Genetic/Familial High-Risk Assessment:

CE NCCN GUIDELINES® INSIGHTS

Breast, Ovarian, and Pancreatic, Version 2.2024

NCCN Continuing Education

Target Audience: This activity is designed to meet the educational valid until October 10, 2024. PAs should only claim credit com-
needs of oncologists, nurses, pharmacists, and other healthcare mensurate with the extent of their participation.
professionals who manage patients with cancer.
All clinicians completing this activity will be issued a certificate of
Accreditation Statements participation. To participate in this journal CE activity: (1) review the
In support of improving patient care, educational content; (2) take the posttest with a 66% minimum
National Comprehensive Cancer Network passing score and complete the evaluation at https://education.
(NCCN) is jointly accredited by the Accredita- nccn.org/node/92941; and (3) view/print certificate.
tion Council for Continuing Medical Education
Pharmacists: You must complete the posttest and evaluation within
(ACCME), the Accreditation Council for Phar-
30 days of the activity. Continuing pharmacy education credit is re-
macy Education (ACPE), and the American Nurses Credentialing
ported to the CPE Monitor once you have completed the posttest
Center (ANCC), to provide continuing education for the healthcare
and evaluation and claimed your credits. Before completing these re-
team.
quirements, be sure your NCCN profile has been updated with your
Physicians: NCCN designates this journal-based CME activity for a NAPB e-profile ID and date of birth. Your credit cannot be reported
TM
maximum of 1.0 AMA PRA Category 1 Credit . Physicians should without this information. If you have any questions, please email
claim only the credit commensurate with the extent of their par- [email protected].
ticipation in the activity.
Release date: October 10, 2023; Expiration date: October 10, 2024
Nurses: NCCN designates this educational activity for a maximum
of 1.0 contact hour. Learning Objectives:
Pharmacists: NCCN designates this knowledge-based continuing Upon completion of this activity, participants will be able to:
education activity for 1.0 contact hour (0.1 CEUs) of con-
tinuing education credit. UAN: JA4008196-0000-23-010-H01-P  Integrate into professional practice the updates to the NCCN
Guidelines for Genetic/Familial High-Risk Assessment: Breast,
PAs: NCCN has been authorized by the American Academy Ovarian, and Pancreatic
of PAs (AAPA) to award AAPA Category 1 CME credit for activi-  Describe the rationale behind the decision-making process for devel-
ties planned in accordance with AAPA CME Criteria. This activity oping the NCCN Guidelines for Genetic/Familial High-Risk Assess-
is designated for 1.0 AAPA Category 1 CME credit. Approval is ment: Breast, Ovarian, and Pancreatic

Disclosure of Relevant Financial Relationships

None of the planners for this educational activity have relevant financial relationship(s) to disclose with ineligible companies whose primary business is
producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.

Individuals Who Provided Content Development and/or Authorship Assistance:

The faculty listed below have no relevant financial relationship(s) with ineligible companies to disclose.

Mary B. Daly, MD, PhD, Panel Chair

Kara N. Maxwell, MD, PhD, Panel Member
Jane Churpek, MD, MS, Panel Member
Wendy Kohlmann, MS, CGC, Panel Member
Mary A. Dwyer, MS, CGC, Senior Director, Guidelines Operations, NCCN
Susan D. Darlow, PhD, Manager, Guidelines Information Standardization, NCCN

The faculty listed below have the following relevant financial relationship(s) with ineligible companies to disclose. All of the relevant financial relationships
listed for these individuals have been mitigated.

Tuya Pal, MD, Panel Vice Chair, has disclosed serving as a scientific advisor for Natera Inc.

To view all of the conflicts of interest for the NCCN Guidelines panel, go to NCCN.org/guidelines/guidelines-panels-and-disclosure/disclosure-panels

This activity is supported by educational grants from AstraZeneca; Exact Sciences; Novartis; and Taiho Oncology, Inc. This activity is supported by an in-
dependent educational grant from Daiichi Sankyo. This activity is supported by independent medical education grants from Illumina, Inc. and Regeneron
Pharmaceuticals, Inc.

