identification of Pre-existing Risk Factors for Cardiovascular

Disease and Cardiac Dysfunction

Risk factors for cardiovascular disease (age, obesity, diabetes, dyslipidemia, hyper-
tension, family history, and poor cardio-respiratory fitness) are so prevalent in our
society that as oncologists we give little thought as to whether a patient should avoid
potentially cardiotoxic therapy unless the individual has previously suffered a major
cardiac event, is of advanced age, or has an abnormal left ventricular ejection frac-
tion (Bowles et al. 2012; Chavez-MacGregor et al. 2013). Left ventricular ejection
fraction is the proportion of blood volume in the left ventricle that is pumped out of
the heart with each contraction and is normally between 55 and 70 %. We stan-
dardly use left ventricular ejection fraction (LVEF) to screen for women who should
not have cardiotoxic therapy because cardiac damage or impairment of ventricular
muscle strength is already present (Lenihan et al. 2013); but a normal LVEF does
not mean normal function. Women with hypertension often have a normal LVEF but
other evidence of cardiac dysfunction (Young et al. 2012). Prior to initiating poten-
tially cardiotoxic therapy, women should be screened for hypertension, diabetes,
hyperlipidemia, and prolongation of the QT interval, even with a normal LVEF as
14 Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors 215

Table 14.1 Screening prior to initiation of cardiotoxic therapy

History Parameter Action
Age/family history
Obesity BMI Avoid further gain, gradual loss
Diabetes HbA1C/Fasting glucose Initiate diabetic therapy
Inactivity Minutes of recreational Encourage 150 min or more
physical activity/week recreational physical activity per week
Fitness VO2 peak/6 min walk Gradual increase with exercise to
moderately fit or better
Hypertension BP Monitor/correct
Dyslipidemia Fasting lipid profile Initiate therapy
Smoking Smoking cessation aids
Cardiac evaluation LVEF: Avoid cardio-toxic drugs if abnormal
Echocardiogram or MUGA Referral to cardiologist
Cardiac evaluation EKG/QT interval Avoid cardio-toxic drugs if abnormal
Referral to cardiologist

measured by multi-gated acquisition (MUGA) scan or 2D echocardiogram.

Treatment should be initiated to correct risk factors prior to chemotherapy where
possible (Ewer and Glück 2009; Lenihan et al. 2013; Mosca et al. 2012). All women
should be encouraged to implement a healthy lifestyle including smoking cessation,
a balanced diet high in fruits and vegetables but low enough in calories to avoid
weight gain, and 150 min of physical activity a week (Mosca et al. 2012) (See
Table 14.1). The complexity of decision making regarding systemic cancer treat-
ment, tight time frames, and reluctance to intrude on what is generally considered
the general internist’s or cardiologist’s territory often relegates initiation of treat-
ment of mild hypertension, type II diabetes and hyperlipidemia, obesity or poor
fitness to the back burner to be dealt with after chemotherapy. There is generally
little discussion by oncologists of behavioral approaches to improve the cardiovas-
cular risk profile. On the other hand automatic referrals of women to general inter-
nists to have their mild hypertension normalized before instituting chemotherapy
can have untoward consequences as decreases in blood pressure and postural hypo-
tension often occur with commonly used chemotherapeutic agents for breast cancer
including anthracyclines and taxanes.
Development of simple evidence based oncology guidelines for the optimal
screening of asymptomatic women for cardiac risk factors, and timing of initiation
of treatment for reversible conditions should have major importance in the survivor-
ship research agenda. This is will take a collaborative effort between Medical
Oncologists, Cardiologists and Primary Care Physicians. The International
CardiOncology Society (ICOS) was founded to review emerging trial evidence and
make recommendations to assess risk and provide treatment recommendations for
patients undergoing treatment for a variety of cancers (Lenihan et al. 2010).
216 C. Fabian

Need for Use of Standard Nomenclature to Describe Risk

and Severity of Cardiac Dysfunction

The increase in rates of clinical heart failure in pivotal trials of trastuzumab in women
with metastatic disease, especially those who were receiving or who had recently
received anthracyclines, prompted establishment of the Cardiac Review and
Evaluation Committee or CREC. Initial CREC criteria used to describe cardiac dys-
function and subsequently employed in many adjuvant trials were (1) cardiomyopa-
thy characterized by a global decrease in left ventricular ejection fraction (LVEF);
(2) signs or symptoms of congestive heart failure (CHF); (3) decline in LVEF of at
least 5 % to less than 55 % with signs or symptoms of CHF; or (4) decline in LVEF
of at least 10 % to less than 55 % without signs or symptoms of CHF (Seidman et al.
2002). The definition of cardiac dysfunction in oncology trials has differed some-
what from trial to trial making cross trial comparisons somewhat difficult. For exam-
ple a drop in LVEF by 10 points or more to less than 55 % was considered evidence
of cardiac dysfunction in the NSABP B-31 trial but the HERA trial required an abso-
lute drop of 10 points or more to an LVEF of less than 50 % (Tan-Chiu et al. 2005;
Piccart-Gebhart et al. 2005). Research in cardiac dysfunction/heart failure in breast
cancer survivors would be facilitated by agreement on standard terminology for
assessment in clinical trials. Use of American Heart Association criteria for heart
failure is appropriate: Stage A risk factors present but no structural damage; Stage B
structural damage but no signs or symptoms; Stage C structural damage with current
or prior symptoms; and Stage D structural damage with symptoms with any physical
activity or at rest (Yancy et al. 2013) (see Table 14.2). Asymptomatic reduction in left

Table 14.2 American Heart Association criteria for heart failure (Yancy et al. 2013) and treatment
by stage
New York
Heart Current Treatment
AHA heart failure stage Association Recommendations (Rx) Research needed
Stage A: High risk but I Correct risk factors: Predictive model of
no structural damage hypertension, transition A to B
hyperlipidemia, diabetes, Protective Rx to prevent
obesity. poor fitness, A to B transition
alcohol and smoking Application research
Stage B: Structural I Correct risk factors Sensitive monitoring
damage but no signs or B blockers, ACEI tools detect A to B
symptoms of heart failure or ARBs as appropriate transition
(LVEF < 50 % but usually Rx to allow cardiotoxic
>40–45 %) drugs
Stage C: Structural heart I-IV Discontinue cardiotoxic Rx to allow
disease. prior or current drug re-institution of
symptoms (LVEF <40 %) Heart failure therapy cardiotoxic drugs once
compensated
Stage D: Symptoms IV Heart failure therapy N/A
at rest or any physical
activity
14 Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors 217

ventricular ejection fraction (LVEF) by 10 or more points to <50 % is generally

viewed as representative of the Stage A to Stage B transition and is associated with a
significant increase in cardiac mortality (Lenihan et al. 2013). Consequently, an
asymptomatic reduction in left ventricular ejection fraction by 10 or more points to
<50 % has come to represent a surrogate endpoint for cardiac injury in clinical trials
and in the remainder of this manuscript will be referred to as subclinical cardiac
toxicity and/or cardiac dysfunction.

Drug Related Cardiac Toxicity

Although many drugs can result in cardiac damage (Yeh et al. 2004; Bovelli et al.
2010), we will focus here on the two most commonly used types of agents with the
greatest potential for cardiac dysfunction, namely anthracyclines and HER-2 tar-
geted agents.

Anthracyclines

Anthracyclines increase free radical formation, mitochondrial oxidative stress, dis-

ruption of myofibrils, apoptosis of cardiomyocytes, and reduction of the cardiac
stem cell pool (Kumar et al. 1999; Zhang et al. 2012; De Angelis et al. 2010).
A recent meta-analysis suggests that without regard to dose, treatment with anthra-
cyclines increases clinical cardiac toxicity, usually manifested as heart failure, by
approximately fivefold, subclinical toxicity by sixfold, and the risk of cardiac death
by fivefold (Smith et al. 2010). The absolute risk of clinical or subclinical cardiac
toxicity depends upon the type of anthracycline, the cumulative dose, exposure to
additional cardiotoxic agents, patient age, African American race, and other co-
morbidities (Bowles et al. 2012; Lotrionte et al. 2013; Perez et al. 2004; Bird and
Swain 2008). By the time significant changes are noted in LVEF (drop of 10 or more
points to <50 %) permanent damage has generally already occurred.
Clinical heart failure is very rare in healthy individuals taking a cumulative
doxorubicin dose of 240 mg/m2 (the average with four cycles of doxorubicin and
cyclophosphamide) unless other cardiotoxic agents are being administered concom-
itantly; but subclinical cardiac toxicity (an asymptomatic decrease in LVEF by 10
or more points to <50 %) was reported in 3.3 % of healthy women with a median
age of 52 receiving four cycles of this anthracycline based regimen with short
follow-up (Perez et al. 2004). A recent review of 18 studies with over 20,000 women
treated with anthracyclines at varying cumulative doses and followed for a median
of 9 years, reports an asymptomatic drop in LVEF to <50 % occurred in 18 %; and
symptomatic cardiac toxicity, primarily heart failure, occurred in 6 % (Lotrionte
et al. 2013). Clinical heart failure in the 40 % of women with breast cancer over 65
treated with anthracyclines is substantially higher due in large part to the underlying
presence of asymptomatic heart disease. Using data from a large SEER data base,
218 C. Fabian

38 % of women age 66–70 at the time they took anthracycline-based chemotherapy

had developed congestive heart failure 10 years later compared to 32 % of women
taking non-anthracycline chemotherapy and 29 % of women not taking any chemo-
therapy (Pinder et al. 2007).
Epirubicin is ~60 % less likely to result in cardiac toxicity than doxorubicin and
liposomal doxorubicin has a 22 % lower risk than doxorubicin. Finally, continuous
infusion doxorubicin over several days has approximately one-fourth of the cardiac
toxicity as bolus doxorubicin (Smith et al. 2010).
The substantially higher rates of congestive failure in women over 65 taking
bolus doxorubicin suggests that most older women should receive either non-
anthracycline containing regimens, less toxic forms of anthracyclines, or protective
therapy. Continuing research in this are using sensitive biomarkers to predict a drop
in left ventricular ejection fraction area the abnormal range with early intervention
prior to drop in ejection fraction is warranted (see below).
Inhibition of topo-isomerase II DNA binding appears to be an important factor in
both anthracycline induced tumor cell death and cardiomyocyte injury. However,
recent evidence suggests that TOP2A may be the primary target for doxorubicin
induced tumor cell death whereas TOP2B may be the primary intermediate in car-
diac induced injury (Vejpongsa and Yeh 2014). These data suggest that develop-
ment of TOP2A specific anthracyclines may be an important future area of research
(Sawyer 2013).

Trastuzumab and Other HER-2 Targeted Agents

The epidermal growth factor receptors are involved in proliferation and regenera-
tion, metabolism, differentiation and cell survival. HER-2 (ErbB2) is one of four
epidermal growth factor receptors expressed on the surface of cardiomyocytes as
well as breast cancer cells. Hetero- or homo-dimerization of receptors is necessary
for downstream signaling. ErbB2 has no identified natural ligand but is the preferred
binding partner for the other ErbB receptors. Dimerization of HER-2 can be induced
by an increase in receptor concentration or by ligand binding (EGF, TGF alpha and
amphiregulin for ErbB1 and neuregulin for ErbB3/4) with one of the other ErbB
receptors. Homo-dimerization of ERbB2 or hetero-dimerization of ErB2 and
ErbB3 in HER-2 amplified breast cancer leads to a dramatic increase in proliferative
and survival signals primarily through the PI3 kinase pathway (De Keulenaer et al.
2010). ErbB2 is expressed at low levels in the adult heart and is up regulated in
response to stress or injury (such as with anthracyclines) (De Keulenaer et al. 2010).
Neuregulin is released by endothelial cells and once bound to ErbB4 results in
hetero-dimerization with ErbB2 and proliferation of cardiac progenitor cells and
possibly de-differentiation and proliferation of differentiated cardiomyocytes (De
Keulenaer et al. 2010; Hervent et al. 2012). Trastuzumab binds with ErB2, disrupt-
ing the Neuregulin 1β /ErB2/ErbB4 complex which in turn prevents proliferation of
cardiac progenitor cells in response to stress (Bersell et al. 2009; Fedele et al. 2012).
Investigators are looking at rational designs for HER-2 targeted agents which will
14 Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors 219

not disrupt the neuregulin/ErbB4 complex (Fedele et al. 2012). Use of neuregulin to
prevent or treat preclinical cardiac damage is also of interest (Bersell et al. 2009).
Trastuzumab without prior anthracyclines or other underlying cardiac risk fac-
tors may be associated with declines in LVEF but generally not irreversible heart
failure. However, both asymptomatic cardiac dysfunction and symptomatic heart
failure occur more frequently in individuals given trastuzumab after or concomi-
tantly with an anthracycline compared to an anthracycline alone (De Keulenaer
et al. 2010; Perez et al. 2008; Gianni et al. 2011; Goldhirsch et al. 2013). Utilizing
CREC criteria, trastuzumab with a taxane in women with prior anthracycline expo-
sure had a cardiac dysfunction rate of 13–16 % and a New York Heart Association
class III or IV heart failure rate of 2–4 % whereas trastuzumab used concomitantly
with anthracyclines was associated with a cardiac dysfunction rate of ~27 % and a
New York Heart Association class III or IV heart failure rate of ~16 % in early trials
(Seidman et al. 2002). A recent update of the Herceptin Adjuvant or HERA trial in
which one or 2 years of trastuzumab was given after adjuvant therapy, cardiac
adverse event leading to discontinuation occurred in 9.4 % of women on the 2 years
arm vs. 5.2 % of women on the 1 year arm. All but 12–20 % of women with signifi-
cant LVEF declines recovered with less than 1 % developing symptomatic conges-
tive heart failure (de Azambuja et al. 2014). Risk factors for cardiac dysfunction in
addition to anthracyclines for women receiving adjuvant trastuzumab are age >60,
a borderline normal left ventricular ejection fraction (50–55 %) at baseline and pre-
existing hypertension (Tan-Chiu et al. 2005). Despite theoretical concerns, using
two HER-2 targeted agents simultaneously such as pertuzumab and trastuzumab or
lapitinib and trastuzumab does not appear to increase cardiac toxicity to a greater
extent than trastuzumab alone, although there is limited long term experience
(Valachis et al. 2013; Baselga et al. 2012).
Older women are likely to have one or more cardiac risk factors at baseline and
were under-represented in clinical trials. An analysis from a Medicare claims data
base of women 67 and older with early breast cancer indicates that 32 % had evi-
dence of cardiac dysfunction or heart failure if they took trastuzumab alone, 42 % if
they received both trastuzumab and anthracyclines but only 18 % of those receiving
no adjuvant therapy (Vaz-Luis et al. 2014). Another population based study of
women >65 most of whom took their trastuzumab concomitantly with chemother-
apy noted a 3.6 % hospitalization rate for cardiac events during treatment (Chen
et al. 2012) Research with cardio-protective regimens coupled with biomarkers of
early injury is needed targeting older women receiving trastuzumab or others with
baseline risk factors for cardiac dysfunction (Wells and Lenihan 2010).

