CHAPTER ONE

Breast Cancer Epidemiology,

Prevention, and Screening
Stella Winters, Charmaine Martin, Daniel Murphy, Navkiran K. Shokar1
Texas Tech University Health Sciences Center, El Paso, Paul L Foster School of Medicine, El Paso, TX,
United States
1
Corresponding author. E-mail address: [email protected]

Contents
1. Introduction 2
2. Breast Cancer Epidemiology 3
2.1 Trends Over Time 5
3. Risk Factors for Breast Cancer 6
3.1 Nongenetic, Nonmodifiable Risk Factors 6
3.2 Nongenetic, Modifiable Risk Factors 8
3.3 Genetic Risk Factors 11
4. Breast Cancer Prevention 13
4.1 Lifestyle/Behavior Change Interventions 14
4.2 Chemoprevention 14
4.3 Surgery 16
5. Breast Cancer Early Detection and Screening 16
5.1 History of Screening 16
5.2 Screening Benefits and Harms 17
5.3 Screening Recommendations 19
5.4 Breast Cancer Screening in Average Risk Women 19
5.5 Genetic Mutations, Breast Cancer Screening Tools, and Screening Methods 20
in High-Risk Women
5.6 Screening Modalities 22
5.7 Breast Ultrasound 23
References 24

Abstract
Globally, breast cancer is both the most commonly occurring cancer and the com-
monest cause of cancer death among women. Available data suggest that incidence
and mortality in high-resource countries has been declining whereas incidence and
mortality in low-resource countries has been increasing. This pattern is likely to be due
to changing risk factor profiles and differences in access to breast cancer early

Progress in Molecular BiologyandTranslational Science, Volume 151

ISSN 1877-1173 © 2017 Elsevier Inc.
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2 Stella Winters et al.

detection and treatment. Risk factors for breast cancer include increasing age, race,
menarche history, breast characteristics, reproductive patterns, hormone use, alcohol
use, tobacco use, diet, physical activity, and body habitus. Mutations in the BRCA 1 and
BRCA 2 tumor suppressor genes are significantly associated with the development of
breast and ovarian cancer by the age of 70. Survival depends on both stage and
molecular subtype. As there are few signs and symptoms early on, early detection is an
important strategy to improve outcomes. Major professional organizations in the
United States and elsewhere recommend screening with mammography with appro-
priate follow up for an abnormal screening test, although they differ somewhat by
recommended ages and frequency of screening. Studies suggest a 15%–40% mortality
reduction secondary to screening, however, there are also concerns about harms, such
as overdiagnosis (5%–54%) and overtreatment leading to long term complications,
and false negatives (6%–46%). Identification of women at risk for BRCA1 and BRCA 2
mutations is also recommended with referral for genetic testing. Preventive interven-
tions, such as lifestyle, medical, and surgical options are available for women testing
positive for BRCA mutations.

1. INTRODUCTION

Breast tissue is composed of lobules that are glands involved in milk

production, ducts that connect the lobules to the nipple and connective
tissue, fatty tissue, and lymphatic tissue. Breast cancer occurs when there is
an unregulated growth of cells within any of the components of the breast,
although this occurs most commonly in the lobules. Although significantly
less common, breast cancer can also occur among males. Breast cancer
develops over time and may go through an in situ phase. Whether in situ or
invasive, it may be detected during routine self-breast exams, mammo-
graphic screening, or once signs or symptoms have developed. Initially,
there are no signs or symptoms associated with breast cancer until a pal-
pable, or visible lump develops within the breast. The most common
physical sign that can be appreciated is a painless breast lump. Swollen
and enlarged lymph nodes may be present within the axillary region during
the early stages of metastasis. Evidence of bloody nipple discharge, heavi-
ness, redness, swelling, breast deformity, or retractions are less common
signs, but a substantial indicator of breast malignancy and maybe more
evident with advanced stages of disease. As, there are few early signs, it is
recommended that all females follow the current breast cancer screening
guidelines to identify those with abnormal breast tissue during the early
evolutionary stages.
Breast Cancer Epidemiology, Prevention, and Screening 3

A majority of breast cancers encompass the invasive type. These malig-

nancies have extended beyond the ducts and glands into surrounding tissues
and lymph nodes. Currently, there are 21 histologically distinct breast can-
cers and four different molecular variations. Each subtype differs in their
overall presentation and type of treatment required1. Invasive malignancies
are evaluated by molecular techniques to determine if hormone receptors are
present, and if there is an excessive concentration of human epidermal
growth factor receptor 2. These molecular techniques have proven that a
majority (74% in the USA) of invasive breast malignancies are either estrogen
or progesterone receptor positive, but human epidermal growth receptor 2
negative (luminal A). These malignancies are characteristically slow growing
and less aggressive. This is contrast to triple negative cancers (12% of cases in
the USA), which have the poorest short term prognosis largely because there
are no targeted therapies. Breast malignancies that are hormone receptor
negative, but human epidermal growth factor receptor 2 positive (HER2-
enriched, 4% of cases in the USA) are also more aggressive and have a poorer
short-term prognosis than hormone positive types, although recent targeted
therapies are reversing this trend.1 Treatment options for breast cancer
include surgery, chemotherapy, radiation therapy, and hormone therapy,
and depend on the stage, as well as histological and molecular subtypes.
Survival depends on stage of diagnosis, but overall, survival in the USA is
89% at 5 years, 83% at 10 years, and 78% at 15 years. Survival rates are highest
for early stages of diagnosis (99% 5 year survival in the USA) versus late
stages (26% 5 year survival in the USA).2

2. BREAST CANCER EPIDEMIOLOGY

Breast cancer is the most frequently diagnosed cancer in women

in all world regions, regardless of per capita income.3,4 Worldwide about
1.7 million cases of breast cancer are diagnosed every year, or approximately
one new case recognized every 18 s.3,4 However, incidence rates vary nearly
fourfold (Fig. 1), with higher incidence documented in higher income
regions (92 per 100,000 in North America) and lower incidence documen-
ted in lower income regions (27 per 100,000 in Middle Africa and Eastern
Asia).4–6 In the United States, breast cancer accounts for 14% of newly
identified cancers.7,8 One in eight US women will be diagnosed with breast
cancer in their lifetime, with the highest percentage occurring in the 55–64
age group.7,8
4 Stella Winters et al.