1000 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 21 Issue 10 | October 2023
 NCCN GUIDELINES® INSIGHTS CE

Genetic/Familial High-Risk Assessment: Breast,

Ovarian, and Pancreatic, Version 2.2024
Featured Updates to the NCCN Guidelines
Mary B. Daly, MD, PhD1,*; Tuya Pal, MD2,*; Kara N. Maxwell, MD, PhD3,*; Jane Churpek, MD, MS4,*;
Wendy Kohlmann, MS, CGC5,*; Zahraa AlHilli, MD6; Banu Arun, MD7; Saundra S. Buys, MD5; Heather Cheng, MD, PhD8;
Susan M. Domchek, MD3; Susan Friedman, DVM9; Veda Giri, MD10; Michael Goggins, MD11; Andrea Hagemann, MD12;
Ashley Hendrix, MD13; Mollie L. Hutton, MS, CGC14; Beth Y. Karlan, MD15; Nawal Kassem, MD, MS16; Seema Khan, MD17;
Katia Khoury, MD18; Allison W. Kurian, MD, MSc19; Christine Laronga, MD20; Julie S. Mak, MS, MSc, LCGC21;
John Mansour, MD22; Kevin McDonnell, MD, PhD23; Carolyn S. Menendez, MD24; Sofia D. Merajver, MD, PhD25;
Barbara S. Norquist, MD8; Kenneth Offit, MD26; Dominique Rash, MD27; Gwen Reiser, MS, CGC28;
Leigha Senter-Jamieson, MS, CGC29; Kristen Mahoney Shannon, MS, CGC30; Kala Visvanathan, MD, MHS11;
Jeanna Welborn, MD31; Myra J. Wick, MD, PhD32; Marie Wood, MD33; Matthew B. Yurgelun, MD34;
Mary A. Dwyer, MS, CGC35,*; and Susan D. Darlow, PhD35,*

ABSTRACT NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform
The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, NCCN consensus that the intervention is appropriate.
Ovarian, and Pancreatic focus primarily on assessment of pathogenic/ Category 2A: Based upon lower-level evidence, there is uniform
likely pathogenic (P/LP) variants associated with increased risk of breast, NCCN consensus that the intervention is appropriate.
ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1,
Category 2B: Based upon lower-level evidence, there is NCCN
PALB2, PTEN , and TP53, and recommended approaches to genetic
consensus that the intervention is appropriate.
counseling/testing and care strategies in individuals with these P/LP
variants. These NCCN Guidelines Insights summarize important up- Category 3: Based upon any level of evidence, there is major
dates regarding: (1) a new section for transgender, nonbinary and NCCN disagreement that the intervention is appropriate.
gender diverse people who have a hereditary predisposition to cancer All recommendations are category 2A unless otherwise
focused on risk reduction strategies for ovarian cancer, uterine cancer, noted.
prostate cancer, and breast cancer; and (2) testing criteria and manage-
ment associated with TP53 P/LP variants and Li-Fraumeni syndrome. Clinical trials: NCCN believes that the best management of
J Natl Compr Canc Netw 2023;21(10):1000–1010 any patient with cancer is in a clinical trial. Participation in
doi:10.6004/jnccn.2023.0051 clinical trials is especially encouraged.