Physical Activity and Cardiorespiratory Fitness

Although, oncologists are increasingly aware of the potential adverse effects of

excessive weight on breast cancer outcomes and mortality, there has not been the
same emphasis on physical activity and cardiorespiratory fitness.
220 C. Fabian

Physical activity is associated with lower cardiovascular, all cause and breast
cancer mortality (George et al. 2011; Irwin et al. 2011; Dhaliwal et al. 2013). In the
Women’s Health Initiative 9 MET hours or about 3 h of fast walking per week pre
or post diagnosis of breast cancer was enough to see an ~40 % decrease in breast
cancer and all-cause mortality compared with sedentary women (Irwin et al. 2011).
The important message then for women is to become active even if they were not
prior to their diagnosis of breast cancer.
Cardiorespiratory fitness as measured by oxygen consumption at peak exercise
(VO2max or VO2peak) is correlated with cardiovascular and all-cause mortality (Peel
et al. 2009). In a general population increasing fitness by only one metabolic equiva-
lent (1 MET corresponds to 3.5 mL/min/kg of oxygen consumption) is estimated to
reduce risk of death by 13 % (Kodama et al. 2009). Individuals with low CRF (<7.9
METs) had a 40 % increase in all-cause mortality and 47 % increase in risk for
cardiovascular events compared with those with intermediate CRF (7.9–10.8
METs). Women with low CRF had a 70 % increase in all-cause mortality and 56 %
increase in cardiovascular events compared to those with high CRF (≥10.9 METs)
(Kodama et al. 2009). Further, fitness may be a more important predictor of mortal-
ity than Body Mass Index (BMI) until one reaches the extremes of obesity where
serious metabolic abnormalities are prevalent. In a recent meta-analysis, fit over-
weight and obese women had similar mortality as fit normal weight women, and
were generally better off than normal weight unfit women unless the obese fit
woman also had a chronic disease (Barry et al. 2014). 150 min of moderate physical
activity per week or that sufficient to expend at least 1,000 Kcal per week is likely
to allow most women to attain at least the lower bound of the intermediate CRF
category (Lee and Skerrett 2001).
Women with breast cancer appear to have lower baseline CR fitness than age-
matched individuals without cancer and fitness declines during treatment (Jones
et al. 2012; Peel et al. 2014). Low fitness was reported in approximately half of
women who had undergone chemotherapy with anthracyclines + taxanes with or
without trastuzumab ~2 years after chemotherapy completion despite a normal
LVEF in all but 8 % (Jones et al. 2007). These rates were dramatically higher than
age-matched controls who had not received chemotherapy (Jones et al. 2007).
Research efforts need to focus on effective interventions which will prevent
reduction of physical activity and fitness during and after treatment. Courneya et al.
using a supervised aerobic and strength training exercise program have demon-
strated that higher volume exercise can be safely delivered during adjuvant treat-
ment, which in turn appears correlated with improved disease free and overall
survival (Courneya et al. 2013, 2014). Higher intensity exercise may also favorably
modulate pro-inflammatory biomarkers associated with cardiovascular disease risk
(Fairey et al. 2005).
Methods to safely increase physical activity and fitness in a more practical,
home-based environment following initial in-person training need to be a research
priority, particularly for older women and those with a low level of fitness at base-
line. Preliminary pilot studies suggest this is possible (Burnett et al. 2013).
Further, simplified methods of assessing fitness which can easily be employed in
14 Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors 221

an oncologist’s office such as the 6 min step test need to be validated against more
complex tools such as VO2max or VO2peak (Hamilton and Haennel 2000; Simonsick
et al. 2006).

Risk Prediction Models for Cardiac Toxicity

Prediction models in older women at highest risk for cardiac toxicity have been sug-
gested using variables of age, type of adjuvant therapy, and prior history of hyper-
tension, diabetes, and symptomatic heart disease (Ezaz et al. 2014). Research is
needed to develop more sensitive and specific cardiac dysfunction prediction mod-
els for women considering potentially cardiotoxic therapy which would include risk
biomarkers and historical variables. These prediction models would ideally have the
ability to include some of the new very sensitive indicators of left ventricular func-
tion (Fallah-Rad et al. 2011), in addition to weighted factor scores for age, BMI, a
measure of physical activity or cardiorespiratory fitness, hypertension, diabetes,
dyslipidemia, and any prior cardiac event. Ideally the models could also be adapted
to include provision for genetic polymorphisms predisposing to cardiac risk such as
the common HER-2 Ile655Val allele in the HER-2 gene (Beauclair et al. 2007), and
polymorphisms in NADPH oxidase, MDR 1, MDR 2, catalase, superoxide dis-
mutase, NADPH:quinone oxidoreductase, carbonyl reductase 3, and glutathione
s-transferase (Wojnowski et al. 2005; Deng and Wojnowski 2007).

Monitoring Cardiac Function During Treatment

with Cardiotoxic Agents

Cardiac MRI is a sensitive method for detecting left ventricular remodeling and
early subclinical cardiac toxicity and is considered by some to be the gold standard
(Fallah-Rad et al. 2011). It is currently being used in the MANTICORE trial to
measure left ventricular end diastolic volumes (see below). However, cardiac MRI
is expensive and thus not optimal for serial monitoring in the clinical community
setting (Bellenger et al. 2000). Longitudinal or global left ventricular strain, which
can be calculated from an echocardiogram with the appropriate software, is a mea-
sure of cardiac muscle deformability. The greater the negative value the more pow-
erful the contraction. Normal strain values vary with age, sex and the software
system used from approximately −15 to −22 (Yingchoncharoen et al. 2013; Cheng
et al. 2013), but a value of −19 or more negative is highly unlikely to be associated
with cardiac dysfunction or clinical congestive heart failure over the ensuing 3
months of cardiotoxic treatment (Sawaya et al. 2011, 2012). Adding a serum tro-
ponin drawn before and immediately after chemotherapy to left ventricular strain
is reported to improve both sensitivity and negative predictive value for left ven-
tricular dysfunction after anthracyclines (Fallah-Rad et al. 2011; Cardinale et al. 2010).
222 C. Fabian

Although some studies have suggested additional serum markers such as and high
sensitivity c-reactive protein (hsCRP) may aid in predicting cardiac dysfunction,
others have not found that the addition of serum biomarkers in addition to troponin
to substantially increase sensitivity (Onitilo et al. 2012), in 78 patients receiving
both doxorubicin and trastuzumab, found the addition of hsCRP and BNP did not
add additional predictive information to ultrasensitive troponin and myeloperoxi-
dase in predicting dysfunction by CREC criteria (Ky et al. 2014). 3D echocar-
diography may be more sensitive than 2D to declines in left ventricular function
(Khouri et al. 2014).
Studies incorporating one or more of these markers into the monitoring process
for cardiac toxicity (i.e., PREDICT trial) are currently ongoing. Left ventricular
strain has perhaps the greatest potential in that the software is relatively easy to add
to an echocardiogram machine and is a non-invasive procedure. Unfortunately,
there are variations in the software and interpretations of results such that at present
there is not a clear indication as to what constitutes a definitely abnormal strain or
the amount of change which should be viewed with alarm.
Trials comparing the relative efficacy of newer sensitive biomarkers of subclinical
injury prior to significant decline in 2D echo left ventricular ejection fraction, includ-
ing high sensitivity troponin and other serum biomarkers, left ventricular strain, and
cardiac MRI are ongoing and results are awaited with interest. Translational trials
incorporating prophylactic treatment with beta blockers and angiotensin converting
enzyme inhibitors at first signs of subclinical dysfunction are warranted.

Treatment of Cardiac Dysfunction

Beta blockers, angiotensin converting enzyme inhibitors (ACEI), and angiotensin

receptor blockers (ARBs) are commonly used to treat heart failure regardless of the
inciting event. They are recommended in the general cardiovascular setting for asymp-
tomatic women with a drop in left ventricular ejection fraction below 40 % or women
with symptomatic congestive heart failure regardless of the amount of decline in
LVEF (Yancy et al. 2013). Patients who develop symptomatic cardiac dysfunction
while on treatment with a cardiotoxic agent should be treated as would anyone not on
chemotherapy (Yeh et al. 2004). For women with early breast cancer, treatment with
the cardiotoxic agent should be discontinued and non-cardiotoxic therapy substituted
where possible. For women with metastatic HER-2 amplified breast cancer, temporar-
ily discontinuing HER-2 targeted agents, treatment with blockers and ACEIs and then
cautious re-introduction of the HER-2 targeted agent is often successful with contin-
ued indefinite use of the beta blocker and ACE inhibitor (Vaz-Luis et al. 2014).
What about asymptomatic women with subclinical cardiac toxicity whose LVEF
is below 50 % but above 40 %? From the general population experience, it is clear
that individuals with an asymptomatic ejection fraction below 50 % have a ~3.5-
fold increase in all- cause mortality over the ensuing 9–10 years (Yeboah et al.
2012a). Use of ACEI and beta blockers in women with LVEF <50 %, and appropriate
14 Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors 223

surgical treatment of heart valve problems resulting from radiation or medical or

surgical treatment of coronary artery blockage is suggested (Lenihan et al. 2013;
Lenihan 2012).

Prophylactic Treatment with Cardioprotective Drugs

An area gaining momentum is the use of prophylactic drugs to reduce the incidence
of asymptomatic left ventricular dysfunction (Swain and Vici 2004; van Dalen et al.
2008), particularly if early warning biomarkers can be used to trigger the use of the
agent. Prophylactic cardioprotective therapy is not a new concept. A decade ago
Swain et al. published a study suggesting doxorubicin induced cardiac toxicity can
be reduced ~70 % by also giving the iron chelating agent dexrazoxane (Smith et al.
2010; Swain and Vici 2004). The current recommendation is that dexrazoxane can
be given prophylactically once the cumulative doxorubicin dose exceeds 300 mg/m2
(Yeh et al. 2004). Dexrazoxane is not widely used in clinical practice due to con-
cerns that it may reduce effectiveness of doxorubicin as it binds to both TOPO 2A
and TOPO 2B (Sawyer 2013).
Since individuals with a low LVEF, even if asymptomatic, have an increased risk of
cardiac events and mortality, prophylactic cardio-preventive treatment trials are ongoing
in the adjuvant setting of HER-2 positive breast cancer. Several small trials have shown
cardioprotective effects of ACEI or beta blockers, especially when given with anthracy-
clines (Kalay et al. 2006; Bosch et al. 2011). Adjuvant trials with endpoints of symptom-
atic heart failure or a 2D echo measured LVEF of <50 % would require a very large
number of participants. An alternative approach is to use a more sensitive indicator of
early cardiac dysfunction. In the MANTICORE trial (Fig. 14.1) women taking trastu-
zumab are randomized to prophylactic cardiac protective therapy with beta blockers
and/or ACEI but the primary outcome is change in left ventricular end diastolic volume
as measured by cardiac MRI (Pituskin et al. 2011). With this endpoint as opposed to 2D
echo LVEF, the trial coordinators are predicting that 158 randomized subjects will be
adequate. Another approach to assess the benefit of prophylactic therapy is to use the
traditional endpoint of LVEF drop by 10 points to <50 % but with a much higher risk
group as the cohort, such as women with HER-2 amplified metastatic disease. Since
these women have generally been previously treated with cardiotoxic drugs and since
survival is dependent on being able to continue to receive HER-2 targeted therapy after
first progression, the study question is of practical importance (Extra et al. 2010). Such
a trial has been proposed in the Southwest Oncology Group Survivorship Committee in
women with first and second line HER-2 amplified metastatic disease on HER targeted
therapy with LVEF >50 % at baseline to determine whether prophylactic beta blocker
therapy with Carvedilol will reduce cardiac dysfunction (See Fig. 14.2). Other target
populations for prophylactic cardio-protective therapy where the event rate is likely to
be high in either the metastatic or adjuvant setting are women 70 or over, high coronary
artery calcium, and hypertension, or a high score on a CVD risk prediction model
(Yeboah et al. 2012b).
224 C. Fabian

Fig. 14.1 Design of the multidisciplinary approach to novel therapies in cardiology oncology
research trial (MANTICORE 101-Breast) (Kalay et al. 2006)

Fig. 14.2 Design of a proposed SWOG trial concept

14 Prevention and Treatment of Cardiac Dysfunction in Breast Cancer Survivors 225

Looking Forward

Priorites for cardio-oncology research in breast cancer are summarized in Table 14.3.
Developing biomarkers and models to predict cardiac dysfunction, developing less
cardiotoxic drug regimens and preventive therapy for high risk individuals, more
sensitive monitoring techniques for cardiac dysfunction and treatment guidelines
which might permit continuation of therapy are all important. This will take a co-
ordinated research efforts of oncologists, cardiologists, and internists. An equally
pressing issue is once these new treatments and guidelines are established, what
type of clinical environment and training will be needed to carry them out all in a
cost effective manner. Are we going to cross train oncologists in cardiology and
cardiologists in oncology? With a forecast of 40 % shortage of medical oncologists
over the next decade, and similar or worse shortages for general internists and car-
diologists is this even reasonable? The answer is yes. After all we all started out
with training in general internal medicine and most oncologists still carry a stetho-
scope. Cardiologists with a particular interest in heart failure can receive training in
this area through combined disciplinary meetings and seminars. Many oncologists
are very interested in prevention and survivorship issues but to date there have been
financial disencentives to anything other than administering chemotherapy. This
needs change. Older oncologists considering retirement might be persuaded to stay
in the field a little longer if their practice could be focused on prevention and survi-
vorship issues, and more emphasis on prevention and survivorship with cross

Table 14.3 Areas of research need and opportunity in cardio-oncology

1. Develop standard nomenclature to describe cardiac dysfunction following treatment
2. Develop Sensitive biomarkers and models which will predict dysfunction (i.e., drop in LVEF
or transition from Stage A to B Heart Failure)
3. Develop less cardiotoxic chemotherapy
Develop TOPO 2A specific anthracyclines
Non-anthracycline containing regimens
HER-2 targeted agents which will not disrupt neuregulin/ERβ
4. Develop cardioprotective drug regimens
Establish efficacy and safety
Clinical and biomarker indications for use
5. Develop behavioral interventions for survivors which improve fitness and CV health
Develop safe but effective home-based interventions to increase fitness
Develop interventions to increase exercise uptake and compliance
Simple office-based techniques for serially assessing fitness
6. Guidelines for monitoring cardiac function during and after cardiotoxic treatment
7. Guidelines for treatment of cardiac dysfunction and continuing/re-instituting cancer
treatment
226 C. Fabian

disciplinary training needs to become an important part of oncology fellowship

training. Guidelines and pathway development will make it easier to incorporate
general internists and nurse practioners pre, during and post treatment phases of
potentially cardiotoxic treatment.