Fig. 1 Estimated breast cancer incidence worldwide. From Ferlay J, Soerjomataram I,

Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN
2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet].
Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://
globocan.iarc.fr/Pages/fact_sheets_cancer.aspx.4

In addition to being most common, breast cancer is also the leading cause
of cancer death in women worldwide.3–6 There were approximately
0.5 million deaths worldwide from breast cancer in 2013, which approx-
imates to almost one death per minute and accounts for 15% of all cancer
deaths.4 Mortality rates vary even more widely than incidence, with breast
cancer survival being significantly lower in low- and middle-income coun-
tries compared to high-income countries.6 According to a recent study that
examined 25 population-based cancer registries from 12 different countries
in diverse world regions, survival for women with localized disease and
regional disease was reported to be around 90% and 75%, respectively for
countries with highly developed health services, whereas survival in women
in countries with less-developed health services with localized disease and
regional disease was 76% for regional disease and 47%, for regional disease9
(Fig. 2) In the United States, it is estimated that 40,450 women will die from
this disease in 2016.8 Breast cancer is the second leading cause of cancer death
in women of all age groups, and the leading cause of cancer death in women
aged 20–59 years.10,11 Breast cancer mortality is highest in the southern belt
region and along the Mississippi river.12
Breast Cancer Epidemiology, Prevention, and Screening 5

Fig. 2 Estimated breast cancer mortality worldwide. From Ferlay J, Soerjomataram I, Ervik
M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. GLOBOCAN 2012
v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon,
France: International Agency for Research on Cancer; 2013. Available from: http://globocan.
iarc.fr/Pages/fact_sheets_cancer.aspx.4

2.1 Trends Over Time

Globally, breast cancer incidence has been on the rise and that trend is
expected to continue. There has been a 3.1% annual rate of rise in global
breast cancer incidence beginning with 641,000 cases in 1980 to over
1.6 million in 2010.13 By 2030, the number of breast cancer diagnoses
worldwide is expected to increase to almost 3.2 million per year.14
In the United States, incidence has been stable since 2005 for women
in their 40s and 50s, but incidence has increased for women and aged 60 or
older.10 For reasons not fully understood, breast cancer cases in the United
States are expected to increase by 64% between 2011 and 2030 with a rising
prevalence of ER positive in situ tumors and a shift in age of diagnosis to
women 70–84 years of age.15,16 Despite this daunting increase in numbers,
significant progress has been achieved over the past 30 years in improving
survival rates following a diagnosis of invasive breast cancer.8,12,17 United
States breast cancer mortality rates have decreased 36% from 1989 to 20128,12
and estimates suggest that 249,000 breast cancer deaths have been averted
among US women within that time period.7 Death rates from breast cancer
have decreased in all age groups, most notably in women ages 20–39 years.7
6 Stella Winters et al.

Relative survival rates for women diagnosed with breast cancer are 89% at
5 years after diagnosis, 83% after 10 years, and 78% after 15 years. Five year
survival rates were highest in women with localized disease and in those with
small tumor size (i.e., less than or equal to 2.0 cm) at time of diagnosis.7,15,18

3. RISK FACTORS FOR BREAST CANCER

3.1 Nongenetic, Nonmodifiable Risk Factors

3.1.1 Age
Breast cancer incidence and mortality increase proportionally with age.
Throughout the world, this disease peaks around age 60 with a sharp incline
beginning at age 40.4,8 There are, of course, some exceptions. For example,
in Latin America, 20%–30% of breast cancers are diagnosed between the ages
of 20 and 44, roughly doubling the corresponding proportion observed in
the combined USA and Canadian registries.19 In a similar vein, the peak
age at diagnosis was 40–50 years in Asian and African Countries versus
60–70 years in Western countries.20,21 In the United States, the median
age at diagnosis is 61, with the median age being younger for black women
(58 years) compared to non-Hispanic white women (62 years)22. The
median age at death due to breast cancer is 68 years overall, with the median
age at death of 62 years for black women and 69 years for non-Hispanic
white women.8
3.1.2 Race
There are significant disparities in long-term breast cancer survival between
black and white women in the United States.8,10 Although the overall
incidence of breast cancer is slightly lower in black women than in white
women, black women have the highest 5 year breast cancer mortality rate for
each known stage at diagnosis.7,22–27 As of 2012, the breast cancer death rate
was 42% higher in blacks than in whites .7 Black women were less likely than
white women to survive their breast cancer despite uniform treatment, even
after controlling for stage of disease, tumor characteristics, follow-up, and
other breast cancer risk factors.22,24,28 In addition to obvious socioeconomic
disparities that occur in some black communities, black women in general
are more likely to have a genetically more aggressive type of cancer.7 Black
women have the largest proportion of HR-/HER2 breast cancers compared
with women of other race/ethnicities.7,22,23 This subtype of breast cancer is
associated with a poorer prognosis.29,30 Additionally, black women have the
Breast Cancer Epidemiology, Prevention, and Screening 7

smallest proportion of localized breast cancers (53%) and the largest propor-
tion of regional (35%) and distant (8%) stage disease compared to other races/
ethnicities in the United States.7
In contrast, Asian/Pacific Islander women have the lowest incidence and
mortality in the United States, with Alaskan natives, American Indians, and
Hispanic women closely behind.7,8The reason for lower breast cancer inci-
dence in these minority groups is thought to reflect variation of reproductive
patterns, including greater number of children, first childbirth at a younger
age, and longer duration of breastfeeding.24,31 Asian/Pacific Islander women,
specifically, are also less likely to consume alcohol and have lower rates of
obesity both of which are associated with lower breast cancer risk.32,33
3.1.3 Early Menarche/Late Menopause
Younger age at menarche and older age at menopause increases breast cancer
risk.34–37 Breast cancer risk is approximately 20% higher among girls
that begin menstruating before age 11 compared to those that begin at
age 13.38,39 In addition, women who experience menopause at age 55 or
older have about a 12% higher risk compared to those who do so between
ages 50–54.38 There is also a disproportionate prevalence of estrogen recep-
tor positive and lobular carcinomas in this population,38 suggesting that both
ovarian synthesis of endogenous hormones, as well as a lengthening in the
total number of reproductive years play a contributory role in breast cancer
development.38,40
3.1.4 Breast Characteristics
Women with a history of breast cancer are at higher risk of developing the
disease again, especially if the initial age at diagnosis was less than 40 years of
age.41 The risk of reoccurrence in women with an initial age at diagnosis
greater than 40 years was 1.5-fold compared to a 4.5-fold increase in women
diagnosed with breast cancer at age less than 40.41 Similarly, women with a
diagnosis of a cancer precursor, such as ductal carcinoma in situ or lobar
carcinoma in situ are 8–10 and 7–12 times, respectively, more likely to
develop a new invasive breast cancer compared to women without a previous
diagnosis.42,43 Other significant associations with increased risk are prolifer-
ative lesions with atypia (i.e., atypical ductal hyperplasia and atypical lobular
hyperplasia), which are associated with 4–5 times higher than average breast
cancer risk and proliferative lesions without atypia (i.e., ductal hyperplasia
and fibroadenoma), which have a 1.5–2 times higher than average risk.44
Lastly, dense breast tissue increases the risk of breast cancer.45,46 Compared
to women with 11%–25% breast density, those with 26%–50% or greater
8 Stella Winters et al.