PLEASE NOTE
The NCCN Clinical Practice Guidelines in Oncology
(NCCN Guidelines®) are a statement of evidence and consen-
1
Fox Chase Cancer Center; 2Vanderbilt-Ingram Cancer Center; 3Abramson sus of the authors regarding their views of currently accepted
Cancer Center at the University of Pennsylvania; 4University of Wisconsin Carbone approaches to treatment. The NCCN Guidelines Insights
Cancer Center; 5Huntsman Cancer Institute at the University of Utah; 6Case highlight important changes in the NCCN Guidelines
Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and recommendations from previous versions. Colored
Cleveland Clinic Taussig Cancer Institute; 7The University of Texas MD Anderson markings in the algorithm show changes and the
Cancer Center; 8Fred Hutchinson Cancer Center; 9FORCE: Facing Our Risk of discussion aims to further the understanding of these
Cancer Empowered; 10 Yale Cancer Center/Smilow Cancer Hospital; 11The Sidney changes by summarizing salient portions of the panel’s
Kimmel Comprehensive Cancer Center at Johns Hopkins; 12Siteman Cancer discussion, including the literature reviewed.
Center at Barnes-Jewish Hospital and Washington University School of Medicine;
13
St. Jude Children’s Research Hospital/The University of Tennessee Health
Science Center; 14Roswell Park Comprehensive Cancer Center; 15UCLA Jonsson The NCCN Guidelines Insights do not represent the full
Comprehensive Cancer Center; 16Indiana University Melvin and Bren Simon NCCN Guidelines; further, the National Comprehensive
Comprehensive Cancer Center; 17Robert H. Lurie Comprehensive Cancer Center Cancer Network® (NCCN®) makes no representations
of Northwestern University; 18O’Neal Comprehensive Cancer Center at UAB; or warranties of any kind regarding their content, use, or
19
Stanford Cancer Institute; 20Moffitt Cancer Center; 21UCSF Helen Diller Family application of the NCCN Guidelines and NCCN Guidelines
Comprehensive Cancer Center; 22UT Southwestern Simmons Comprehensive Insights and disclaims any responsibility for their application
Cancer Center; 23City of Hope National Medical Center; 24Duke Cancer Institute; or use in any way.
25
University of Michigan Rogel Cancer Center; 26Memorial Sloan Kettering Cancer
Center; 27UC San Diego Moores Cancer Center; 28Fred & Pamela Buffett Cancer The complete and most recent version of these
Center; 29The Ohio State University Comprehensive Cancer Center - James NCCN Guidelines is available free of charge at NCCN.org.
Cancer Hospital and Solove Research Institute; 30Mass General Cancer Center;
31
UC Davis Comprehensive Cancer Center; 32Mayo Clinic Comprehensive Cancer © 2023 National Comprehensive Cancer Network® (NCCN®),
Center; 33University of Colorado Cancer Center; 34Dana-Farber/Brigham and All rights reserved. The NCCN Guidelines and the illustra-
Women’s Cancer Center; and 35National Comprehensive Cancer Network. tions herein may not be reproduced in any form without the
express written permission of NCCN.
*Provided content development and/or authorship assistance.

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Overview associated with TP53 P/LP variants and Li-Fraumeni

The NCCN Clinical Practice Guidelines in Oncology (NCCN syndrome (LFS).
Guidelines) for Genetic/Familial High-Risk Assessment:
Breast, Ovarian, and Pancreatic were developed with an Cancer Risk Reduction Strategies for
acute awareness of the preliminary nature of much of Transgender, Nonbinary, and Gender Diverse
our knowledge regarding the clinical application of the People With Hereditary Cancer Syndromes
rapidly emerging field of molecular genetics, and with Risk reduction strategies for ovarian (including ovarian, fal-
an appreciation for the need for flexibility when apply- lopian tube, and peritoneal cancer), uterine, prostate, and
ing these guidelines to individual families. These NCCN breast cancer for transgender, nonbinary, and gender di-
Guidelines are intended to serve as a resource for health verse people who have a hereditary predisposition to can-
care providers to identify individuals who may benefit cer are now described in these NCCN Guidelines (see
from cancer risk assessment and genetic counseling TNBGD-2 and TNBGD-3, pages 1006 and 1007, and in the
and testing; provide genetics health care professionals full version of these guidelines at www.nccn.org). This ad-
with an updated tool for the assessment of individual dition is part of an ongoing NCCN initiative that began in
breast cancer, ovarian cancer, and pancreatic cancer 2020, which states that the guidelines recommendations
risk and to guide decisions related to genetic testing; should fully address the needs of individuals of all sexual
and facilitate a multidisciplinary approach in the com- orientations and gender identities. The terms transgender,
prehensive care of individuals at increased risk for he- nonbinary and gender diverse include a wide variety of
reditary breast, ovarian, and pancreatic cancer. These physical and psychological states referring to individuals
NCCN Guidelines Insights describes key updates re- whose gender identity differs from the biologic sex as-
garding: (1) a new section for transgender, nonbinary signed at birth. According to a recent Gallup poll, transgen-
and gender diverse people who have a hereditary predis- der individuals represent 0.7% of all US adults and 2.1% of
position to cancer focused on risk reduction strategies those born from 1997 to 2003.1 A 2022 Pew Research Cen-
for ovarian cancer, uterine cancer, prostate cancer, and ter survey of US adults showed that 5.1% of individuals
breast cancer; and (2) testing criteria and management aged ,30 years identify as transgender or nonbinary.2