Conclusion

Development of easy to use tools which will combine clinical factors and biomarkers
to identify those individuals at highest risk for development of cardiac dysfunction,
sensitive biomarkers of cardiac injury which will detect reversible cardiac structural
change and to develop prophylactic treatments to prevent women from developing
early stage cardiac dysfunction or progression to a later stage is a challenge for
cardio-oncology survivorship research.

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Chapter 15
Psychological Adjustment in Breast
Cancer Survivors

Annette L. Stanton and Julienne E. Bower

Abstract Women living with a diagnosis of breast cancer constitute more than
20 % of the cancer survivor population in the United States. Research on trajectories
of psychological adjustment in women recently diagnosed with breast suggests that
the largest proportion of women evidences relatively low psychological distress
either from the point of diagnosis or after a period of recovery. Substantial hetero-
geneity exists, however, and some women are at risk for lingering depression, anxi-
ety, fear of cancer recurrence and other long-term psychological effects. Most
women diagnosed with breast cancer also report a number of benefits that arise from
their experience of cancer. Longitudinal studies have illuminated risk and protective
factors for psychological adjustment in breast cancer survivors, which we describe
in this chapter. Effective psychosocial interventions, as evidenced in randomized
controlled trials, also are available for bolstering breast cancer-related adjustment.
We offer directions for research to deepen the understanding of biological, psycho-
logical, and social contributors to positive adjustment in the context of breast can-
cer, as well as suggestions for the development of optimally efficient evidence-based
psychosocial interventions for women living with the disease.

Keywords Breast cancer • Psychological distress • Quality of life • Randomized

controlled trial • Intervention • Survivorship

Introduction

At the beginning of 2012, the number of women living with a history of breast
cancer in the United States was nearly three million, or 22 % of the survivor popula-
tion. By 2024, the cancer survivor population is projected to approach 19 million
(American Cancer Society 2014). In this chapter, we aim to characterize negative

A.L. Stanton (*) • J.E. Bower

Departments of Psychology and Psychiatry/Biobehavioral Sciences,
Jonsson Comprehensive Cancer Center, University of California, Los Angeles CA, USA
e-mail: [email protected]; [email protected]

© Breast Cancer Research Foundation 2015 231

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_15
232 A.L. Stanton and J.E. Bower

and positive psychological outcomes in women diagnosed with breast cancer, as

well as their contributors. We also address implications for future investigation in
this area, including psychosocial intervention research. Although they are important
phenomena that certainly have psychological concomitants and consequences, we
do not discuss outcomes that are covered in other chapters in this volume (i.e.,
fatigue, cognitive dysfunction, neuropathy, sexual health). We also do not address
the experience of women with metastatic breast cancer, as covered in Chap. 16, or
prominent issues for young breast cancer survivors, as described in Chap. 2.

The Nature of Psychological Adjustment

in Breast Cancer Survivors

What constitutes “good” psychological adjustment in the breast cancer context?

Most research focuses on low or absent symptoms of depression, anxiety, or general
or cancer-specific distress (e.g., fear of cancer recurrence, intrusive thoughts and
feelings related to cancer) to indicate positive psychological adjustment. Reports of
positive quality of life in social, physical, psychological, and spiritual realms,
positive mood, and perceptions of cancer-related benefits (e.g., deepened relation-
ships) also are used to signify positive adjustment.
Initially, receiving a breast cancer diagnosis is profoundly stressful for most
women. Many feel that cancer is a death sentence and poses an immediate threat to
their physical well-being; they may also be concerned about side effects of breast
cancer treatments. Indeed, research suggests that symptoms of anxiety and depres-
sion are highest at the time of breast cancer diagnosis (Stafford et al. 2013). Patients
may experience symptoms of shock, disbelief, denial, or despair as they struggle to
accept and incorporate the reality of the diagnosis. This initial stage may be fol-
lowed by a period of turmoil and distress, characterized by symptoms of anxiety,
sadness, ruminative thoughts, irritability, and difficulty sleeping, eating, and con-
centrating. These symptoms typically stabilize as patients adjust to new informa-
tion, make decisions about treatment, and resume their normal activities. However,
elevations in symptoms may occur during other transition points, including treat-
ment onset, treatment completion (the “re-entry” phase), and cancer recurrence.
Prospective research suggests that a diagnosis of breast cancer also confers risk
for compromised longer-term adjustment, although substantial heterogeneity exists.
Specifically, population-based longitudinal research documents decrements in
quality of life and indicators of psychological and physical functioning that can
persist for years among women who receive a breast cancer diagnosis versus those
with no incident cancer. For example, 759 women were diagnosed with breast can-
cer over a 4-year period in the Nurses’ Health Study cohort of 48,892 women
(Michael et al. 2000). In analyses controlling for multiple covariates, diagnosed
women, and particularly those aged 40 and younger (Kroenke et al. 2004), evi-
denced an increase in pain and declines in physical and social function, vitality, and
15 Psychological Adjustment in Breast Cancer Survivors 233

ability to perform emotional and physical roles, relative to women who did not
receive a cancer diagnosis. Problems resolved over time, but significant group
differences persisted in four of seven quality of life domains up to 4 years after
diagnosis. Of note, mental health (including feelings of anxiety and sadness) was
the one domain that did not decline following a breast cancer diagnosis, suggesting
that initial elevations in these symptoms do not persist for most women.
Although such large-scale studies document the life disruption that accompanies
a breast cancer diagnosis, they do not pinpoint specific periods in cancer survivor-
ship during which women are at risk for decrements in psychological and physical
health. In addition, studies that examine overall patterns of adjustment may mask
individual differences in patient outcomes—for example, do all (or most) women
evidence declines in quality of life after breast cancer diagnosis, or are these declines
driven by a subgroup of survivors? Over the past decade, studies have begun to
examine distinct trajectories of adjustment, which provide insight into the periods
that are most distressing and the people who are most at risk for distress. As shown
in Fig. 15.1, an investigation in the Netherlands beginning prior to surgery and
concluding 6 months after treatment completion indicated four unique trajectories
of psychological distress in 171 women diagnosed with breast cancer: 36 % reported
no or minimal distress across the five assessment points, 33 % evidenced distress
from the point of diagnosis through medical treatment and then a decline in distress
(i.e., recovery), 15 % reported heightened distress beginning at treatment comple-
tion and through the next 6 months (i.e., re-entry phase), and 15 % experienced high
distress throughout the study period (Henselmans et al. 2010).

Fig. 15.1 Trajectories of distress in the first year after breast cancer diagnosis (N = 171;
Henselmans et al. 2010). Predicted (solid lines) and observed (dashed lines) levels of distress are
displayed. “Case” indicates psychological morbidity (i.e., a score of 4 or greater on the General
Health Questionnaire-12)
234 A.L. Stanton and J.E. Bower

Another trajectory study that assessed 285 breast cancer patients in China from
5 days to 8 months after surgery also found four trajectories: 66 % reported low
distress across the assessment period, 12 % reported elevated distress at 5 days and
1 month that resolved by 3 months after surgery (i.e., recovery pattern), 7 % showed
increased distress that recovered by 8 months (delayed recovery), and 15 % experi-
enced high distress across the assessment period (Lam et al. 2010). In a trajectory
study with extended follow-up, which began shortly after initiation of chemotherapy
and spanned more than 4 years after diagnosis (Helgeson et al. 2004), the largest
proportion of the breast cancer patient sample reported quality of life matching or
exceeding population norms on both mental (43 %) and physical (55 %) functioning
across the 4 years, with other trajectories indicating either recovery or relatively
poor and/or declining functioning.
Overall, this research highlights the psychological resilience of women with
breast cancer and suggests that the largest proportion of breast cancer survivors can
expect generally positive adjustment either from the point of diagnosis and treat-
ment or after a period of recovery. However, heterogeneity is evident, and a notable
proportion (approximately 15 %) appears at risk for distress and life disruption from
the point of diagnosis onward for months or years (note that this group also likely
includes women whose relatively poor psychological adjustment precedes the can-
cer diagnosis). It also is possible that the most distressed women are more likely to
decline participation in research, leading to underestimates of prevalence of distress
and life disruption. Furthermore, there is evidence that groups with particular char-
acteristics, such as low-income and Latina women (e.g., Christie et al. 2010; Yanez
et al. 2011), experience relatively high distress and low quality of life. Next, we
address specific domains of adjustment, with a focus on depression and anxiety, as
well as the factors that confer risk for or protection from negative outcomes.

Negative Psychological Outcomes and Their Contributors

Depression

A meta-analysis of 66 studies of interview-diagnosed major depression in cancer

survivors in non-palliative care settings, including 24 studies of breast cancer
patients alone, demonstrated a 16.3 % prevalence of major depression, with a simi-
lar 14.1 % prevalence in breast cancer patients specifically (Mitchell et al. 2011).
These proportions contrast with general population norms of 12 % for women
aged 40–59 years and 7 % for women 60 years and older (Pratt and Brody, 2014).
The risk of depression appears to be most elevated in the first 1–2 years after diag-
nosis in cancer survivors generally (Krebber et al. 2014; Mitchell et al. 2013) and
in breast cancer patients specifically (Avis et al. 2013). Depression contributes to
decreases in quality of life and psychosocial and occupational functioning, inter-
feres with treatment adherence, and has been associated with shorter recurrence-free
survival (Satin et al. 2009).
15 Psychological Adjustment in Breast Cancer Survivors 235

Several risk factors for high depressive symptoms in breast cancer survivors have
empirical support. Most of the evidence comes from cross-sectional rather than
longitudinal studies, however, and reciprocal relationships or reverse causation is
likely. Psychosocial factors appear to be the strongest predictors of elevated depres-
sive symptoms, including prior history of depression, occurrence of other stressful
life events, use of avoidant coping strategies, loneliness, low social support, and
pessimism (Avis et al. 2013; Bardwell et al. 2006; Jaremka et al. 2013; Stanton and
Snider 1993). Other risk factors include younger age, fewer financial resources, and
presence of physical symptoms. Chemotherapy may be associated with elevated
risk for depression (e.g., Torres et al. 2013), but other disease and treatment-related
variables are typically not (Bardwell et al. 2006).

Anxiety and Fear of Breast Cancer Recurrence

The experience of breast cancer can trigger general feelings of anxiety, as well as
more specific concerns about cancer recurrence. A meta-analysis found that the
prevalence of interview-diagnosed anxiety disorders was 10.3 % among cancer
patients in non-palliative care settings (Mitchell et al. 2011). This figure is compa-
rable to the 13 % 6-month prevalence of anxiety disorders in the general population
of women (Pigott 2003). Whereas depression tends to improve in the year or two
after cancer diagnosis, anxiety is more likely to persist in the years after cancer
treatment. A meta-analysis comparing depression and anxiety in long-term cancer
survivors (i.e., those at least 2 years post-diagnosis) with healthy controls found an
elevated prevalence of anxiety in survivors (17.9 %) vs. controls (13.9 %) but no
differences in depression (Mitchell et al. 2013). Of note, this review included both
interview-diagnosed anxiety and patient-reported scales, which often yield higher
prevalence rates.
One of the factors that may maintain anxiety among breast cancer survivors is
concern about cancer recurrence. Indeed, worry that breast cancer may return after
treatment is among the most commonly experienced psychological sequelae (Koch
et al. 2012). In a review in cancer survivors generally, Koch et al. (2012) found that
most long-term survivors experience modest to moderate levels of fear of recur-
rence. Healthcare professionals find fear of recurrence challenging to manage
(Thewes et al. 2013).
Fear of breast cancer recurrence can be amplified or reactivated by several
triggers, such as follow-up medical visits, the experience of physical symptoms
such as new or persistent pain or fatigue, and cancer diagnosis or death of a public
figure, friend, or family member (Gil et al. 2004). Heightened fear of recurrence is
reported by adult survivors of younger age, lower educational level, fewer significant
others, and Hispanic or non-Hispanic white race/ethnicity (Crist and Grunfeld 2013;
Phillips et al. 2013). Lower optimism and social support, more family stressors,
depressive symptoms, pain, and other physical symptoms also are linked to higher
fear (Crist and Grunfeld 2013; Phillips et al. 2013).
236 A.L. Stanton and J.E. Bower

Cancer-related post-traumatic stress disorder (PTSD), as assessed via validated

interview or questionnaire, typically is found to occur in less than 10 % of cancer
survivors after treatment completion and to decline over time (e.g., Kangas et al.
2002). Women at most risk tend to be younger, have more serious disease and
aggressive therapy, and be more likely to have experienced PTSD previously
(e.g., O’Connor et al. 2011). Symptoms of subthreshold PTSD, however, such as
intrusive thoughts and feelings, re-experiencing of cancer-related events, and avoid-
ance of reminders of cancer, are common among survivors in the 2 years after diag-
nosis. For example, in a nationwide Danish cohort of women receiving surgery for
breast cancer, 20.1 % and 14.3 % reported severe posttraumatic stress symptoms at
3 and 15 months after surgery, respectively (O’Connor et al. 2011). There is evidence
that African American and Asian American women are more at risk for breast
cancer-related post-traumatic stress symptoms than their non-Latina white counter-
parts (Vin-Raviv et al. 2013).