than 50% breast density have about a 1.6 or 2.3 times, respectively, higher risk
of breast cancer.47,48 Complicating this issue is the fact that denser breasts
impair mammographic detection of breast cancer, which couples higher risk
with a more elusive diagnosis.49

3.2 Nongenetic, Modifiable Risk Factors

3.2.1 Income, Education, and Insurance Status
Throughout the world, there exists a disparity in breast cancer survival based
on the median income of each country, as well as their Human Development
Index, which is a measure of national well-being calculated from average life
expectancy, mean years of schooling, and gross national income per capita.
Studies have shown that the mortality-to-incidence ratio of breast cancer was
found to be significantly lower in countries with a very high human devel-
opment index compared to those with high-, medium-, and low-human
development indices.50,51
Similar disparities exist in the United States. Although incidence of breast
cancer increases among women living in areas with better socioeconomic
conditions,52–55 the 5 year survival rates for each stage of diagnosis are lower
among breast cancer patients who reside in lower-income areas.52,54–62
Moreover, the level of educational attainment was found to be inversely
related to poor breast cancer outcomes.56 Specifically, women who resided in
zip codes with the lowest educational attainment were more likely to present
with metastatic breast cancer, large tumor size, triple negative tumors, or
high-grade breast cancer compared to women residing in areas of higher
educational attainment.56. Finally, payer status may affect access to health care
and influence breast cancer stage at diagnosis. Reduced access to health care
has also been linked to poor outcomes. The highest mortality bracket
includes those women with no insurance or those with Medicaid only.63–67
3.2.2 Changing Reproductive Patterns
Delayed childbearing, smaller family size, decreased duration of breastfeed-
ing, and hormonal contraceptives have been linked to increased breast cancer
risk. On the contrary, women having a first child at a younger age and having
a greater number of children is associated with decreased breast cancer
risk.48,68,69 There seems to be particular importance in timing of pregnancy
relative to menarche, with a smaller time gap associated with decreased risk
(i.e., 50% reduced lifetime risk in women having first child before
age 20).18,70–72 Another study showed that the risk of premenopausal breast
cancer is increased by 5% for each additional year that first birth is delayed.73
Breast Cancer Epidemiology, Prevention, and Screening 9

Increased parity is, overall, a long-term protective feature. Each full term
pregnancy leads to a 12% reduction of postmenopausal breast cancer risk.73
Although there is a transient (approximately 10 years duration) increased risk
after childbirth, the cumulative incidence of breast cancer is lower in mul-
tiparous women.74–76 Inherent to this protection is a time-sensitive caveat.
Compared to nulliparous females, those with first full-term birth after age 35
were shown to have a 1.26 greater risk of developing the disease within
5 years after delivery, although after 15 years, they were found to have lower
risk than their nulliparous counterparts.68,69,74,77 Furthermore, the parity-
specific effects on breast cancer risk seem to be limited to ER positive/PR
positive histologic types.78
Breastfeeding for 1 or more years reduces a woman’s overall risk of breast
cancer (reduced by 4% for every 12 months of breastfeeding).79,80 Regarding
hormonal contraceptives, there is a general increased risk associated with
earlier age at onset of use and higher estrogen formulations.81–88
3.2.3 Menopausal Hormone Use
There are two general formulations of hormonal therapy for controlling
menopausal symptoms: combined estrogen and progestin versus estrogen-
only therapy. Combined estrogen and progestin therapy increases the risk
of developing breast cancer.89,90 Higher risk correlated most with longer
use and starting therapy soon after the onset of menopause.89–92 However,
the increased risk appears to be temporary and goes back to baseline risk
after 5 years of discontinuation.91,93,94 The studies analyzing risk of breast
cancer associated with estrogen-only hormonal therapy have yielded mixed
results. Although one large RCT study found that women who used
estrogen-only therapy for an average of 6 years had a 23% lower risk of
developing breast cancer,95 other studies looking at estrogen-only therapy
have found a positive correlation with breast cancer risk, specifically when
used by lean women and when starting therapy soon after the onset of
menopause.91,94,96,97
3.2.4 Tobacco
Based on current available information there is evidence to suggest that
smoking prior to menopause increases breast cancer risk. Greater risk was
seen in women who started smoking before their first pregnancy (up to 21%
higher risk) and in those who were heavy, long-term smokers (i.e., more than
40 pack years).98–103 On the contrary, some studies show that women who
took up smoking after menopause had a significant decrease in breast cancer
risk, likely due to tobacco’s antiestrogenic effect.99,102,104 There have been
10 Stella Winters et al.