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Transgender, nonbinary, and gender diverse people breast cancer in transgender women, compared with cis-
encounter many challenges to health care, including stig- gender men (standardized incidence ratio [SIR], 46.7;
matization, discrimination, abuse, and possible higher 95% CI, 27.2–75.4).7 However, the incidence of breast
rates of mortality due to lack of access to appropriate pre- cancer in transgender women receiving hormone treat-
ventive care and guidance.3 In addition, these individuals ment was not significantly greater than breast cancer in-
face health disparities associated with cancer. Most elec- cidence in cisgender women (SIR, 0.3; 95% CI, 0.2–0.4).
tronic health data, including SEER data, census data, and Testosterone, a gender-affirming hormone therapy that
electronic health records (EHRs), do not incorporate gen- may be used by transgender men, has been shown to re-
der identity, thus hindering the collection of health data in duce breast glandular tissue and increase connective tis-
these populations and denying appropriate screening invi- sue in these individuals.8,9
tations to these individuals. A narrative review showed that There are no prospective data on appropriate preven-
transgender women may have lower prostate cancer in- tion and/or screening options for transgender, nonbinary,
cidence relative to cisgender men,4 but this analysis was or gender diverse individuals, regardless of whether they
based on only 2 studies.5,6 For breast cancer, incidence are at average risk or hereditary risk. Therefore, recommen-
is greater among transgender women than cisgender dations for risk reduction must be made on a case-by-case
men, but lower among transgender men than cisgender basis depending on variables involved, which include age,
women.4 family history, presence of a pathogenic variant in relevant
Many transgender individuals pursue gender affirm- genes, and duration of use of gender-affirming hormone
ing hormonal and/or surgical treatments at some point therapy. One way to approach risk reduction choices is to
in their lives, which may impact their cancer risks, al- focus on those organs at risk based on biologic sex at birth.
though management of their risk is challenging as a re- Specifically, organs at risk in individuals assigned female at
sult of limited data on the impact of these treatments on birth include the ovaries and uterus, and organs at risk in
cancer risk in transgender individuals. A retrospective co- those assigned male at birth include the prostate. Breast
hort study conducted in the Netherlands showed that es- cancer risk should be considered elevated regardless of
trogen therapy may be associated with increased risk of whether an individual is assigned male or female at birth.