Positive Psychological Outcomes and Their Contributors

Along with the distress and life disruption attendant upon the experience of breast
cancer, many women find benefit in their experience and maintain positive mood
and quality of life. Indeed, we have found that more than 80 % of breast cancer
survivors report at least one positive change or benefit related to their cancer experi-
ence (Sears et al. 2003). Primary self-reported benefits involve strengthened inter-
personal relationships, life appreciation and commitment to priorities, spirituality,
personal regard, and attention to health behaviors. These changes have also been
described as “posttraumatic growth” (Tedeschi and Calhoun 1996). Reports of ben-
efit finding increase from the diagnostic and treatment phase through re-entry and
early breast cancer survivorship and level off at approximately 1 year after diagno-
sis (Danhauer et al. 2013; Manne et al. 2004). Long-term breast cancer survivors
also report cancer-related benefits (Mols et al. 2005), although finding benefit may
decrease in the long term (Bower et al. 2005).
Although findings are not completely consistent, longitudinal research suggests
that greater impact of the breast cancer diagnosis, in the form of higher perceived
threat and life disruption, promotes benefit finding. Greater intentional engagement
in the cancer experience, as indicated by more problem-focused coping and inten-
tional positive reappraisal, for example, also predicts benefit finding (Danhauer
et al. 2013; Sears et al. 2003; Stanton et al. 2006). Younger women typically report
higher levels of benefit finding than older women, and the correlates of benefit
finding may differ depending on age. Specifically, negative impact seems to be more
important for older women, whereas engagement may be more important for
younger women in promoting benefit finding. Social support can also enhance the
ability to find benefit in the experience of breast cancer (Danhauer et al. 2013;
McDonough et al. 2014; Schroevers et al. 2010). Although finding benefit can be
valuable in its own right, it also can contribute to improved psychological and health-
related outcomes into longer-term survivorship, as demonstrated by longitudinal
15 Psychological Adjustment in Breast Cancer Survivors 237

and experimental research (e.g., Bower et al. 2005; Carver and Antoni 2004; Stanton
et al. 2002). Benefit finding has also been linked to neuroendocrine and immune
function in women with breast cancer, including steeper diurnal cortisol slope (Diaz
et al. 2014), reduced serum cortisol (Cruess et al. 2000), and increased lymphocyte
proliferation (McGregor et al. 2004).

Directions for Psychosocial and Biobehavioral

Intervention Research

Randomized, controlled trials (RCTs) of interventions to reduce psychological

morbidities and enhance well-being in women with breast cancer have accumulated
rapidly over the past two decades. See Table 15.1 for examples of the approaches to
psychosocial intervention that have been most commonly used. Most of the research
has focused on the diagnostic and treatment phase, although RCTs designed to
promote adaptive survivorship into the re-entry phase and beyond are accruing
(Stanton et al. 2015). Reviews and meta-analyses demonstrate that efficacious cog-
nitive-behavioral and psychoeducational approaches exist for women diagnosed

Table 15.1 Psychosocial interventions for women diagnosed with breast cancer: major approaches,
goals, and mediators of effects
Major intervention approaches Primary intervention goals
Cognitive-behavioral therapy Identify and challenge unhelpful cognitions
and behaviors
Coping skills training Teach and practice contextually adaptive
coping strategies; Promote helpful thoughts
and behaviors
Psychoeducation Provide information about cancer and
strategies for adjustment
Supportive-expressive therapy Express feelings and thoughts in a group
supportive context
Problem-solving therapy Train in constructive set toward problems and
problem-solving
Mindfulness-based stress reduction Cultivate non-judgmental awareness of present
experiences
Relaxation training Teach relaxation skills (e.g., progressive
muscle relaxation)
Couples therapy Enhance disclosure, intimacy, and couple-
focused coping skills
Evidence-based classes of mediators of interventions’ effects
Altered cognitions (e.g., expectancies, illness representations)
Improved self-efficacy for using coping strategies and skills targeted by the intervention
Improved cancer-related psychological and physical symptoms (e.g., mood disturbance, pain)
Bolstered psychosocial resources (e.g., self-esteem)
Note Table content on mediators was based on a review of mediators of 16 psychosocial interven-
tions for cancer survivors that included examination of mediators of the intervention’s effects
(Stanton et al. 2013)
238 A.L. Stanton and J.E. Bower

with breast cancer (Faller et al. 2013; Stanton 2012; Tatrow and Montgomery 2006)
with regard to improving both psychological adjustment and symptoms specifically
related to cancer treatments (e.g., menopausal symptoms; Mann et al. 2012). Of
note, cancer survivors who are more distressed appear to get the most benefit from
these interventions (Faller et al. 2013), suggesting that treatments should be targeted
to those who are experiencing difficulties with adjustment.
Recent research also documents the efficacy of mind-body and other approaches
for improving psychological adjustment. For example, RCTs demonstrate the ben-
efits of yoga on depression and anxiety in breast cancer patients, at least over the
short-term and for women in active cancer treatment (Cramer et al. 2012).
Furthermore, mindfulness-based stress reduction is promising in its effects on
depression and anxiety in survivors of breast cancer (Zainal et al. 2013a.
Mindfulness-based interventions have also been shown to reduce fear of recur-
rence (Lengacher et al. 2009) and improve positive psychological outcomes in
breast cancer survivors, including peace and meaning in life (Bower et al. 2014).
Physical activity also can enhance quality of life and reduce breast cancer con-
cerns in women with breast cancer (Speck et al. 2010; Vallance et al. 2007).
Continued development of efficient interventions for women and their loved ones,
extension to diverse groups, and dissemination research are needed. Designing inter-
ventions for dissemination remains a significant challenge (Glasgow et al. 2012).
Effectiveness and efficiency of interventions will be promoted through several lines
of research. First, research to identify key mechanisms for interventions’ effects will
promote incorporating and strengthening those mechanisms to increase intervention
efficacy (Stanton et al. 2013). Second, in light of the evidence that a substantial pro-
portion of women adjust well psychologically in their own environments, research is
warranted to develop and test stepped-care interventions consistent with breast can-
cer survivors’ psychosocial needs and to target women most in need of psychosocial
care (see American Society of Clinical Oncology guidelines for screening, assess-
ment and care of symptoms of depression and anxiety in adults with cancer; Andersen
et al. 2014). Such research will increase efficiency and accessibility of interventions,
as will research to create broad reach of interventions through advanced technolo-
gies. Third, comparative effectiveness research to identify approaches that reduce
both cancer-related psychological morbidities and medical costs (e.g., emergency
room visits, interim physician appointments, medical treatment nonadherence) will
help justify weaving them into the fabric of standard care.

Research Challenges and Opportunities

Substantial progress over the past few decades is evident in the specification of
psychosocial and behavioral concomitants of breast cancer, identification of associ-
ated risk and protective factors, and development of evidence-based interventions to
improve psychosocial adjustment. Going forward, inter-professional collaborations
promise to develop the research base further. Translation of empirical findings into
increasingly effective and efficient strategies to prevent and treat psychosocial
15 Psychological Adjustment in Breast Cancer Survivors 239

morbidities are needed. In addition, evidence-based approaches to enhance well-

being and health require further development.
Continued investigation is vital to identifying biopsychosocial etiologies of spe-
cific problems (and symptom clusters), such as depression, fatigue, and pain. Intensive
longitudinal and experimental research is needed to assess biomarkers, psychological
processes, and social contexts that promote or impede positive psychosocial outcomes
in samples of breast cancer survivors. Examination of cohorts of breast cancer survi-
vors followed over time and compared to their disease-free counterparts are necessary
to understand the distinct influence that the cancer experience has on psychosocial and
biobehavioral outcomes. Research with existing large population cohorts [e.g.,
Hispanic Community Health Study/Study of Latinos (SOL)] would allow prospective
examination of adults from prior to cancer diagnosis through periods of survivorship
with respect to psychological and physical health outcomes. Use of brief, valid self-
report instruments, administered over time, can provide efficient assessment of prog-
ress and deterioration on those outcomes for both research and clinical use (Andersen
et al. 2014; Basch et al. 2012; Vodermaier et al. 2009).
Although relevant evidence is accruing, the existing psychosocial knowledge
base largely derives from studies of white, middle class, early-stage breast cancer
survivors treated at large cancer centers. Additional study is needed of women with
metastatic disease, fewer financial resources, and diverse backgrounds. Research
suggests that quality of life is compromised in ethnic/racial minorities diagnosed
with breast cancer relative to their majority group counterparts (e.g., Janz et al.
2008; Yanez et al. 2011). Although socioeconomic disparities account for some of
the difference in psychological outcomes, other factors clearly are at play in influ-
encing adjustment, and these warrant study. Research and intervention development
are needed with regard to lack of access to survivorship resources, the role of spe-
cific culturally grounded beliefs (e.g., fatalism) to psychosocial outcomes, and bar-
riers to effective communication with the medical team.
Nearly a decade has passed since the Institute of Medicine (IOM 2006, 2008)
urged comprehensive survivorship care after medical treatments are completed,
including provision of psychosocial care. As the mandate grows to integrate psy-
chosocial care into routine medical treatment over the survivorship trajectory
(Jacobsen and Wagner 2012), inter-professional collaborations in research and clin-
ical care will be essential (IOM 2013). Although much work remains, equipped
with the science at hand, we are well positioned to contribute to the next generation
of research and evidence-based practice to promote the well-being and health of the
millions of adults who are living beyond a breast cancer diagnosis.

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Chapter 16
Living with Metastatic Breast Cancer

Patricia A. Ganz and Annette L. Stanton

Abstract Although prevalence estimates are imprecise, growing numbers of

women in the United States are living longer with metastatic breast cancer, attribut-
able at least in part to the availability of effective targeted therapies. Women living
with metastatic disease are understudied, however, and substantial heterogeneity
exists in both the clinical characteristics of metastatic tumors and the physical and
psychological experience of patients living with the disease. Survivorship issues are
complex for patients who are living with metastatic disease over extended periods
of time, from years to decades. Newly diagnosed patients with stage IV disease are
confronting cancer for the first time, while others have metastatic disease as a result
of breast cancer recurrence. Many patients are able to live for years on stable medi-
cal regimens, and yet others live with a moving target of aggressive disease with
arduous treatments and uneven response. The psychological common denominator
is the experience of profound life threat and the accompanying uncertainty, for
both the affected woman and her loved ones. Maintaining life balance in the face of
metastatic disease, as well as managing pain, fatigue, and other physical and psycho-
logical symptoms are major challenges. Increasingly, the clinical approach to meta-
static disease reflects the consensus that palliative and supportive care are essential
from the point of diagnosis. To remedy the paucity of systematic research on women
living with metastatic breast cancer for extended periods, we offer directions for
research to understand the experience of metastatic breast cancer and to provide
evidence-based inter-professional care.

Keywords Metastatic breast cancer • Advanced cancer • Psychological distress •

Quality of life

P.A. Ganz (*)

UCLA Schools of Medicine and Public Health, Jonsson Comprehensive
Cancer Center, Los Angeles, CA, USA
e-mail: [email protected]
A.L. Stanton
Departments of Psychology and Psychiatry/Biobehavioral Sciences,
Jonsson Comprehensive Cancer Center, University of California,
Los Angeles, CA, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 243

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_16
244 P.A. Ganz and A.L. Stanton

Introduction

With all of the attention given to early breast cancer detection and the highly favor-
able outcomes for so many breast cancer patients (Desantis et al. 2014), the small
number of women with stage IV disease at diagnosis or who are living for extended
periods of time with metastatic disease as a result of breast cancer recurrence are
relatively neglected. Now, growing numbers of women and men live for extended
periods of time with metastatic disease, some with long durable remissions and oth-
ers moving from one treatment to the next. This change is attributable to the increased
numbers of targeted therapies, especially for hormone sensitive and HER-2 positive
disease. Some patients, particularly those with stage IV disease at diagnosis, may
enjoy complete remissions or long-lasting control of their disease for extended peri-
ods. Others, who experience recurrence of breast cancer after an initial disease-free
interval, usually have a more varied course both physically and emotionally. In this
chapter, we address the prevalence and clinical heterogeneity of metastatic breast
cancer, the physical and psychological consequences of long-term cancer-directed
therapy, the experience of women living with metastatic disease, ideally how care
should be delivered to these survivors, and the research challenges and opportunities
related to studying this growing population of breast cancer survivors.

The Nature of Metastatic Breast Cancer Today

Of the more than 232,000 cases of female breast cancer in 2014, only 5 % of white
women and 8 % of African American women are expected to be diagnosed initially
with stage IV breast cancer (Siegel et al. 2014). For many of these women meta-
static disease at presentation is occult and is identified due to aggressive staging,
although a substantial number have clinically apparent and symptomatic disease.
Very little attention has been devoted to newly diagnosed stage IV patients in
terms of their presentation characteristics and psychosocial needs. An interesting
and provocative analysis by Johnson et al. (2013) suggested that while the inci-
dence pattern of stage IV disease at diagnosis has been stable among women older
than 40 years, it has steadily increased among younger women, with estrogen
receptor positive disease accounting for much of the increase. Approximately
12,000 newly diagnosed women enter the ranks of those living with metastatic
breast cancer each year.
In contrast, it is exceedingly difficult to find data on the number of women who
are living with metastatic cancer as a result of recurrence—that is, how many are
newly recurrent each year for the first time (incidence) and the prevalence of women
living with recurrent metastatic disease. As one breast cancer advocate for patients
with metastatic breast cancer commented to us, “If we are not counted, we do not
exist.” The nature of metastatic disease varies substantially, with local recurrences
on the chest wall or skin that may seem limited, but can be a potential harbinger of
more distant disease. More often, recurrences are in regional or distant sites, and are
usually identified due to symptoms. Patterns of recurrence vary depending on the
16 Living with Metastatic Breast Cancer 245

initial tumor characteristics. Hormone receptor positive tumors can have very late
recurrences, often decades later. Thus the period of risk for recurrence can be
lengthy, especially in younger women for whom competing causes of death are less
frequent; for younger women, breast cancer is most often the cause of death, in
contrast to older women (Early Breast Cancer Trialists’ Collaborative Group 2005).
Thus, women living with metastatic breast cancer for long periods of time may have
a higher representation of younger women than for incident breast cancer. With
these two sources of women living with metastatic cancer (incident stage IV and
recurrent breast cancer), some have estimated that there may be as many as 160,000
women and men living with metastatic disease (http://mbcn.org/education/category/
most-commonly-used-statistics-for-mbc), but this estimate is uncertain.
Just as we now recognize multiple genomic subtypes of breast cancer at diagno-
sis, these subtypes can play out in different patterns of metastatic disease (e.g., early
vs. late recurrence; soft tissue vs. visceral disease; bone dominant). The options for
therapy will depend not only on the site and pattern of disease, but the disease-free
interval, what prior therapy has been given, and whether or not endocrine or HER
2-directed therapies are appropriate and available. Unlike the situation several
decades ago, we now have many additional endocrine therapies, and the ability to
use several sequential HER2-directed therapies has completely transformed what
was a rapidly fatal form of breast cancer. In addition, women with isolated ipsilat-
eral local recurrence that is excised have a survival benefit from the reintroduction
of chemotherapy, particularly in the setting of hormone receptor positive disease
(Aebi et al. 2014). Thus, the treatments and outlook for women living with meta-
static breast cancer today are varied, with some subsets of women living for extended
periods of time with stable, well controlled disease, and others requiring continuous
and serial therapies, with only modest responses. It is therefore difficult to general-
ize about the medical aspects of living with metastatic breast cancer.
While this chapter could focus on the important issues associated with end-of-
life care for women with advanced metastatic breast cancer, we have chosen instead
to address the complexities of survivorship for breast cancer patients who are living
with disease over extended periods of time from years to decades. As recently rec-
ognized in the Institute of Medicine report on the Delivery of High-Quality Cancer
Care (Institute of Medicine 2013), palliative and psychosocial care services should
be delivered to all patients with advanced cancer, as part of cancer care. We will
assume that we will strive toward this goal in all women who are living with meta-
static breast cancer, and in the sections below, focus on the consequences of endur-
ing ongoing disease-directed therapy in this setting.