no conclusive studies regarding the association of second hand smoke and

breast cancer risk, however some studies have found a connection with
premenopausal breast cancer.99,105,106
3.2.5 Alcohol
Alcohol consumption has been linked to increased breast cancer risk. Some
studies have found a dose-dependent relationship,107–112 while others found
an association with cumulative average alcohol consumption over long
periods of time.113,114 Specifically, consumption of 5–9.9 g/day (i.e., 3–6
glasses of wine per week) was associated with up to a 10% increased risk.113
Others found an association with binge-drinking (i.e., 1.5 RR for 10–15
drinks per weekend and 2.5 RR for 16–21 drinks per weekend).115–117
There was no difference whether alcohol consumption was prevalent before
age 40 or after age 40.115 There was also no difference based on type of
alcohol (i.e., beer, wine, or liquor).108,109,114,118 The mechanism behind
these findings is likely related to the ability of alcohol to increase levels of
estrogen in the blood. As such, the majority of breast cancers linked to
alcohol consumption are of the ER+ subtype.89,119–122
3.2.6 Fitness and Nutrition
Breast cancer risk is decreased in women performing regular physical activity
and in those who consume high amounts of fruits and vegetables. Women
who walk at least 7 h per week have a 10%–25% lower risk of breast cancer
compared to women who are inactive, with an even greater protective effect
in postmenopausal women.123–126 Fruit and vegetable consumption, as
measured by plasma carotenoid levels, was inversely related to breast cancer
risk, especially among nonobese women. Furthermore, these women tended
to have less aggressive cancers.115,127 One study found that plasma alpha
carotene levels above the lowest quartile were associated with over 40% lower
risk of invasive breast cancer.127
Elevated BMI and breast cancer risk is contingent on menopausal
status.95,128–130 Obesity seems to have a protective effect in development
of premenopausal breast cancer, however, is linked to increased breast cancer
development after menopause.131,132 Overweight and obese premenopausal
women (40 and 49 year old) had a 14% and 26%, respectively lower risk of
developing breast cancer compared to premenopausal women who were
normal weight.48 This is likely due to the lack of ovulation commonly
experienced by overweight and obese women.133–135 On the contrary, there
is an increased risk of breast cancer in postmenopausal overweight and
obese women.95,128,129,133,134,136 Risk is approximately 1.5 times higher
Breast Cancer Epidemiology, Prevention, and Screening 11

in overweight postmenopausal women and 2.1 times higher in obese post-

menopausal women compared to postmenopausal lean women.95,134 This is
likely explained by higher levels of circulating estrogen released from
adipose tissue in elderly women with elevated BMI.134 Elevated BMI is also
highly correlated with type II diabetes, which is an independent risk
factor for breast cancer development.137,138
The relationship between weight gain and weight loss with breast cancer
risk is less clear, likely because these changes, especially the latter, are not
sustained and therefore difficult to study prospectively. However, a recent
metaanalysis found that each 5 kg (about 11 pounds) gained during adult-
hood increases the risk of postmenopausal breast cancer by 11%.139 There is
currently inconclusive evidence regarding the role of weight loss and breast
cancer risk.140–143

3.3 Genetic Risk Factors

3.3.1 BRCA1 and BRCA 2 Mutations
Hereditary breast and ovarian cancer syndrome is usually caused by genetic
mutations in one of two BReast CAncer (BRCA) susceptibility genes,
BRCA1 and BRCA2. Mutations in these genes can cause cancer in the
breasts and in other organs, such as the ovaries, pancreas, and prostate. In
the United States, 1 in 500 may carry one of these mutations.144,145
Approximately 3% of breast cancers and 10% of ovarian cancers are caused
by these gene mutations.146 Women who carry these mutations are more
likely to develop cancer by age 70 compared with the general population,
65% with BRCA1 and 45% with BRCA 2.147 Women with close relatives
that have triple negative breast cancer, premenopausal breast cancer, and
ovarian cancer, bilateral breast cancer, or breast cancer in a male relative or
multiple relatives with breast cancer is likely to have a gene mutation in
BRCA1 and BRCA2. Ashkenazi Jews or Eastern European descent have a
much higher risk (1 in 40).146
Tumor suppressor genes are essential to the normal biophysiology of
human function and development. Tumor suppressor genes are key to regu-
lating and inhibiting cell growth and proliferation. Specific proteins are created
from these genes that have numerous functions and specialize in DNA repair,
initiating apoptosis, block tumor cell adhesion, and preventing metastasis.
Mutations can occur within these genes leading to inappropriate and dysfunc-
tional proteins that are unable to perform effectively. Once mutations occur,
there is an increased risk of tumor formation and malignancy. Specific tumor
12 Stella Winters et al.

suppressor genes, including the breast cancer genes, BRCA1 and BRCA2,
are fundamental in cellular processes through genomic integrity and transcrip-
tional regulation.148 Mutations within these two genes are linked to the
development of breast and/or ovarian cancer. These mutations can occur
through an inherited, or sporadic process leading to malignancy.
Those with inherited BRCA mutations also have an inactivated BRCA
allele. During puberty, the estrogen dependent–breast epithelium undergoes
rapid cell replication and proliferation. These changes exert a stress on the
DNA repair system that is incapable of repairing damaged DNA, therefore
resulting in cell death. During this process, a small population of cells with
damaged DNA will escape cellular death resulting in protein production
based on mutated and damaged DNA. Multiple DNA regions that are
damaged will often affect genes responsible for cell cycle checkpoint activa-
tion. Once a cell is able to bypass this checkpoint, it will permanently escape
cell death and will undergo uncontrolled cell proliferation. With the loss of
BRCA1 mammary cells, this typically produces mutated p53 checkpoint
genes leading to mammary tumors.149
Sporadic BRCA mutations are similar to the pathophysiology seen with an
inherited process. With the rapid proliferation within breast epithelium stim-
ulated by estrogen, the rate of mutations that occur within the BRCA gene is
increased. Inactivation of either BRCA alleles, or a hypofunctional active allele
are required in sporadic malignancy. Clinical symptoms and presentation
typically present later in life as mutations and cell inactivation increase.148
Transcriptional silencing has also been considered a factor contributing to
BRCA expression. The BRCA alleles are dependent on regulatory proteins.
Inactivation of positively regulated proteins results in decreased expression of
these tumor suppressor cells, whereas an increased expression of negative
regulatory proteins, decreases gene expression resulting in an increased risk
of malignancy.148
More than 1800 mutations have been identified within the BRCA1
gene, which increases the risk of breast cancer in both men and women.
These mutations that occur are present within every cell in the body, and
therefore can be passed on to future generations. Statistically, women are
35%–60% more likely to develop ovarian cancer in comparison to the 1.6%
seen in the general population.150