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See TNBGD-2 and TNBGD-3 (pages 1006 and 1007) for a involving human participants, care must be taken to
complete list of cancer risk reduction strategies for trans- preserve the privacy and protection of this vulnerable
gender individuals with a hereditary risk for these cancers. population.
Individuals pursuing gender-affirming care should
be followed at centers of excellence with access to a mul- Li-Fraumeni Syndrome
tidisciplinary team that understands their unique needs Li-Fraumeni syndrome (LFS) is a rare hereditary cancer
and provides a safe and welcoming environment. The syndrome that is frequently associated with germline TP53
team should include surgeons, primary care specialists, P/LP variants.10 The classic form of LFS is highly penetrant
oncologists, radiologists, pathologists, endocrinologists, and characterized by a wide spectrum of neoplasms oc-
pediatricians, psychologists, genetic counselors, and so- curring at a young age and throughout the lifespan. An ob-
cial workers, all of whom are trained in the appropriate servational cohort study including 480 carriers with a TP53
care of the transgender population and can address med- P/LP variant enrolled in NCI’s longitudinal LFS study
ical, psychologic, and social care needs. There is a need showed that LFS is associated with a greater incidence of
for formal education in the care of transgender, nonbinary, cancer than the general population (SIR, 23.9; 95% CI,
and gender diverse individuals at every level of the health 21.9–26.0), with the highest comparative incidence from
care system. There is also a need for research regarding childhood to age 30 years.11 An analysis from the NCI LFS
the impact of gender-affirming hormones and puberty- study (n5286) showed a cumulative lifetime cancer inci-
blocking agents and how they interact with hereditary sus- dence of nearly 100%.12 Soft tissue sarcomas, osteosarcomas
ceptibility to cancer syndromes so that optimal prevention (except Ewing sarcoma), premenopausal breast cancer,
strategies for these populations may be developed. Finally, adrenocortical tumors, and brain tumors are referred to as
a national registry on the health outcomes of transgender, the “core” cancers of LFS because they account for the ma-
nonbinary, and gender diverse populations is needed to jority of cancers observed in individuals with germline TP53
fill the gaps in the magnitude and management of risks P/LP variants. In one study, of 91 carriers of a germline TP53
associated with gender-affirming treatment in the setting P/LP variant, at least one of these cancers was found in one
of hereditary cancer susceptibilities. As in all research or more members of all families with a germline TP53 P/LP

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variant.13 Certain cancers are strongly associated with LFS, with a sarcoma and a first-degree relative diagnosed with
such as hypodiploid acute lymphoblastic leukemia,14–16 cho- cancer at age #45 years; and an additional first- or
roid plexus tumor,17 and anaplastic rhabdomyosarcoma.18,19 second-degree relative in the same lineage with cancer
Beyond the core cancers, LFS has also been associated with diagnosed at age ,45 years or a sarcoma diagnosed at
other leukemias, colon cancer, gastric cancer, bronchoalveo- any age (see CRIT-7, page 1002). Classic LFS criteria have
lar and other lung cancers, prostate cancer, melanoma, and been estimated to have a high positive predictive value
other central nervous system tumors.10,11,13,20–29 However, it (estimated at .50%, and .70% in some studies) as well
is important to mention that estimations of cancer risks as a high specificity, although the sensitivity is relatively
associated with LFS are limited at least to some degree by low (estimated at 40%).10,13,31 Because individuals with
selection bias, because dramatically affected kindreds are TP53 P/LP variants are likely to have cancers beyond the
more likely to be identified and become the subject of LFS core cancers, the classic criteria will miss a signifi-
further study. In addition, most data are from LFS cohorts cant portion of families.23,32
composed of self-identified white individuals. Other groups have broadened the classic LFS criteria
Given the broad tumor types seen in LFS families, a to facilitate identification of individuals with LFS.33,34 For
number of different sets of criteria have been used to example, criteria for TP53 testing proposed by Chompret
help identify individuals who have a high likelihood of et al34 recommend testing in patients with multiple pri-
having LFS, including classic, Chompret, Eeles, and Birch mary tumors of at least 2 “core” tumor types (ie, sarcoma,
criteria. For the purposes of the NCCN Guidelines, 2 of breast cancer, adrenocortical carcinoma, brain tumors)
these criteria, classic and Chompret, are used to facilitate diagnosed at before 36 years of age or patients with adre-
the identification of individuals who are candidates for nocortical carcinoma diagnosed at any age, regardless of
testing for TP53 P/LP variants. family history (see CRIT-7, page 1002). The Chompret cri-
Classic LFS criteria include, based on a study by Li teria have an estimated positive predictive value of 20%
and Fraumeni et al30 involving 24 LFS kindreds, a mem- to 35%13,34 and, when incorporated as part of TP53 testing
ber of a kindred with a known TP53 P/LP variant; a com- criteria in conjunction with classic LFS criteria, have
bination of an individual diagnosed at age #45 years been shown to improve the sensitivity to 95% (ie, the