The Metastatic Disease Experience and Consequences

of Long-Term Therapy

Just as the medical presentation of metastatic breast cancer is heterogeneous, so too

is the psychosocial experience for women living with the disease. Some women are
confronting cancer for the first time, others with recurrent disease are able to live for
246 P.A. Ganz and A.L. Stanton

many years on stable, well-tolerated medical regimens, and yet others live with a
moving target of more aggressive disease with arduous treatments and variable
response. The psychological common denominator is the experience of profound
life threat and concomitant uncertainty, for both the affected woman and her loved
ones. Maintaining a balance of attending to threatening and difficult thoughts, feel-
ings, and requisite medical demands while pursuing a meaningful and rewarding
life, is a major task of living with metastatic disease. Another common psychologi-
cal experience includes the need to alter major life goals as the cancer and its treat-
ment impinge on the ability to function in central roles or as one pursues specific
cherished life priorities while at the same time contending with limited energy.
Interpersonal challenges include garnering effective support and dealing with
concerns for the well-being of close family, children, and friends. In qualitative
interviews of women with recurrent breast or gynecologic cancer, most women
reported receiving emotional support from family and friends. Erosion of social
support also was evident, however, in perceptions of intentional distancing by some
close others, others’ lack of understanding that recurrent cancer indicates a chronic
illness, and women’s curtailing their requests for support so as not to burden others
(Thornton et al. 2014).
These and other challenges of living with metastatic disease are summarized in
Table 16.1. Some of the tasks overlap with those encountered by women managing
early-stage disease, but often are intensified in women with metastatic breast cancer
(e.g., fatigue), and others are unique to the experience of metastasized disease, such
as accepting stable disease as a desirable outcome of treatment. Particularly fre-
quent or severe problems are addressed in this section.
Pain and fatigue are the two most common symptoms experienced by women
living with metastatic breast cancer. Pain is often the first symptom of recurrent
breast cancer; in women with stage IV disease at diagnosis, it may also be a present-
ing symptom. Pain can result from the after effects of initial breast cancer surgery
and radiation, as well as in association with local recurrence and/or lymphedema.
The latter may produce both psychological consequences and physical sequelae,
such as arm heaviness and pain. Bone metastases and skeletal events (e.g., fractures)
have become less frequent with bisphosphonate therapy; however, women still may
suffer from severe pain and limitation of function as a result of bone metastases and
nerve entrapment syndromes. Fortunately, skeletal metastases are often very respon-
sive to radiation as well as analgesics, but the chronic and ongoing nature of pain
when metastatic disease is in the bones can be burdensome. Similarly, visceral dis-
ease (e.g., liver, intra-abdominal or thoracic) can be responsible for substantial pain
that is often more challenging to control. Cumulative toxicities from chemotherapy
and radiation therapy can also contribute to pain syndromes, such as post-taxane
neuropathy and radiation fibrosis and nerve entrapment. Scar tissue can lead to
functional limitations and associated pain.
Among the challenges of pain management in women living with metastatic
disease is their desire to be alert and functional, and not be dragged down by the
sedation of narcotics. Many women continue to work and actively manage their
households, and their reluctance to take analgesics on a regular basis may reduce the
quality of their pain control. Complementary and alternative medicine (CAM)
16 Living with Metastatic Breast Cancer 247

Table 16.1 Adaptive tasks faced by women with metastatic breast cancera
Physical and medical challenges
Managing physical symptoms and side effects (e.g., pain, fatigue)
Dealing with constant or changing treatment schedules
Accepting stable disease as a desirable outcome of treatment
Maintaining adequate communication with the medical treatment team
Fearing abandonment by the medical team
Deciding to end curative treatment and accepting palliative care
Psychological challenges
Coping with uncertainty and unpredictability
Perceiving a lack of control
Fearing dependency on others
Progressively losing functional ability
Maintaining valued life goals
Fearing death and suffering
Balancing hope with realistic preparations for the future
Managing complex emotions
Having unmet informational needs
Interpersonal challenges
Communicating with friends and family about illness and death
Feeling socially isolation and lacking emotional or instrumental support
Having concerns for loved ones
Spiritual and existential challenges
Making sense of and accepting the cancer diagnosis in the context of spiritual beliefs
Finding meaning in one’s life and death
Practical concerns
Knowing when and how to seek home help, transportation assistance, or other services
Managing financial and legal affairs
a
Adapted from Low et al. (2007) with permission

approaches are used by many women, although systematic and evidence-based data
are lacking. Cancer-directed therapies will often relieve pain, e.g., radiation, chemo-
therapy. CAM therapies may help with management of treatment side effects as
well. Because women living with metastatic breast cancer are hopeful for treatment
responses, they are highly motivated to find a therapy that will relieve pain as well
as prolong life. Some women move through serial treatments and look for experi-
mental opportunities.
Fatigue, which is another serious problem for women living with metastatic
breast cancer, is multi-factorial; contributors include the disease itself, treatments,
and probably deconditioning from the physical symptoms associated with the
disease. Proinflammatory cytokines, frequently elevated in advanced cancer (de
Raaf et al. 2012), may be responsible for cancer-related fatigue that can seem out of
proportion to the tumor burden. In addition, chemotherapy, radiation, and many of
the newer targeted therapies (e.g., everolimus) can contribute to ongoing fatigue
(Baselga et al. 2012). Although physical activity may be effective in relieving cancer-
related fatigue in patients with less tumor burden, in patients with metastatic disease,
some balance of energy conservation and physical activity may be the most appro-
priate strategy (Howell et al. 2013). CAM therapies such as yoga and Tai chi may be
effective, but may have to be done cautiously in the setting of bone metastases.
248 P.A. Ganz and A.L. Stanton

Table 16.2 Factors associated with poor psychological adjustment in the

context of metastatic breast cancera
Severe physical symptoms (especially pain) and poor functional status
Younger age
Low dispositional optimism
Low perceived social support
Suppression of emotional experience or expression
High coping through avoidance and low coping through approach-oriented
strategies
a
Adapted from Low et al. (2007) with permission

Clinically significant depression, anxiety, and adjustment disorders are prevalent

in adults with advanced cancer (Miovic and Block 2007) and in women with recur-
rent or metastatic breast cancer specifically (Burgess et al. 2005; Okamura et al.
2000). For example, in a 5-year study of women diagnosed with early-stage breast
cancer within 5 months of study entry (Burgess et al. 2005), depression and anxiety
diagnosed via interview using standard diagnostic criteria were more prevalent
(45 %) in the 3 months following diagnosis of recurrent cancer than after initial
breast cancer diagnosis (36 %). Cancer-related distress, in the form of intrusive
thoughts and feelings about the disease, also is elevated after diagnosis of recurrent
breast cancer (Andersen et al. 2005; Oh et al. 2004). Whereas cancer-specific dis-
tress and general quality of life improve over the year after diagnosis, problems with
physical symptoms and functioning persist (Yang et al. 2008b). Although very few
longitudinal studies are available, attributes associated with poorer psychological
adjustment in women with recurrent and metastatic disease (see Table 16.2) include
such factors as younger adult age, more severe physical symptoms (e.g., pain,
fatigue), low social support, and more coping with the cancer experience through
avoidance and less approach-oriented coping (e.g., planning, positive reappraisal;
Yang et al. 2008a).
Certainly, a diagnosis of metastatic breast cancer generates psychological, inter-
personal, and physical demands. It appears, however, that most women maintain or
recover generally positive psychological health. In addition, adults with advanced
cancer report that benefits such as enhanced relationships, deepened spirituality, and
strengthened life appreciation and priorities can accompany the experience (Moreno
and Stanton 2013).

Care of Women with Metastatic Disease

Women living with metastatic breast cancer have frequent and ongoing contact with
the oncology care system. Initial treatment planning should be multidisciplinary, as
is recommended for initial diagnosis and treatment (Cardoso et al. 2012). Even
when disease is controlled and stable, as with responsive endocrine sensitive cancer,
16 Living with Metastatic Breast Cancer 249

regular visits to the oncologist will occur at least every 2–3 months. Monitoring of
disease status will often focus on tumor markers and specific scans, and patients
may have need for symptomatic management of disease-related or treatment-related
symptoms. Often, women will be able to continue working and do other meaningful
activities, but some may have serious fatigue, cognitive difficulties or pain that may
make activities difficult.
Living with the uncertainty of how long a specific treatment regimen will pro-
vide benefit is one of the critical challenges that the patient and her physician must
face. The tempo of the disease recurrence as well as the burden of metastatic disease
sites (a few or many; soft tissue vs. visceral) will provide some indication of whether
or not complex multi-agent therapy is recommended or single agent serial treat-
ments are appropriate. Increasingly, the approach to metastatic disease (Cardoso
et al. 2012) reflects the consensus that palliative and supportive care are essential,
and that the patient’s preferences need to be taken into consideration (Table 16.3
from Cardoso). In addition, a recent consensus panel outlined specific strategies for
addressing the supportive and palliative care needs of women living with metastatic
disease, from a global perspective, with organ-specific approaches (Cleary et al.
2013). However, most of these recommendations are consensus based, with few
randomized studies available.

Table 16.3 Guideline statement for management of advanced breast cancer (ABC)a
(1) The management of ABC is complex and, therefore, involvement of all appropriate specialties
in a multidisciplinary team (including but not restricted to medical, radiation, surgical
oncologists, imaging experts, pathologists, gynecologists, psycho-oncologists, social
workers, nurses, and palliative care specialists), is crucial
(2) From the time of diagnosis of ABC, patients should be offered appropriate psychosocial care,
supportive care, and symptom-related interventions as a routine part of their care. The
approach must be personalized to meet the needs of the individual patient
(3) Following a thorough assessment and confirmation of MBC, the potential treatment goals of
care should be discussed. Patients should be told that MBC is incurable but treatable, and
women can live with MBC for extended periods of time (many years in some circumstances).
This conversation should be conducted in accessible language, respecting patient privacy and
cultural differences, and whenever possible, written information should be provided
(4) Patients (and their families, caregivers or support network, if the patient agrees) should be
invited to participate in the decision-making process at all times. When possible, patients
should be encouraged to be accompanied by persons who can support them and share
treatment decisions (e.g. family members, caregivers, support network)
(5) There are few proven standards of care in ABC management. After appropriate informed
consent, inclusion of patients in well-designed, prospective, randomized trials must be a
priority whenever such trials are available and the patient is willing to participate
(6) The medical community is aware of the problems raised by the cost of ABC treatment.
Balanced decisions should be made in all instances; patients’ well being, length of life and
patient’s preference should always guide decisions
(7) Validated patient reported outcome measures provide useful information about symptom
severity and the burden and the impact of these symptoms on overall quality of life. Systematic
collection of such data should be integrated with other clinical assessments and form part of
the decision-making about treatment and care
a
Adapted from Cardoso et al. (2012) with permission. MBC is metastatic breast cancer
250 P.A. Ganz and A.L. Stanton

Compared with efficacious psychosocial interventions tested in randomized

controlled trials (RCTs) for adults with early-stage cancer (e.g., Faller et al. 2013),
the number of trials for women with metastatic disease is small. Women with meta-
static breast cancer often are not included or included in such small numbers in
those trials that reliable subgroup analyses are not possible. A recent review and
meta-analysis of ten psychological RCTs with 1,378 women diagnosed with meta-
static breast cancer included three trials of distinct individual approaches and seven
group psychotherapy trials (four supportive-expressive therapy trials and three
cognitive-behavioral trials) (Mustafa et al. 2013). Although some trials produced
psychological benefit, the meta-analysis did not yield a clear pattern of psychologi-
cal effects, given that a wide variety of outcome measures and follow-up durations
were used. Across three trials, however, supportive-expressive group therapy
produced a significant reduction in pain compared to usual care. In addition, there
was some evidence of a survival benefit associated with intervention participation at
1 year (six trials) but not at 5 years (four trials) after the interventions.