3.3.2 BRCA Mutation Screening

It has been clearly defined and proven that BRCA1 and BRCA2 function
as tumor suppressor genes. Of the mechanisms described earlier, the
Breast Cancer Epidemiology, Prevention, and Screening 13

commonality seen amongst each possible mechanism is an increased preva-

lence of breast and/or ovarian malignancy. Risk factors for potentially harm-
ful BRCA mutations include breast cancer diagnosed before the age of 50,
bilateral breast malignancy, presence of both breast and ovarian cancer,
presence of breast cancer in at least one male–related family member, mul-
tiple cases of breast cancer, and Ashkenazi Jewish ethnicity. Women who
have at least one family member diagnosed and treated for BRCA-related
breast or ovarian cancer should be considered for genetic testing. Several
tools are available to assess the risk of having a BRCA mutation and
this guides whether referral for consideration of testing should occur. The
United States Preventive Service Task Force has evaluated and recommended
the use of several assessment tools to identify patients at risk. These tools
include the Ontario Family History Assessment Tool, Manchester Scoring
System, Referral Screening Tool, Pedigree Assessment Tool, or the Family
History Screening 7.151
BRCA genetic testing should be recommended in individuals who have
had breast and/or ovarian cancer, or a family history of BRCA related
malignancies. It is important for patients to be evaluated by a professional
who is trained in interpreting the results. Individuals who have a family
history of specific, known mutations or from specific ethnicities, may be
tested for those specific mutations, or mutations known to be present with
certain ethnic groups. If there is no specific history or ethnic background, a
more comprehensive BRCA genetic testing is recommended. Results of
genetic testing are reported as positive, variants of uncertain clinical signif-
icance, uninformative-negative, or true negative. It is important that these
results are discussed with a genetic counselor, or a professional trained in
interpreting the results.151
Screening for BRCA mutations may begin once the individual
has reached an age of consent, with periodic follow-up evaluations to
determine if any changes have occurred with the patient or within the
family.

4. BREAST CANCER PREVENTION

Interventions are available exist for those with positive genetic

testing for BRCA mutation(s). Options should be discussed with the patient,
including adverse effects of each treatment, and potential long-term
consequences.
14 Stella Winters et al.

4.1 Lifestyle/Behavior Change Interventions

More than 2/3 of the U.S. adult population is either overweight or obese. As
females transition through menopause, the increase adipose tissue increases
the amount of circulating estrogen levels putting individuals at an increased
risk of breast cancer by 12%. In comparison, those who lost and maintained
more than 10 kg of weight demonstrated more than 50% reduction in breast
cancer risk.152
Moderate to vigorous physical activity has demonstrated an overall
reduction in breast cancer risk. Women who engage in recreational physical
activity, who achieve greater than 42 MET-h/week, have demonstrated an
overall breast cancer risk reduction of at least 25%. Women who walked at
least 7 h/week had a 14% reduced risk of postmenopausal breast cancer in
comparison to those who only walked less than three hours per week.153
In addition to poor physical activity, as discussed earlier, consumption of
alcohol increases the risk of breast cancer. During 1980–2008, a large pro-
spective, cohort study was conducted on 105,986 women enrolled in the
Nurses’ Health Study. This study identified a modest, but significant increase
in breast cancer risk with low level alcohol consumption. Low-level con-
sumption was defined as 5–9.9 g/day, or 3–6 glasses of wine per week
(multivariate RR, 1.15; 95% CI, 1.06–1.24; 333 cases/100,000 person-
years). Women who consumed at least two alcoholic drinks per day, or more
than 30 g daily, had a greater risk of developing breast cancer (RR 1.51; 95%
CI, 1.35–1.70; 413 cases/100,000 person-years).154 In this sample, a com-
bination of weight reduction, physical activity, and limited alcohol consump-
tion reduced the overall risk of breast malignancy.

4.2 Chemoprevention
Chemoprevention has demonstrated benefits in reducing the risk of breast
cancer. Selective estrogen receptors modulators, such as Tamoxifen and
Raloxifene, have demonstrated evidence for the reduction of breast cancer
risk. In 2013, the American Society of Clinical Oncology, recommended
that physicians discuss the use of Tamoxifen as an option to reduce the risk of
invasive breast cancer, especially those with estrogen receptor positive breast
cancer, premenopausal, or postmenopausal women older than 35 at an
increased risk, or those with lobular carcinoma in situ. Raloxifene has similar
recommendations, but should not be used in premenopausal women. The
STAR trial, which compared Tamoxifen with Raloxifene, is the only ran-
domized controlled trial comparing breast cancer risk reduction between the
two medications. The STAR trial demonstrated an overall risk reduction
Breast Cancer Epidemiology, Prevention, and Screening 15

between 31% and 67%. After a follow-up period of 4.6 years, the efficacy
of Tamoxifen and Raloxifene were equal. At 6 years, women taking a
Raloxifene were 24% more likely to develop invasive breast cancer in com-
parison to women taking Tamoxifen (RR 1.24; 95% CI, 1.05–1.47).155
Physicians should engage in a shared conversation and decision when
considering the use of Tamoxifen or Raloxifene in women with an increased
risk of breast cancer.
The use of chemoprevention is dependent on several factors, such as age,
race, breast cancer risk, the presence of a uterus, and the type of medication
being considered. The International Breast Cancer Intervention Study-1
demonstrated an increased risk of endometrial cancer and venous thrombo-
embolism. This randomized controlled trial was conducted on premeno-
pausal and postmenopausal women aged 35–70 years of age. There was an
increase in endometrial cancer, but this was not statistically significant.
Unfortunately, there was a significant increase in deep venous thrombosis
during the same study. Fifty of the 3,579 (1.4%) women receiving Tamoxifen
developed a deep venous thrombosis in comparison to 29 (0.8%) women
who were not on Tamoxifen therapy [OR 1.73(95% CI 1.07–2.85)].156
In comparison, Raloxifene has a lower risk of cataracts, endometrial
cancer, and thromboembolic disease. Women younger than age 50, and
young black women may benefit from the use of Tamoxifen, whereas
women greater than age 50 would benefit from using Raloxifene if the
patient still has a uterus. The STAR trial demonstrated significantly lower
risk of thromboembolic disease, uterine cancer, uterine hyperplasia, and
cataracts. Raloxifene also demonstrated a significantly lower incidence of
ovarian cysts, endometrial polyps, hot flashes, vaginal discharge, and vaginal
bleeding during a retrospective analysis of data from the NSABP-P1 and
STAR trials).155
In addition to the use of selective estrogen receptor modulators, chemo-
prevention can also be implemented with the use of aromatase inhibitors.
Exemestane, which functions to inhibit the conversion of androgens to
estrogen, is recommended by the American Society of Clinical Oncology.
Postmenopausal women who are at an increased risk of breast cancer, have a
history of atypical hyperplasia, or lobular carcinoma in situ are encouraged
to discuss with their physician the benefits of starting Exemestane for
chemoprevention.152
Bisphosphonates, such as Zoledronate, have a threefold benefit in treating
individuals with breast cancer. Bisphosphonates aid in reducing skeletal
related events, such as pathological fractures, bone pain, and hypercalcemia
16 Stella Winters et al.