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Chompret criteria added to classic LFS criteria detected considered.36 Several studies have investigated the likeli-
95% of patients with TP53 P/LP variants).13 Although not hood of a germline TP53 P/LP variant in this popula-
part of the original published criteria set forth by Chom- tion.13,35,38–41 Among females aged ,30 years with breast
pret et al,34 the panel recommends adopting the 2015 Re- cancer and without a family history, the incidence of TP53
vised Chompret Criteria, including testing individuals P/LP variants has been reported to be 3% to 8%.13,39,41,42
with choroid plexus carcinoma or rhabdomyosarcoma of Some studies have also suggested that amplification of
embryonal anaplastic subtype diagnosed at any age and HER2 may arise in conjunction with germline TP53 P/LP
regardless of family history (for inclusion in criterion 3), variants.43–45 TP53 P/LP variants are a common finding
based on reports of considerable incidence of TP53 P/LP across cancer types on tumor-only genomic testing,46,47 but
variants found in patients with these rare forms of can- usually do not warrant consideration of germline testing.48
cer.13,21,35–37 The panel supports the broader age cutoffs A recent analysis showed that the germline conversion rate
proposed by Tinat et al,37 based on a study in a large (defined as the fraction of patients with a TP53 P/LP variant
number of families, which detected germline TP53 P/LP on tumor-only testing that is determined to be germline on
variants in affected individuals with later tumor onsets.35 blood or saliva-based genetic testing) of TP53 P/LP variants
These age cutoffs are: (1) individuals diagnosed with LFS was only 0.9% for tumors from patients of all ages and 5.1%
spectrum cancer before 46 years of age who also have at for patients aged ,30 years.48 In the absence of paired
least one first-degree or second-degree relative with a germline analysis, germline testing should be offered if the
LFS spectrum cancer diagnosed before 56 years of age or personal or family history provides sufficient clinical suspi-
with multiple tumors; and (2) individual with multiple tu- cion of a germline P/LP variant. Consistent with ESMO
mors from a LFS spectrum cancer, with the first diag- recommendations,49 the panel also recommends that
nosed before 46 years of age.37 germline testing be offered to all patients who were di-
Patients with early-onset breast cancer (age of diag- agnosed with any cancer before 30 years of age.
nosis #30 years) who were assigned female at birth, with Lastly, when TP53 is included on multigene germline
or without family history of core tumor types, are another panels, the NCCN testing criteria for LFS are often not
group for whom TP53 gene P/LP variant testing may be met. It has been argued that a spectrum of heritable