Research Challenges and Opportunities

The most pressing challenge today is the lack of systematic research on women liv-
ing with metastatic breast cancer for lengthy periods of time. Although many
women have a relatively rapid progressive course from inception of metastatic
recurrence to end-of-life care, there are both intermediate and long-term survivors
for whom we have little information about their disease trajectory and experience of
living with ongoing therapy that includes disease-related symptoms and treatment
toxicity. For example, at one extreme, women who experience an ipsilateral breast
cancer recurrence may have a variable course, with a continuous risk of recurrence
after tumor excision that can be improved with the addition of adjuvant chemo-
therapy, especially in patients with estrogen receptor negative tumors in the CALOR
trial (Aebi et al. 2014). Five year disease-free survival in those treated with chemo-
therapy was 69 vs. 57 % in those who did not receive chemotherapy. When multiple
site metastatic recurrence occurs, the outcomes are less favorable, although durable
periods of remission may occur for those with limited soft-tissue and bone-dominant
disease that is hormone sensitive, as well as with patients for whom both endocrine
and HER 2 targeted therapies are available. The major challenge for researchers is
to be able to identify these patients and engage them in trials. The CALOR trial took
many years to accrue and closed without meeting its initial accrual goal. In our own
experience in a major metropolitan area, it also is difficult to recruit women living
with metastatic disease for studies of psychosocial outcomes. Why do we have such
a limited database? What are the issues we should study?
Adequate assessment of quality of life, cancer- and treatment-related symptoms
and side effects, health behaviors, and psychosocial status is essential in women
with metastatic disease. Patient-reported outcomes, such as quality of life and symp-
toms (e.g., fatigue, pain), are important targets of intervention as well as indicators of
16 Living with Metastatic Breast Cancer 251

prognosis in metastatic disease (Gotay et al. 2008; Quinten et al. 2011). Especially
in the context of metastatic disease, in which energy to complete assessments might
be limited, development of measures that are brief, reliable, and valid is vital. For
example, the Patient-Reported Outcomes Measurement Information System
(PROMIS) contains a number of pertinent measures (e.g., fatigue, pain, depressive
symptoms, anxiety; Alonso et al. 2013) for use in research and clinical practice.
Psychometrically sound and valid assessments of experiences specific to women
with metastatic disease also are needed.
One of the most important opportunities and challenges we face in management
of metastatic breast cancer is the integration of palliative care into standard disease
management. Because treatment for metastatic breast cancer often involves both
medical and radiation oncologists, those specialists are looked to as the managers of
care. Many women resist consideration of pain and symptom management while
they are undergoing active treatment, such that referral to palliative care specialists
does not occur until late in the treatment of metastatic disease. Breast cancer patients
living with metastatic cancer are often interested in exploring experimental thera-
pies and may perceive referral to palliative care as an indication of the oncology
care team giving up on their cancer-directed care. To the extent that palliative care
is integrated into cancer-directed treatment from the time of metastatic recurrence,
symptom management and psychological concerns can be effectively co-managed
without a sense of abandonment or change in course (Smith et al. 2012; Von Roenn
2013) (see Fig. 16.1).
Other major concerns for patients living with metastatic disease involve how best
to live with the disease. Should they continue working? Can they afford their
medical care? On whom do they rely for social support, especially as their health
declines? Do they have an aging spouse or young children who require care?

Supportive Care End-of-Life Care

Anti-Cancer Therapy Bereavement Care

Focus (curative, life-prolonging or
of palliative in intent)
Care

Diagnosis Time 6-Month Death

Prognosis
Illness Bereavement
Acute Chronic Advanced
Life-Threatening

Fig. 16.1 Comprehensive cancer care [Adapted from National Cancer Institute.
EPEC™-O. Education in palliative and end-of-life care for oncology. Available at : http://www.
cancer.gov/cancertopics/cancerlibrary/epeco. Accessed 20 Sept 2014]
252 P.A. Ganz and A.L. Stanton

Table 16.4 Key elements of individualized care for patients with advanced cancera
1. Patients should be well informed about their prognosis and treatment options, ensuring that
they have opportunities to make their preferences and concerns regarding treatment and
supportive care known
2. Anticancer therapy should be discussed and offered when evidence supports a reasonable
chance of providing meaningful clinical benefit
3. Options to prioritize and enhance patients’ quality of life, should be discussed at the time
advanced cancer is diagnosed and throughout the course of illness along with development of
a treatment plan that includes goals of therapy
4. Conversations about anticancer interventions should include information on likelihood of
response, the nature of response, and the adverse effects and risks of any therapy. Direct costs
to the patient in terms of time, toxicity, loss of alternatives, or financial impacts that can be
anticipated should also be discussed to allow patients to make informed choices
5. Whenever possible, patients with advanced cancer should be given the opportunity to
participate in clinical trials or other forms of research that may improve their outcomes or
improve the care of future patients
6. When disease-directed options are exhausted, patients should be encouraged to transition to
symptom-directed palliative care alone with the goal of minimizing physical and emotional
suffering and ensuring that patients with advanced cancer are given the opportunity to die
with dignity and peace of mind
a
Adapted from Peppercorn (2011)

Unfortunately, all the resources that have been brought to bear for breast cancer
survivors, that is, patients diagnosed with early stage disease and treated with cura-
tive intent who are living disease-free, do not seem to be suitable for women who
are living with chronic and active cancer. Advance care planning is especially
important for women living with metastatic breast cancer, yet it can remain unad-
dressed, primarily because of the slower trajectory of advancing disease, and the
serial effective therapies that are available and offered to these patients (Peppercorn
et al. 2011). Essential elements of that care are described in Table 16.4. Much more
research is needed in women living with advanced breast cancer to determine how
best they can maximize physical, emotional and spiritual well-being, while
addressing their advance care planning needs.
Effective approaches to prevent and address cancer-related symptoms and side
effects, as well as to promote positive psychosocial adjustment, are crucial for
women living with metastatic breast cancer. Current evidence suggests that support-
ive expressive group therapy is effective for easing pain in this group (Mustafa et al.
2013), but strong evidence is lacking for the effects of interventions on other symp-
toms and psychosocial outcomes. To the extent that they address problems experi-
enced across the cancer trajectory, efficacious psychosocial interventions (Faller
et al. 2013) might generalize to women with advanced disease. Women with meta-
static breast cancer can face distinct or more severe problems (e.g., life goal adjust-
ment, progressive loss of function), however. Therefore, unique intervention
approaches for women with metastatic cancer require development. In addition,
disseminable approaches are needed which are readily accessible for women who
might be experiencing physical compromise as a result of metastasized cancer and
16 Living with Metastatic Breast Cancer 253

its treatment and therefore cannot attend in-person treatment regularly. For exam-
ple, we recently found that, compared to standard care, an intervention (Project
Connect Online) designed to facilitate personal website development and use to
communicate with friends and family about the breast cancer experience produced
improvements in depressive symptoms, positive mood, and life appreciation. Effects
of this online intervention were particularly evident for breast cancer patients in
active medical treatment, most of whom had metastatic disease (Stanton et al. 2013).
Clearly, much work remains to promote quantity and quality of life and health for
women who live with metastatic breast cancer.

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Chapter 17
Quality of Care, Including Survivorship
Care Plans

Dawn L. Hershman and Patricia A. Ganz

Abstract With the expectation of prolonged survival in the vast majority of women
diagnosed with breast cancer, making initial treatment decisions that minimize or
prevent late complications, and maximize the quality as well as quantity of life, is
absolutely critical. Unfortunately, such care is not uniformly delivered. Patient, pro-
vider, and system barriers contribute to delays in cancer care, lower quality of care,
and poorer outcomes in vulnerable populations, including low income, underin-
sured, and racial/ethnic minority populations. Covering the costs of cancer care is a
major concern for many cancer survivors, and as a result, a major challenge will be
to provide cost-effective follow-up care by reducing overuse of unnecessary tests
and procedures so that access to effective medications can be preserved. One of the
recently promoted means of improving the coordination of care for breast cancer
survivors has been the use of survivorship care planning, as coordination of care
will be absolutely essential to deliver high-quality care. Patient navigation is another
approach to help overcome healthcare system barriers and facilitate timely access to
quality medical care. Understanding the challenges and opportunities in delivering
high-quality cancer care is one of the most critical issues of the day. With the large
numbers of breast cancer patients and the tremendous advances in our understand-
ing of the disease and treatments (leading to large numbers of survivors), breast
cancer will likely be the focus of new models for the delivery of better and more
efficient cancer care.

Keywords Breast cancer survivorship • Quality of care • Cost • Disparities

D.L. Hershman (*)

Associate Professor of Medicine and Epidemiology, Herbert Irving Comprehensive
Cancer Center Columbia University, 161 Fort Washington, 1068, New York, NY 10032, USA
e-mail: [email protected]
P.A. Ganz
UCLA Schools of Medicine and Public Health, Jonsson Comprehensive
Cancer Center, Los Angeles, CA, USA
e-mail: [email protected]

© Breast Cancer Research Foundation 2015 255

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6_17
256 D.L. Hershman and P.A. Ganz

Current Challenges in the Delivery of Quality Care

to Breast Cancer Survivors

Definition of Cancer Survivor

Among all of the common epithelial cancers, breast cancer has evidenced one of the
most substantial improvements in survival over the past three decades (Siegel et al.
2012). This has occurred through the introduction of population wide screening
mammography, as well as the application of adjuvant chemotherapy, adjuvant endo-
crine therapy, and the two combined in almost all women with breast cancer (Berry
et al. 2005). The establishment and dissemination of standards of care for breast
cancer treatment have been facilitated by the regular meta-analytic synthesis of
clinical trials data by the Early Breast Cancer Clinical Trialists Group who have
come together regularly at Oxford University for over two decades (Early Breast
Cancer Trialists’ Collaborative Group 2005). Their findings have been rapidly trans-
lated into clinical guidelines promoted by the American Society of Clinical Oncology
(ASCO), as well as by other professional and governmental organizations.
At the time of the 2000 NIH consensus conference on the adjuvant therapy of
breast cancer (National Institutes of Health 2001), all women with tumors larger than
a centimeter were advised to receive chemotherapy, with the addition of endocrine
therapy (tamoxifen) for 5 years if the tumor was positive for hormone receptors.
Since that time, we have seen the development of new endocrine therapies (e.g.,
aromatase inhibitors), the emergence of different and longer endocrine treatment
strategies, as well as an explosion in new knowledge about the different genomic
subtypes of breast cancer (Perou et al. 2000; Sorlie et al. 2001). These subtypes of
breast cancer are now treated with therapies that offer the best chance for cure (e.g.,
HER2 positive breast cancer) (Romond et al. 2005), and in many cases, toxic chemo-
therapy can be avoided in women with a very low risk of recurrence (Paik et al.
2004, 2006). Today, most women are diagnosed with stage I breast cancer, and can
expect survival outcomes that differ very little from other women their age (DeSantis
et al. 2014). However, there is a human and financial cost to these outcomes, given
the extended and sometimes complex treatments these women receive.
Conceptualizing when breast cancer survivorship begins is challenging.
Historically, one was not considered a cancer survivor until 5 years after diagnosis,
and even then, patients with breast cancer were known to experience late recurrences,
especially in the setting of hormone receptor positive tumors. However, with the can-
cer survivorship movement that began in the mid-1980s (Mullan 1985), the founding
of the National Coalition for Cancer Survivorship (NCCS) in 1986 led to the first
definition of a cancer survivorship as “being from the time of diagnosis through the
balance of life,” including family, friends and caregivers as part of that journey and as
co-survivors (http://www.canceradvocacy.org/about-us/our-history/). This broad
definition obviously includes many individuals who may not survive for extended
periods of time. However, in the case of breast cancer, this definition is central to
delivery of high quality care. With the expectation of prolonged survival in the vast
17 Quality of Care, Including Survivorship Care Plans 257

majority of women diagnosed with breast cancer, making initial treatment decisions
that minimize or prevent late complications, and maximize the quality as well as
quantity of life, is absolutely critical. Unfortunately, such care is not uniformly deliv-
ered (Institute of Medicine 2013), and we discuss these issues in this chapter.
For newly diagnosed breast cancer patients, the following issues are relevant to
minimizing the long term or persistent effects of treatment, as well as rare late
effects. Women of childbearing age who wish to preserve their fertility should be
informed about whether the planned breast cancer treatment will have an effect on
this, and should be afforded the opportunity to discuss fertility preservation options
with a reproductive endocrinologist (Loren et al. 2013). Based on the literature, this
is not consistently done even in medical oncology practices that are focused on
improving the quality of care (Neuss et al. 2013). While cost may be an important
barrier, patients have told us that even if they choose not to take action, the fact that
this is discussed with them is deemed very important (see earlier Chap. 9 on repro-
ductive outcomes). In addition, women need to be informed of the potential for many
of the long term toxicities of contemporary treatments, including lymphedema, neu-
ropathy, cardiac dysfunction, cognitive dysfunction, and fatigue (see earlier Chaps. 5,
6, 7, 8, 14), many of which are associated with particular local or systemic treatment
regimens. To the extent there is flexibility in the exact primary treatment plan, con-
cerns and preferences of the patient should be taken into account, as well as pre-
existing risk factors that might increase the likelihood of one of these late effects
(Fig. 17.1). Premature menopause is extremely common in women over age 40 years

Structural Barriers Physician/Clinical Factors Patient Factors

Health insurance Physician Socioeconomic

status recommendations status

Clinical stage Patient preferences/

Type of decision-making
health insurance
Other clinical
prognostic indicators Cost/Co-payment
Type of institution Co-morbidity
where care is
received Transportation
Pain assessment

Geographic region Physician Time required

where care is perceptions/biases for treatment
received
Family/
other support

Fig. 17.1 Conceptual framework for receipt of optimal cancer care (Adapted from Shavers and
Brown, JNCI 2002 with permission)
258 D.L. Hershman and P.A. Ganz

who receive chemotherapy (Ganz et al. 2011b), and women need to be made aware
of this likely occurrence, as well as be reassured that their symptoms will be appro-
priately and effectively managed. Being prepared for what to expect during and after
treatment, is part of good survivorship care and starts at the time of diagnosis with
initial treatment planning (Ganz et al. 1998, 2006, 2011a; Wyatt et al. 1998).
After the initial treatment decisions are made, and treatments are underway,
many women want to know what is coming next, and that is where formal survivor-
ship care planning for the post-treatment period has emerged as a major gap in
quality care (Hewitt et al. 2006; Ganz and Hahn 2008; Ganz et al. 2008). For almost
a decade since the Institute of Medicine (IOM) report on adult cancer survivorship
care (Hewitt et al. 2006), various organizations have worked diligently to improve
the post-treatment communication and coordination of care, specifically at the
transition between active treatment and follow-up care. In breast cancer patients,
this usually occurs at the end of adjuvant chemotherapy and/or radiation therapy.
For many women, extended adjuvant endocrine therapy will be prescribed; this is a
critical and lifesaving component of treatment and not all women understand the
importance of this therapy. Non-adherence to oral endocrine therapy is very com-
mon and results in poorer breast cancer outcomes (Hershman et al. 2010, 2011).
Non-adherence can occur because of uncontrolled and bothersome symptoms, as
well as concerns about the financial cost of treatment. Failure to adhere to this treat-
ment is an important quality of care issue, and lack of communication and trust in
physicians doing the follow-up care can contribute to this (Kahn et al. 2007).
Breast cancer survivorship does not occur in a vacuum. As discussed elsewhere in
this volume, although the average age of breast cancer incidence is 61 years, about
25 % of incident cases are in women younger than 50 years and the majority are over
65 years of age. Life stage, partnership status, financial and other resources, including
the generosity of health insurance plans, may contribute substantially to the quality of
the survivor’s life after cancer. In addition, continuing symptoms (e.g., menopause
related, sexuality and intimacy concerns, fatigue, and depression) can disrupt relation-
ships and the ability to work and care for children. The human cost of breast cancer is
substantial. Finally, as described in Chap. 16 in this volume on living with metastatic
breast cancer, there are more than a 100,000 women living for extended periods of
time on cancer directed therapy for whom active disease and its consequences (e.g.,
pain, physical limitations, treatment toxicities) further complicate the quality of life.
We hope these introductory remarks set the stage for a more detailed discussion of the
challenges of delivering high quality care to breast cancer patients and survivors.