related to breast cancer metastasis. The use of aromatase inhibitors decreases

the amount of circulating estrogen leading to decreased bone strength. The
use of bisphosphonates can help with stabilizing the bone during treatment.
In addition, bisphosphonates have demonstrated a decrease in bone recur-
rence, and breast cancer–related death in postmenopausal patients. The Early
Breast Cancer Trialists’ Collaborative Group included 5 oral clodronate trials
(N = 5,053), and 17 aminobisphosphonates trials (N = 12,738).157 This
metaanalysis concluded that treatment with bisphosphonates reduced the
risk of bone recurrence by 34%, and the risk of breast cancer death by 17% in
postmenopausal women.

4.3 Surgery
Mutations in BRCA1 and BRCA2 tumor suppressor genes increase the risk
of breast cancer. The option of prophylactic mastectomy should be discussed
and offered to those with this mutation(s). Body image is a concern and must
be discussed when individuals are considering a mastectomy. Genetic risk
and psychological assessment should be completed, along with an evaluation
by a breast surgeon. The option for reconstructive surgery is necessary to
maintain a patient’s self-identify and confidence.158
Overall, several different preventive options are available, and each should
be discussed thoroughly with the patient. Comprehension of the disease
pathophysiology and potential side effects of preventive treatment, will allow
the patient to make an informed decision based on what is most appropriate.

5. BREAST CANCER EARLY DETECTION AND SCREENING

Screening tests detect life-threatening diseases at early stages. Earlier

diagnosis of disease can lead to improved outcomes in those with disease and
lessen the incidence of a disease presenting at later stages. It is important to
have discussions with patients to compare potential benefits and harms.

5.1 History of Screening

In 1913, Albert Salomon, a German surgeon, performed a roentgeno-his-
tological study on 3000 mastectomies. Through X-rays he was able to find
differences in normal and cancerous breast tissue. In 1930, Stafford Warren
described and categorized the appearance of normal breasts. He also dis-
cussed the importance of comparing the right and left breasts in side-by-side
Breast Cancer Epidemiology, Prevention, and Screening 17

views.159 In the 1950’s, after more than a decade of research, Gershon-

Cohen and Strickler published a report on the variations of a normal mam-
mogram. Gershon-Cohen and colleagues went on to define the criteria for
normal and characteristic findings of benign and malignant disease. In 1965,
through the work of Robert Egan, the American College of Radiology
sponsored a conference that led to recommended dosages and reproducible
techniques for diagnostic examinations of the breasts.159
In the 1950s mammography was gaining usefulness as a diagnostic modal-
ity and 20 years later, Betty Ford, the First Lady of the United States, and
Rose Kushner, an American journalist, was diagnosed with breast cancer and
the two became prominent advocates for breast cancer awareness in the
United States. Betty Ford openly discussed her disease in public and used
her illness to help “ . . . save other lives . . . ” Rose Kushner adamantly
refused to have the “one-step” procedure. This procedure involved an
immediate mastectomy of the breast with biopsy proven cancer. In 1979,
the National Institutes of Health conference on breast cancer treatment
concluded that “the 1-step procedure was no longer appropriate and other
less disfiguring surgeries combined with radiotherapy, chemotherapy, or
both afforded the same survival.”160 Years later Nancy Reagan, former
First Lady of the United States, and Nancy Brinker, sister of Susan G.
Komen, began to increase public awareness of breast cancer even further.
This led to “legislative, regulatory, and funding changes” that have brought
breast cancer into mainstream and greatly improved research into the diag-
nosis and treatment of this disease.161

5.2 Screening Benefits and Harms

Breast cancer will affect the majority of the population through patient,
personal, and family or friend experiences. Screening mammography in
women aged 40 years and older during the 1980s–90s in the United States
led to a large increase in cases of early-stage cancer diagnoses (112–234
cancers per 100,000), a decrease in late stage cancer diagnoses (102 to 94
cases per 100,000 women), and a decrease in the death rate from breast
cancer (71 to 51 deaths per 100,000 women).162 Case-control studies,
RCTs, and observational studies have also shown a decrease in breast
cancer mortality secondary to screening mammograms.163,164 These
studies have shown 15%–40% reduction in mortality from breast cancer
secondary to screening mammograms. Contributing to this reduction is a
combination of advanced screening, better treatments, and underreporting
of breast cancer as a cause of death.163,165 Breast cancer screening does save
18 Stella Winters et al.

lives, however, as with any screening test, there is the potential risk of harm
from screening.
Harms associated with screening mammograms include false negative
results, overdiagnosis, radiation-induced cancer, and false positives. False-
negative mammograms result in undetected breast cancer and estimates
range from 6% to 46% of women screened, and they may be more common
in younger women with denser breasts.2 It can result in women erroneously
confident that they do not have breast cancer and this can cause late stage
diagnosis of breast cancer or death. Radiation-induced cancers from digital
mammograms are rare and are estimated to be 0.4–1.2 per 10, 000 women
screened over a lifetime. Screening mammograms may also lead to false-
positive results.1,147,164 Women with false-positive results may require fur-
ther imaging and often a breast biopsy.122 Fifty percent of women screened
annually for 10 years will experience a false positive and 7%–17% will have
biopsies.2,18 On average, of 10% of women recalled for further testing, 5 out
of 100 women will have cancer.2 Screening low-risk women at younger ages
may cause unnecessary further imaging and biopsies. This particular harm
needs to be discussed with women prior to initiating screening. Women may
experience anxiety and psychological distress for up to 2 years after a false
positive result.122,147 Another important potential harm is overdiagnosis,
which is the diagnosis and treatment of noninvasive and invasive breast
cancer that would ultimately not cause symptoms, threaten life or cause
death. Women may be exposed to disfiguring surgery, radiation, hormone
therapy or chemotherapy, and the adverse consequences of these treatments
(scarring, cardiac toxicity, and lymphedema).164 Observing trends using the
surveillance, epidemiology, and end results data from 1976 through 2008, the
estimated proportion of overdiagnosed breast cancers varies widely between
5% and 54%.1,2,162,164 It is estimated that 1 in 8 women diagnosed with
screening mammograms from the ages 50 to 75 years are overdiagnosed,122
see Table 1.