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TP53-related cancer syndromes exist.50 One study de- this new table was to expand on potentially mosaic TP53
scribed families with TP53 P/LP variants falling into a findings. A panel working group reviewed evidence and
spectrum from classic LFS to attenuated families who do current practice in this area and determined that the
not meet criteria. These definitions will help future LFS NCCN Guidelines previously did not sufficiently point out
research describe the populations being studied, but at the possibility of postzygotic (somatic or constitutional)
this time LFS management is recommended for all indi- mosaicism (PZM) versus abnormal clonal expansions (ACE;
viduals with TP53 P/LP variants regardless of the presen- including clonal hematopoiesis of indeterminate potential
tation in the family.51 [CHIP] and clonal cytopenias of undetermined significance
If a TP53 P/LP variant is found in blood, saliva, or [CCUS]) and did not provide adequate guidance regarding
buccal samples, especially in individuals whose personal how to care for these patients. A review of 84 TP53-positive
or family history does not meet LFS criteria, this warrants probands identified through multigene testing on blood or
consideration of testing of an alternative tissue, usually saliva from 2012 to 2019 showed constitutional mosaicism
cultured skin fibroblasts, and close relatives to try to in 8.3%.52 Ancillary tissue testing and cascade testing of
distinguish between germline, constitutional mosaicism, children in all PZM and ACE TP53 P/LP variant carriers is
and somatic findings, such as clonal hematopoiesis (CH) recommended, because this will further facilitate diagnosis
or tumor contamination of peripheral blood. For patients and management.53 In addition, the clinical features that
who have a personal history of cancer, the panel also rec- suggest CH versus PZM when a TP53 P/LP variant is in the
ommends looking for signs of tumor somatic interfer- range of 30% to 70% variant allele frequency, in a patient
ence and technical limitations (see LIFR-A 1 and LIFR-A with no prior chemotherapy and no hematologic abnor-
2 in the complete version of these NCCN Guidelines, mality, continue to be unknown.
available at www.nccn.org).
For the 2024 NCCN Guidelines update, the panel LFS Surveillance
added a table describing workup and management de- Discussions with patients about LFS management should
pending on etiology of TP53 P/LP variant found on ge- address the limitations of screening for the many cancers
netic testing (see LIFR-A 3 of 6, page 1003). The intent of associated with this syndrome. It is also important to