Challenges for Survivors: Dealing with the Costs

of Cancer Care

Covering the costs of cancer care is a major concern for many cancer survivors.
Cancer-related medical costs have accelerated at a rate beyond those of other medi-
cal treatments (Vanchieri 2005). It is projected that US health care spending will
17 Quality of Care, Including Survivorship Care Plans 259

reach $4.3 trillion and account for 19 % of the national gross domestic product by
2019 (Schnipper et al. 2012). This increase has been driven by a dramatic rise in
both the cost of therapy and the extent of care, especially in the last few months of
life. Physicians directly or indirectly control or influence the majority of cancer care
costs, including the use and choice of drugs, the types of supportive care, the fre-
quency of imaging and the number and the extent of hospitalizations (Smith and
Hillner 2011). In addition there are numerous unmeasured costs associated with
loss of work and subsequent loss of insurance. Given the long life expectancy of
patients with breast cancer, it is not surprising that total costs of breast cancer care
in both the metastatic and non-metastatic setting can be higher than other cancers.
Patients are most directly affected by out-of-pocket costs, which have increased
as more therapies have switched from intravenous to oral therapies. It is estimated
that more than one quarter of the 400 antineoplastic agents now in the pipeline are
oral drugs. Oral cancer therapies are often advertised as being more convenient than
parenteral therapies as they can reduce patient travel, eliminate time spent in the
infusion center, and avoid issues related to intravenous access. However there are a
number of concerns about oral therapies that have arisen. As with other new cancer
therapies, they are accompanied by increased costs and financial burdens for patients
(Vanchieri 2005; Benson et al. 1998). Total prescription medication costs exceeded
$234 billion by 2008, an annual rate of increase of over 10 % (Kaiser Family
Foundation 2010). Some of the most expensive oral cancer drugs are used to treat
patients with breast cancer, such as everolimus, which can cost $100,000 or more
per year. The financial burden borne by patients prescribed these drugs can be very
high, with co-pays running from hundreds up to thousands of dollars per month. It
is known that as out of pocket costs increase, the likelihood of compliance with
medications decreases, which can adversely affect survival outcomes. It is well-
known that adherence to hormonal therapy is a large problem in breast cancer, and
co-payment amount has an independent effect on adherence and early discontinua-
tion of hormone therapy (Neugut et al. 2011). Furthermore, the cost of oral support-
ive care medications, such as anti-emetic therapies, can be prohibitive for some
patients, resulting in unnecessary toxicity and decreased quality of life. Not surpris-
ingly, out-of-pocket expenses are the largest in countries of low and lower-middle
income, despite the fact that people in these countries have the lowest resources to
cover these extra costs (Anderson et al. 2011).
A major challenge as the number of cancer survivors increases will be to provide
cost effective follow-up care by reducing overuse of unnecessary tests and proce-
dures so that access to effective medications can be preserved. Public health efforts,
such as the Cancer Treatment Fairness Act, which requires insurance to cover oral
cancer treatment medications the same as they cover intravenously and injected
cancer treatment medications, may increase drug price transparency, improve access
and reduce out of pocket costs for life-saving cancer treatments. Efforts at decreas-
ing economic disparities in breast cancer care are especially important given the
rapid increase of expensive oral cancer therapies.
260 D.L. Hershman and P.A. Ganz

Cancer Care Trajectory

Cancer-Free
Survival

Recurrence/
Start Here Second Cancer

Treatment With Medical Outcomes

Intent to Cure and Quality of Life

Diagnosis and
Staging

Safer therapies Survivor health care delivery:

Palliation, Prevention
and Health Promotion

Risk assessment and intervention

Fig. 17.2 Model depicting the role cancer survivorship care and the cancer care trajectory

Disparities in Breast Cancer Treatment and Outcome

Patient, provider, and systems barriers contribute to delays in cancer care, lower
quality of care, and poorer outcomes in vulnerable populations, including low
income, underinsured, and racial/ethnic minority populations (Fig. 17.2). Compared
to non-Hispanic white women, overall breast cancer incidence is lower among black
women but breast cancer mortality is higher (about 40 %) with trends that vary
depending on age and location (American Cancer Society 2011). The racial differ-
ence in outcome has increased over time, and may reflect disparities in diagnosis and
treatment. Despite the fact that nationally the use of mammography is nearly equiva-
lent for blacks and whites (American Cancer Society 2013), black women have a
much higher rate of incidence before the age of 40 years, are more likely to be diag-
nosed with larger tumors (>5.0 cm), and have higher rates of distant-stage disease at
diagnosis (American Cancer Society 2011). Differences between blacks and whites
also exist with regard to access to clinical trials and innovative cancer treatments
(Sateren et al. 2002; Tejeda et al. 1996); receipt of biomarker testing, follow-up care
post-treatment, and surveillance mammography (Shavers and Brown 2002).
The factors contributing to the striking difference in mortality between blacks
and whites (Li et al. 2003; Wheeler et al. 2013) are likely to be multi-factorial and
complex, and have been attributed to differences in tumor biology (Bowen et al.
2006; O’Brien et al. 2010; Carey et al. 2006; Lund et al. 2009), psychological,
behavioral factors, and social factors and access to care (Magai et al. 2008; Gerend
17 Quality of Care, Including Survivorship Care Plans 261

and Pai 2008; O’Brien et al. 2010; Du et al. 2007, 2008), and access to and response
to new adjuvant treatments including hormonal therapy (Menashe et al. 2009; Jatoi
et al. 2003; Caudle et al. 2010). Interestingly, when you look at differences in survival
between races over time, the separation began in the 1980s and has continued since
that time, as white women have had improvements in breast cancer survival and
black women have not. This separation coincides with an increased understanding
of the importance of adjuvant treatment, and suggests that this disparity is modifi-
able (2010). Also of interest, recent studies suggest that the evolution of racial
disparities in breast cancer survival are different in different cities in the US, which
may be a reflection of state level screening programs, access and public health
education (Hunt et al. 2014).
Recent studies have suggested that black women more often did not receive
timely treatment compared to other women (Shavers and Brown 2002); are less
likely to receive optimal systemic adjuvant therapy than white women (Hassett and
Griggs 2009; Bickell et al. 2006); and are more likely to have delays in the initiation
of adjuvant chemotherapy and radiotherapy, which are all associated with worse
survival (Hershman et al. 2006a, b). Despite the fact that black women are more
likely to have triple negative breast cancer, the racial disparities gap is greatest
among the hormone-sensitive subtypes of breast cancer and because non-adherence
to anti-estrogen treatment has been shown to adversely impact survival, differences
in the utilization of this treatment may well explain some of the black-white breast
cancer mortality disparity (Shavers and Brown 2002).
In low and middle-income countries advanced stages at presentation and poor
diagnostic and treatment access contribute to lower breast cancer survival than in
higher income countries (Harford et al. 2011). In 2010 the Breast Health Global
Initiative reported an executive summary of their consensus meeting. Challenges for
improving outcomes include little community awareness that breast cancer is treat-
able, inadequate pathology services for diagnostics, fragmented treatment options
and establishment of data registries to show progress with interventions (Anderson
et al. 2011).
Much work has been done to define the problem and establish modifiable factors
that may contribute. Efforts going forward will need to focus on interventions and
public policy changes to reduce the disparity in outcome by intervening in factors
that can easily be modified.

Research Underway to Address These Issues and Future

Strategies/Policy

Reduce Overdiagnosis and Over Treatment

With the expansion of population based mammography screening described earlier,

there has been a stage shift to earlier stage breast cancer, as well as an explosion
in the detection of non-invasive ductal cancers or ductal carcinoma in situ (DCIS).
262 D.L. Hershman and P.A. Ganz

In 2013, there were expected to be 64,640 DCIS cases and 232,340 cases of invasive
cancer (DeSantis et al. 2014). The continued increase in diagnosis of DCIS has not
reduced the number of invasive cases of breast cancer and is felt to be overdiagnosis
of precancerous disease that would not likely become invasive or not be detected
and cause death (Esserman et al. 2009, 2013; Esserman and Thompson 2010). This
also leads to over treatment, as patients with DCIS are subjected to the same local
therapy approaches (i.e., surgery and radiation therapy) that are applied to patients
with invasive cancer. Moreover, the psychological distress associated with the diag-
nosis of DCIS is substantial (Ganz 2010).
Reduction in the age of initiation of screening mammography to the 40–50 years
age group, as well as the interval frequency for mammography screening in women
over 50 years remains controversial, in spite of evidence based reviews that suggest
that starting at age 50 years is sufficient, and that the interval can be less frequent
than annually. Among the biggest challenges with DCIS is the identification of high
risk disease that would in fact lead to significant morbidity and mortality, or the
converse, those women who need minimal if any treatment. In the case of stage I
hormone receptor positive breast cancer, where low risk disease patients can avoid
chemotherapy, there have been only a few trials that have looked at the omission of
radiation therapy, and the uptake of avoiding this therapy has been limited (Giordano
2012). The NRG clinical trials group is hoping to do a large simple trial to address
this question in early stage patients. This will reduce both morbidity and cost if
treatment can be avoided. Future trials will hopefully be able to incorporate genomic
and molecular markers to identify high and low risk patients and to tailor the inten-
sity of treatment to the tumor characteristics.
Among the many challenges we face in this area is changing the beliefs of women
regarding the value of mammographic screening, given the 30 years campaign by
various health professional organizations supporting the use of this technique for
early detection of breast cancer (Welch and Passow 2014). Women and their physi-
cians are reluctant to give up the idea that earlier detection of a cancer will make a
difference. Translating data from the population to the individual patient is chal-
lenging, and patients do not want to be denied a procedure that they think might be
lifesaving. The same applies to other imaging technologies that may be used for
screening, staging or monitoring of breast cancer, such as breast MRI and PET-CT
scans. These currently have no role in the management of breast cancer, with excep-
tion of breast MRI in women at high risk for breast cancer (e.g., BRCA1/2 gene
carriers), but their use is widespread, and in fact, the use of breast MRI may be
contributing to the recent increase in bilateral mastectomy, even when unilateral
breast conserving treatment would be appropriate. Whether these choices are ratio-
nal, or driven by overzealous treatment recommendations of physicians, is uncer-
tain. The ability to perform immediate breast reconstruction at the time of initial
treatment, and the advances in cosmetic results (e.g., nipple sparing surgery), have
encouraged both patients and physicians to opt for this therapy. The misunderstand-
ing and confusion about the appropriateness of this extreme therapy for high risk
gene carriers (e.g., Angelina Jolie) and not for the general population of women
with breast cancer has increased the demand for this treatment. Unfortunately, many
17 Quality of Care, Including Survivorship Care Plans 263

physicians go along with these approaches, and it is uncertain whether these recom-
mendations are independent of financial considerations. Finally, in the post-
treatment phase, many women cannot accept the fact that surveillance testing for
recurrence is unproven (Khatcheressian et al. 2013), and it is easier for physicians
to offer testing, than to spend time discussing the lack of value in these assessments.
Everyone feels better when the blood work and scans come back normal, but when
the tumor marker or imaging provides a false positive result, much anxiety and
additional testing results. ASCO and other professional societies are participating in
the ABIM Foundation Choosing Wisely campaign, which have identified these
types of services as being of low value and a target for quality improvement efforts.

Survivorship Care Plans: Assessment and Referral

to Appropriate Clinicians

One of the recently promoted means of improving the coordination of care for
breast cancer survivors has been the use of survivorship care planning (Ganz and
Hahn 2008), and a care plan document, as a means of summarizing what treatments
have been received, what surveillance is needed to identify recurrence, and how to
manage persistent symptoms that do not resolve in the post-treatment period, as
well as be on the lookout for rare but important late effects of treatment. With the
IOM report on adult cancer survivors in 2005 (Hewitt and Ganz 2006; Hewitt et al.
2006), there was a flurry of activity to try to move forward with the idea of care
plans. Sadly, it has had relatively modest uptake in clinical practice, but the most
widely studied cancer has been breast cancer (Tevaarwerk et al. 2014; Birken et al.
2014; Haq et al. 2013). It was not until the recent decision by the American College
of Surgeons Commission on Cancer to set survivorship care planning as a standard
for accreditation in 2015 that clinical cancer delivery settings have identified strate-
gies to make this happen. One of the authors has been extensively involved in the
dissemination of care plans during the past decade, and it is good that we are finally
seeing some uptake. Nevertheless, the care plan document, which has been the
focus of many studies, is not really the issue. It is the communication and coordina-
tion of care that is critically important as part of the post-treatment care planning.
With the anticipated work shortages for all oncology health professionals and the
increasing number of cancer cases expected in the next decade (Institute of Medicine
2013), medical and surgical oncologists will have limited space in their practices to
provide ongoing care for early stage, low risk breast cancer patients, and they must
develop strategies to share the care with primary care providers who can continue
the monitoring of these patients while addressing age-related comorbid conditions
as well as persistent cancer treatment related symptoms such as fatigue, menopausal
symptoms, depression and others. As called for in the recent IOM report on the
delivery of high quality cancer care (Institute of Medicine 2013), coordination of
care will be absolutely essential to deliver high-quality cancer care. Breast cancer
patients are an ideal target for innovations in the delivery of quality care.
264 D.L. Hershman and P.A. Ganz

In addition to post-treatment care planning and coordination of care, we need to

emphasize the importance of psychosocial care services and palliative care in breast
cancer survivors. This is extensively called out in the recent IOM report on quality of
care (Institute of Medicine 2013) as being an essential component of high quality can-
cer care from the time of diagnosis. Among the breast cancer survivors that present for
consultation at UCLA, almost all have had superb and technically appropriate medical
care. However, few if any have had their psychosocial needs addressed and many are
seeking help for severe and debilitating symptoms (e.g., fatigue, cognitive dysfunc-
tion, neuropathy) that are not being addressed in the routine follow-up care they are
receiving, usually by at least 2–3 oncology specialists. Some research (see Chaps. 5, 6,
7, 8, 9 on various symptoms), is beginning to identify genetic or behavioral risk pro-
files that may allow us to identify patients at high risk for persistent post-treatment
symptoms. Possible strategies in the future may include a battery of questionnaires and
blood tests that will facilitate risk profiling and allow tailoring of treatments and/or
early interventions to reduce the risk of persistent problems. Much more prospective
observational, biopsychosocial data collection will be necessary. Ideally this should be
conducted within the setting of clinical trials, but might be feasible within the learning
health care systems of the future (Abernethy et al. 2010; Institute of Medicine 2013).
To accomplish these goals, we must build and develop a knowledge base as well
as improve the self-efficacy among primary care providers who have not been heav-
ily engaged in the follow-up care of cancer patients for several decades (Cheung
et al. 2013; Han et al. 2013; Potosky et al. 2011; Blanch-Hartigan et al. 2014).
Primary care providers would like to share the care of cancer patients with oncolo-
gists and find the idea of care plans very attractive and helpful to them (Shalom
et al. 2011; Hewitt et al. 2007). Here again, breast cancer is an excellent model for
this type of shared care. There are many women’s health primary care providers
who have large numbers of breast cancer survivors in their practices. These physi-
cians often have an interest in menopause-related issues, such as vasomotor symp-
tom management and bone health. This makes them excellent primary care providers
for the follow-up of the post-treatment, low risk breast cancer patient. With specific
recommendations about which cancer surveillance tests are necessary, and when the
oncologist needs to re-engage in care, these providers can manage breast cancer
survivors very competently, as has been shown in several randomized trials
(Grunfeld et al. 1996, 2006). Oncology professional societies must lead the way in
working with other health care provider professional groups to develop curricula
and educational strategies to enhance the competencies of all care providers who
will be following breast cancer survivors in the post-treatment period (2013).