Table 1 Lifetime Benefits and Harms of Biennial Screening Mammography, 1000

Variable Ages 40–74 years Ages 50–74 years
False-positive test results (n) 1529 (1100–1976) 953 (830–1325)
Unnecessary breast biopsies (n) 213 (153–276) 146 (121–205)
Overdiagnosed breast tumors, (n) 21 (12–38) 19 (11–34)
Women screened: model results compared with no screening.
Adapted with permission of the Final Recommendation Statement—Breast Cancer: Screening. U.S.
Preventive Services Task Force. November 2016. https://www.uspreventiveservicestaskforce.org/Page/
Document/RecommendationStatementFinal/breast-cancer-screening1166.
Breast Cancer Epidemiology, Prevention, and Screening 19

5.3 Screening Recommendations

In the USA, the U.S. Preventive Services Task Force (USPSTF) and other
professional organizations make recommendations for prevention and screen-
ing based on periodic assessments of the evidence base, and also evaluate the
level of the recommendation based on the strength of the evidence, see Table 2
for the level of evidence recommendation categories for the USPSTF.122,166
The breast cancer screening guidelines also address women at an increased risk
for breast cancer, women who request screening outside of the standard age
ranges and the use of breast cancer risk screening tools to obtain a thorough
family and personal history to assist the clinician and patient to identify
individual risks and make informed decisions for breast cancer screening.122

5.4 Breast Cancer Screening in Average Risk Women

The USPSTF recommends screening asymptomatic women aged 50–74
years old with biennial screening mammograms (B recommendation).122,166
Screening women aged 40–49 years with mammograms is a C recommen-
dation.122,166 This C recommendation indicates that healthcare providers
discuss the pros and cons of screening to ensure patients understand the
potential harms associated with screening mammograms, such as false-posi-
tives, false-negatives, and overdiagnosis so that they can make an informed
decision about whether to get screened. In RCTs, screening mammograms
are shown to be effective in women aged 40–49 in averting breast cancer

Table 2 United States Preventive Services Task Force Grades and Suggestions for
Practice
Grades Definitions Suggestions for Practices
A Net benefit, recommend Offer or provide this service
service
B Moderate net benefit, Offer or provide this service
recommend service
C Small net benefit, Offer service for select patients
selectively provide
service
D No net benefit, do not Discourage use of service
recommended
I statement Current evidence is If service is offered, patients should
insufficient to assess net understand the uncertainty about
benefit harms and benefits
Adapted with permission of the Final Recommendation Statement—Breast Cancer: Screening. U.S.
Preventive Services Task Force. November 2016. https://www.uspreventiveservicestaskforce.org/Page/
Document/RecommendationStatementFinal/breast-cancer-screening1166.
20 Stella Winters et al.

death [RR 0.92 (0.75–1.02)], but to a lesser degree compared to women

aged 60–69 years [RR 0.67 (0.54–0.83)].147 Women aged 40–49 years, do
receive a greater number and proportion of negative additional imaging
and breast biopsies compared to older women122 (Table 1). Women aged
60–69 years benefit the most from mammographic screening and are most
likely to avoid death from breast cancer. Screening younger women is based
on individual risk factors and requires a thorough family history of certain
cancer syndromes. The USPSTF has no recommendations for screening
women 75 years and older (I statement). The USPSTF also supports that
women have an awareness of changes in their bodies (i.e., breasts) but does
not recommend teaching breast self examinations.122,166
Other national guidelines are similar to the USPSTF. The American
College of Radiology (ACR), Appropriateness Criteria,167 and the
American College of Obstetricians and Gynecologists (ACOG) recommend
that women start annual screening at age 40.168,169 The ACR defines women
of average risk as having a <15% lifetime risk of breast cancer and breast that
are not classified as dense. The health provider should discuss the benefits and
potential harms of screening starting at aged 40 years.122 ACOG also recom-
mends clinical breast exams in women aged 20–39 years old every 1–3 years
and annually in women aged 40 years. ACOG, USPSTF, and ACS promote
“breast self-awareness”18,166,169; ACOG includes instruction for and
encourages self-breast examinations for high-risk women.169 The
American Cancer Society (ACS) has a strong recommendation that women
with average risk for breast cancer should undergo screening for breast
cancer: women aged 45–54 years should begin annual screening for breast
cancer (qualified recommendation).18 Women 55 years and older should
transition from annual to biennial screening or can continue with annual
screening after discussion with health provider (qualified recommendation).
Women aged 40–44 years should have the opportunity to start annual
screening (qualified recommendation). Finally, women should continue
mammograms as long as they are healthy and there is at least a 10 year life
expectancy (qualified recommendation). The ACS does not recommend
clinical breast exam for any patient (qualified recommendation).18

5.5 Genetic Mutations, Breast Cancer Screening Tools, and

Screening Methods in High-Risk Women
As discussed previously mutations in BRCA1 and BRCA2 can cause
cancer in the breasts and in other organs, such as the ovaries, pancreas,
and prostate. In the United States, approximately 3% of breast cancers and
Breast Cancer Epidemiology, Prevention, and Screening 21

10% of ovarian cancers are caused by these gene mutations.145 The

USPSTF recommends screening women to identify relatives with these
hereditary syndromes and refer them for genetic counseling.166 Women
referred to genetic counseling discuss possibilities for genetic testing and
receive counseling on early mammographic screening with adjunctive
imaging (MRI), medications, chemotherapy, and risk reducing surgery
(mastectomy and oophorectomy).
There are various online clinical screening tools that can assist the clini-
cian in stratifying patients into different risk categories. The National Cancer
Institute has developed the Breast Cancer Risk Assessment Tool (BCRAT), a
validated calculator to estimate invasive breast cancer risk for women in the
United States (https://www.cancer.gov/bcrisktool/), which is based upon
the Gail Model that has been validated for white women.18 Family history is a
key element of this tool as with most other breast cancer screening tools. The
BCRAT is not meant for women with a diagnosis of breast cancer, DCIS,
LCIS, or for women who may have received radiation to the chest for
Hodgkin lymphoma. Women with LCIS can use the IBIS Breast Cancer
Risk Evaluation Tool (www.ems-trials.org). For women with known
BRCA1 or BRCA2 gene mutations, the BOADICEA (Breast and
Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)
model (www.ccge.medschl.cam.ac.uk) can be used to estimate their breast
cancer risk. This model is a computer program that calculates the risk of
breast and ovarian cancer in women based on their family history. There are
also tools available for screening and providing information on BRCA gene
mutations. A BRCA decision support tool can be found at www.
KnowBRCA.org and through a digital media campaign that provides infor-
mation on (http://www.cdc.gov/cancer/breast/young_women/bring/
your/brave)145 hereditary breast and ovarian cancer syndrome.145 Women
who screen positive would benefit from a referral to a breast specialty center
for genetic counseling, further testing, and management.
According to ACR guidelines, women deemed high risk should be
screened earlier; ages 25–30 or 10 years earlier (whichever is later) for
women with a first-degree relative with premenopausal breast cancer; ages
25–30 years for women who are carriers of the BRCA gene 1, or having a
lifetime risk of 20% of developing breast cancer on the basis of family
history122,158; 8 years after radiation therapy but not before age of 25 years
for those who have received mantle radiation between 10 and 30 years of age;
and any age for women with biopsy proven lobular neoplasia, atypical ductal
hyperplasia, DCIS, or invasive breast cancer.158,168
22 Stella Winters et al.

The ACS also includes personal and family history of BRCA1 and
BRCA2 gene mutations, Li-Fraumeni syndrome (autosomal dominant
disorder also known as the Sarcoma, Breast, Leukemia and Adrenal Gland
cancer syndrome) or Cowden syndrome (a germline mutation in the phos-
phatase and tensin homolog (PTEN) gene with harmartomatous tumor
development) as risk factors for the development of breast cancer. Women
with any of these conditions are encouraged to begin mammographic
screening at age 30 years.1

5.6 Screening Modalities

As stated earlier, mammography is a procedure that allows visualization of the
internal structures of the breasts. Across all ages screening mammogram has a
sensitivity of 77%–95% and a specificity of 94%–97%.166 Three types of
mammography are film, digital, and breast tomosynthesis. Film uses X-ray
equipment to record images of the breasts and digital mammography (DM)
uses specialized computer equipment and delivers lower doses of radiation.
DM has mainly replaced film mammography.18
Dense breasts are a risk factor for breast cancer.122 A classification system
for dense breasts from the American College or Radiology’s Breast Imaging
Reporting and Data System (BI-RADS) is a four-category scale (Table 3).
Dense breast tissue reduces mammography sensitivity from 87% to 73%
and specificity from 96% to 90%.166 Many states in the United States
require patient notification of breast density status when a mammogram
is performed. Some states require that adjunctive screening should at least
be considered.166 According to data from BSCS, 25 million women
aged 40–74 years have a BI-RADS Class D. Relative risk for developing
invasive breast cancer in women with extremely dense breasts is, 1.23 aged
40–49 years, 1.29 for women aged 50–64 years, and 1.30 for women aged
65–74 years.122 DM accounts for the majority of mammography screening
in the United States and has a higher sensitivity that increases with age and
decreases with denser breast tissue.147 The USPSTF does not recommend

Table 3 Breast Tissue167

Breast Composition Categories
a. The breasts are almost entirely fatty
b. There are scattered areas of fibroglandular density
c. The breasts are heterogeneously dense, which may obscure small masses
d. The breasts are extremely dense, which lowers the sensitivity of mammography
Permission granted from the ACR Appropriateness Criteria.
Breast Cancer Epidemiology, Prevention, and Screening 23

use of adjunctive imaging, such as breast MRI, breast ultrasound, or

digital breast tomosynthesis (DBT) in women with a normal screening
mammogram.166
In 2011, the FDA approved use of DBT or 3-dimensional (3-D) mam-
mography. A 3-D image of the breast is constructed with multiple high-
resolution X-rays and can be used in combination with a 2-D or DM with
single breast compression. DBT allows for the display of breast tissue in
1 mm sections, which reduces superimposition of breast tissue.168 DBT
with digital mammogram results in less recall rates for women to come
in for additional imaging compared to conventional screening (7.8% vs.
12.3% recall). Cancer detection is 5.9 per 1000 with 3-D compared to
4.4 per 1000 with 2D alone. The combined radiation does is higher but
still within acceptable limits and is still within the FDA approved limit.170
Breast MRIs use magnetic fields instead of X-rays to produce very
detailed, cross sectional images of the body. There is use of contrast, either
gadolinium or DTPA that is injected into a vein. Breast MRI is comple-
mentary imaging to mammography for women who are high risk.1 In high-
risk women, breast MRI has a higher sensitivity than mammography and
combined with mammography has the highest sensitivity (92.7%).168 If a
woman cannot undergo an MRI then an ultrasound is recommended.168 It is
important to note that nephrogenic systemic fibrosis is related to underlying
severe renal disease with the administration of gadolinium-based contrast
agents. It occurs primary in patients with estimated glomerular filtrations
rates of <30 mL/min/1.73 m2

5.7 Breast Ultrasound

Ultrasound of the breasts can detect more cancer than mammogram alone
especially in women with dense breast tissue. Ultrasound should not be used
alone to screen for breast cancer.18 It can be used on women with incon-
clusive mammogram findings, to guide for different breast biopsies, and to
distinguish a solid from a nonsolid mass.169 It can also be used in high-risk
women who need adjunctive imaging and cannot tolerate an MRI.168
Breast cancer screening saves lives. The recommendations for average-
risk women follow age-based protocols. Women undergoing screening
should routinely be assessed for personal and family history and other risk
factors that place them at an increased risk of breast cancer. There are
calculators that estimate a women’s risk for having gene certain mutations
(BRCA1 and BRCA2) and a women’s risk of developing breast cancer based
on family history. When screening women, especially younger women, it is
24 Stella Winters et al.

important to discuss the limitations and possible harms from mammography

screening, such as overdiagnosis and false positives that can lead to additional
imaging, biopsies, and even treatment. DM is the foremost screening tool,
however, breast DBT in addition to DM results in less recalls for additional
imaging, better detection of cancer, and less false positives in some cases.
MRI of the breasts is a complementary test and is usually reserved for high-
risk women based on their family history. Healthcare providers should
strongly consider referral for women considered high risk for developing
breast cancer.

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