Improving Quality and Reducing Health Care Disparities

In recent years there has been progress in increasing screening rates for breast
cancer, however, despite this, the gap between white and black breast cancer mortality
rates is still widening because early detection does not reduce mortality unless those
17 Quality of Care, Including Survivorship Care Plans 265

diagnosed are subsequently treated in a timely and effective way. One interventional
approach has been through patient navigation. Patient navigation refers to the
individualized assistance offered to patients, families and caregivers to help over-
come healthcare systems barriers and facilitate timely access to quality medical care
(Freeman and Wasfie 1989). Patient navigation has repeatedly been shown to
improve rates and timeliness of follow-up of cancer screening abnormalities in
various populations (Paskett et al. 2011). Less is known about treatment adherence,
satisfaction with care and survival. The challenge will be to figure out the best
implementation among patients with the greatest need in a cost-efficient manner.
Other interventions are currently being tested to improve adherence to hormone
therapy for breast cancer such text messaging and email reminders.
To improve outcomes of breast cancer survivors it will be necessary to focus on
interventions to improve the quality of care. To do this requires the development of
breast cancer specific quality indicators. Based on the work done by the National
Initiative on Cancer Care Quality, ASCO and NCCN developed several quality indi-
cators, three of which were specifically for the treatment of breast cancer patients.
They have advocated for the use of radiation therapy following breast conservation
therapy for women under the age of 70, adjuvant hormonal therapy for women hor-
mone sensitive breast cancer and combination chemotherapy for women with
tumors that are not hormone sensitive. The establishment of ASCO’s Quality
Oncology Practice Initiative and the Commission on Cancer reporting standards
have impacted physician behavior, and research has shown that, for the most part,
physicians are compliant with these quality indicators. The problem is that these
measures are very limited in providing measurement of complex care delivery for
a disease such as breast cancer. Research has shown consistency where the infor-
mation is clear-cut i.e. high level evidence, and more deviations in care where the
treatment or management scenarios are not as well defined. Much work is being
done to identify quality indicators, and the expectation is that physician reimburse-
ment, financial incentives and practice certification requirements will continue to
ensure that the most beneficial treatments are offered to all patients.

Summary

The quality of cancer care delivery in the US varies substantially, with patients at
risk for too little or too much care, and with a cost that is exploding. Eliminating
wasteful variability in care and focusing on pathway or guideline consistent care is
an important goal. Other international health care systems (e.g., Canada, UK,
Australia) tend to have more consistent evidence-based care, where treatments and
diagnostic tests that are not recommended are less often used. A priority in breast
cancer is guaranteeing everyone life-saving treatment in a timely way and eliminat-
ing modifiable factors that contribute to healthcare disparities. As payment reform
occurs in the US health care system, moving to bundled payments or reimbursement
for episodes of care, the incentives to utilize low value procedures are expected to
266 D.L. Hershman and P.A. Ganz

diminish, as the fee for service payment system does little to discourage over-
utilization. With the plethora of new, and often expensive cancer treatments, atten-
tion will need to be paid to the cost-effectiveness of new treatment strategies
compared to existing, less expensive strategies. However, the need for more care
that enhances patient engagement in self-management and decision-making will
require adequate educational and informational strategies, as well as clinical staff to
work with breast cancer patients from the time of diagnosis through the post-treat-
ment phase. With the expected growth in the numbers of new breast cancer patients
as the population ages, better use of team-based care, and coordination of care
between oncology specialists and primary care providers will be required. No lon-
ger can cancer care be isolated from general medical care to the extent that it has
been during the past 50 years. Risk stratification will be necessary to ensure that
those patients in greatest need of oncology clinicians on an ongoing basis will
remain in those practice settings, while low risk patients can resume care in settings
where health promotion and chronic disease prevention are more generally managed,
including access to psychosocial services. Understanding the challenges and oppor-
tunities in delivering high-quality cancer care is one of the most critical issues of the
day. Breast cancer, because of its large numbers of patients, and because of the tre-
mendous advances in our understanding of the disease and treatments, will likely be
the focus of new models for the delivery of better and more efficient cancer care.

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Index

A 77–85, 92, 97, 102, 117–128, 132,

Advanced cancer, 245, 247, 248, 252 133, 145, 147, 160, 161, 163, 166,
Aromatase inhibitors, 4, 30, 89–97, 118, 120, 169, 180, 181, 195, 196, 204, 215,
123, 147, 160, 179, 181, 186, 196, 218–222, 225, 234, 235, 245–247,
204, 256 250, 256, 258, 261, 262, 265
swelling, 91 Chemotherapy-induced peripheral neuropathy
Arthralgias, 4, 79, 89–97, 203 (CIPN), 4, 77–85
Cognitive complaints, 4, 53–57, 63–67, 69
Comorbidities, 5, 6, 26–30, 37, 109, 155–169,
B 183
Biologic mediators, 6, 185–187, 190 Competing cause mortality, 157–159, 169
Breast cancer, 1–9, 23–34, 39–48, 53, 78, 90, Cost, 7, 8, 41, 47, 81, 102–109, 132, 178, 194,
102, 103, 116, 143–150, 155–169, 198, 201, 208, 225, 238, 249, 252,
194, 213–226, 231–239, 243–253, 256–260, 262, 265
256–261
disparities, 40–41
subtypes, 2, 5, 12, 13, 145, 146, 163, 181, D
182, 185–188, 245, 256, 261 Diagnosis, 2, 3, 6–8, 11, 12, 14, 15, 17–19, 23,
survival, 149, 156, 161, 165, 169, 31, 42–44, 46, 48, 54, 56, 64, 69,
180, 261 101–105, 107–109, 116–118, 123,
survivorship, 1–8, 132, 236, 256, 258 125, 128, 134, 150, 157, 159, 161,
165, 166, 168, 169, 178, 179, 183,
184, 186, 189, 195, 197–201, 205,
C 207, 208, 214, 220, 232–236, 239,
Cancer 244–249, 256, 258, 262, 264, 266
and aging, 23–25, 27, 31–33 Diet, 2, 6, 15, 41, 47, 149, 150, 165, 178, 184,
control continuum, 4, 39–48, 109 185, 187, 188, 190, 198–202,
survivors, 1–8, 15, 24, 25, 46, 54, 55, 101, 204–206, 215
102, 116, 124, 149, 156, 178, 194, Disparities, 4, 8, 25, 39–48, 103, 106, 156,
213–225, 231–239, 244, 255–266 157, 159, 166, 168, 169, 239,
Chemotherapy, 1, 4, 12, 14, 17, 27–29, 31, 40, 259–261, 264–265
46, 54–56, 59–61, 63, 65, 68, 69,

© Breast Cancer Research Foundation 2015 271

P.A. Ganz (ed.), Improving Outcomes for Breast Cancer Survivors,
Advances in Experimental Medicine and Biology 862,
DOI 10.1007/978-3-319-16366-6
272 Index

E Metastatic breast cancer, 2, 7, 13–15, 79, 168,

Epigenetics, 143–150 232, 243–253, 258
Exercise, 18, 32, 41, 47, 64, 68, 93, 96, 105,
106, 108, 126, 149, 194–198,
200–209, 215, 220, 225 N
Neuropathy, 4, 77–85, 148, 163, 232, 246,
257, 264
F
Fatigue, 4, 7, 15, 45, 46, 53–69, 116, 120, 125,
129, 163, 195, 196, 198, 203, 208, O
232, 235, 239, 246–251, 257, 258, Obesity, 2, 6, 41, 102, 106, 149, 156, 162, 163,
263, 264 166, 178–189, 194, 200, 203, 206,
Fertility, 3, 8, 10, 12, 14, 18, 116–119, 208, 209, 214–216, 220
127–128, 132, 134, 135, 257 Older patient, 25–32, 34, 168
Outcomes, 2, 3, 12, 17, 25, 29, 41, 57, 81, 90,
106, 126, 143–150, 155–169,
G 177–190, 194, 219, 232, 244, 256
Geriatric assessment, 26, 28, 29, 31, 32

P
H Patient reported outcomes (PRO), 57, 82, 85,
Hereditary breast cancer, 3, 11, 17 90, 91, 94, 96, 97, 198,
Hot flashes, 116, 118–124, 126, 129, 130, 235, 249–251
133–135, 147 Pharmacogenetics, 146–148
Physical activity, 2, 6, 62, 64, 65, 67, 103,
108, 144, 146, 150, 156, 165, 178,
I 182–184, 186, 188–190, 193–209,
Infertility, 5, 14, 115–135 214–216, 219–221, 238, 247
Inflammation, 31, 54, 57–62, 67, 68, 105, 182, Premature menopause, 3, 8, 14, 55, 116, 117,
183, 186, 199, 204, 206 214, 257
Interventions, 4, 6, 7, 15, 17, 18, 26, 30, 32, Prevention, 2, 4, 10, 11, 15, 19, 40–43, 45, 47,
43–45, 48, 62–68, 79, 80, 82, 48, 80–82, 93, 96, 97, 103,
92–95, 97, 104, 106–108, 118, 119, 105–109, 116, 122, 132, 134, 146,
123, 124, 126–135, 146, 149, 179, 148, 200, 201, 203, 213–226, 266
182–189, 193–209, 218, 220, 225, PRO. See Patient reported outcomes
232, 237–239, 249, 250, 252, 253, (PRO)
261, 264, 265 Prognosis, 42, 97, 144, 145, 148–150, 156,
157, 159, 162, 163, 168, 169, 179,
181–189, 195, 196, 198–200, 202,
L 207, 251, 252
Lymphedema, 4, 101–109, 163, 196, 203, 208, Psychosocial distress, 15, 18, 233, 262
246, 257
swelling, 5, 102, 104–107
Q
Quality of care, 6, 42, 43, 166, 255–266
M Quality of life, 3, 6, 7, 15–18, 28, 30, 40, 45,
Medications, 6, 26, 30, 57, 67, 68, 93, 123, 47, 48, 54, 55, 65, 77, 79, 90, 92, 96,
147, 157, 166–169, 182, 198, 199, 97, 102, 105–109, 157, 162–165,
204, 205, 207, 208, 259 169, 178, 183, 195, 196, 198, 199,
Menopause, 3, 5, 8, 10, 14, 55, 91, 92, 201, 203, 232–234, 236, 238, 239,
115–135, 214, 257, 258, 264 248–250, 252, 253, 258, 259
Index 273

R T
Radiation therapy, 2, 28, 40, 45, 59, 60, 62, Taxanes, 4, 78–80, 82–84, 92, 146, 148, 182,
195, 214, 246, 258, 262, 265 215, 219, 220, 246
Randomized controlled trial (RCT), 64, 66, Toxicity, 4–6, 8, 10, 14, 27–29, 31, 34, 56, 57,
67, 80, 93, 105, 126, 129, 160, 60, 69, 77, 78, 80, 82–85, 92, 94,
179–182, 184, 186, 188, 190, 197, 147, 160, 164, 183, 217–219,
199–204, 237, 238, 250 221–223, 246, 250, 252, 257–259
Research priorities, 6, 7, 159, 161, 165–169, Treatment, 1–3, 10, 24, 25, 40, 53, 54, 77, 90,
178, 187–190, 194, 198, 220 101, 116, 144, 145, 156, 178, 196,
Risk factors and prevention of cardiac toxicity 213–226, 232, 244, 256
with breast cancer treatment, 213–226 Tumor heterogeneity, 144
Risk reduction, 103–104, 106–108, 150,
193–209
V
Vitamin D, 5, 92–94, 149–150
S
Sexual health, 1, 115–135, 232
Special populations, 3, 11, 39–48 W
Survivorship, 1–8, 14, 15, 19, 25, 30–32, 40, Weight, 2, 6, 14, 47, 83, 103, 106, 108, 116,
45–48, 106, 107, 132, 134, 135, 162, 178, 179, 182–189, 193–209,
165, 169, 203, 207, 214, 215, 223, 214, 215, 219, 220
225, 226, 233, 236, 237, 239, 245,
255–266
Symptoms, 3–7, 14, 15, 18, 30, 46, 47, 53–69, Y
77–85, 89–97, 101–109, 115–135, Younger women, 2, 3, 6, 9–19, 24, 25, 63,
195, 196, 216, 232, 233, 235–238, 117, 127, 128, 134, 168, 236,
244, 246–253, 258, 263, 264 244, 245