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address the psychosocial and quality-of-life aspects of with those not undergoing surveillance (59.6%; P5.013).
this syndrome. Given the complexity of LFS management Based on these study results, the panel recommends an-
and that this disease is rare, individuals with LFS should nual whole-body MRI.54
be followed at centers with expertise in management of It is important to note that, to date, data on the effec-
this syndrome. Personal and family history of cancer tiveness of whole-body MRI have come from centers per-
should be taken into consideration for screening (ie, spe- forming a high volume of these cancer screenings. Also,
cific screenings, 5–10 years before earliest diagnosis). It is whole-body MRI protocols may vary. The panel acknowl-
also important for patients’ primary care providers and/ edges that this surveillance method may not be uniformly
or pediatricians to be informed about patients’ diagnoses available or affordable. Patients who do not have access to
of LFS. For the 2023 NCCN Guidelines update, the panel whole-body MRI should be encouraged to enroll in clinical
added a section on pediatric surveillance in LFS (see trials and to work with their clinicians to develop an alter-
LIFR-A 6 of 6, page 1005). Patients should be advised native screening program based on available cancer
about the risk to relatives, and genetic counseling for rel- screening approaches. The panel also acknowledges that
atives is recommended.54 whole-body MRI screening of all individuals with LFS may
Breast screening in adults with LFS is described in the result in false-positives and overdiagnosis.58,61 Further-
guidelines (see LIFR-A 4 of 6, page 1004) and includes more, the utility of whole-body MRI has not been evalu-
clinical examination, breast imaging (MRI and mammo- ated in individuals with a TP53 P/LP variant who do not
gram, as indicated), and breast awareness. Although there have a classic family history of LFS, a group that is increas-
are no data regarding risk reduction surgery, individuals ingly being identified through multigene testing. The brain
with LFS who were assigned female at birth have in- may be examined as part of whole-body MRI or as a sepa-
creased breast cancer risk that warrants consideration of rate examination.
risk-reducing mastectomy (RRM). Given the high risk of In addition to whole-body MRI, the panel recom-
contralateral breast cancer in LFS, the option of contra- mends additional screening modalities for certain can-
lateral RRM should be discussed with patients diagnosed cers. Individuals assigned female at birth should begin
with breast cancer.55 Counseling for risk-reducing sur- breast cancer screening with annual clinical breast exam-
geries may include discussion of extent of cancer risk ination and breast MRI at age 20 years, with the addition
reduction/protection, risks associated with surgeries, de- of annual mammograms at age 30 years. In all individu-
gree of age-specific cancer risk, reconstructive options, als with a TP53 P/LP variant, the panel recommends co-
and competing risks from other cancers. Family history lonoscopy and upper endoscopy every 2 to 5 y starting at
and life expectancy should also be considered. age #25 years in the context of prior abdominal radiation
Use of a screening protocol that includes MRI may or family history. Dermatologic examinations are recom-
improve early cancer detection in individuals with mended. Finally, prostate cancer screening with prostate-
LFS.54,56 Whole-body MRI for screening of cancers asso- specific antigen testing is recommended beginning at
ciated with LFS continues to be evaluated in multiple in- age 40 years.
ternational trials. Use of whole-body MRI is appealing Many of the other cancers associated with germline
due to its wide anatomic coverage, the lack of radiation, TP53 P/LP variants do not lend themselves to early detec-
and the potential to reduce the number of imaging stud- tion. Thus, additional recommendations for adults with
ies that a patient undergoes.57 A meta-analysis including LFS are general and include comprehensive physical ex-
578 individuals with TP53 P/LP variants across 13 pro- aminations (including neurologic examination) every 6 to
spective cohorts showed that baseline whole-body MRI 12 months, especially when there is a high index of suspi-
identified cancer in 7% of the sample, with 83% of the cion for second malignancies in cancer survivors and
cancers being localized and able to be treated with cura- rare cancers (see CRIT-7, page 1002). Clinicians should
tive intent.58 In a prospective observational study, a clini- address screening limitations for other cancers associated
cal surveillance protocol for carriers of a TP53 P/LP with LFS. Education regarding signs and symptoms of
variant from families affected by LFS was incorporated.59 cancer is important. Cancer screening in LFS should take
Eleven-year follow-up of this study, which included 89 into account prior treatment with radiation therapy.
carriers of a TP53 P/LP variant, showed that this surveil- Individuals with a TP53 P/LP variant are at in-
lance protocol may be beneficial, with 84% (16 of 19) of creased risk of second malignant neoplasms.36,62 Ra-
patients who were diagnosed with cancer while under diosensitivity in individuals with a TP53 P/LP variant
surveillance being alive at final follow-up, compared is not significantly different than in the general popu-
with 49% (21 of 43) of patients who were not being sur- lation,63,64 but carriers seem to be more susceptible to
veilled and were diagnosed with cancer due to symp- radioresistance.17,64,65 Although use of therapeutic ra-
toms (P5.012).60 The 5-year overall survival was greater diotherapy should generally be avoided in individuals
for patients undergoing surveillance (88.8%) compared with a TP53 P/LP variant, clinical decision-making should

1008 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 21 Issue 10 | October 2023
Genetic/Familial High-Risk Assessment: NCCN GUIDELINES® INSIGHTS CE
Breast, Ovarian, and Pancreatic, Version 2.2024

take into account the availability of other curative treat- Breast, Ovarian, and Pancreatic. To date, this is the first
ment options. guidance geared toward care of transgender, nonbinary,
There is little evidence regarding care of TP53 P/LP and gender diverse people in the NCCN Guidelines. Addi-
variant carriers with PZM or hypomorphic variants. Until tionally, updates to these guidelines include new guidance
more data are available on these carriers, they should be regarding workup and management depending on the etiol-
cared for as LFS, as opposed to patients with TP53 CH, ogy of the TP53 P/LP variant found on genetic testing, as
which should not be managed as LFS (see LIFR-A 3 of 6, well as pediatric surveillance in LFS. LFS is a highly pene-
page 1003). Instead, given that the TP53 mutation is con- trant cancer syndrome associated with a high lifetime risk
sidered a high-risk clinical feature in CH, patients with for many cancers, including breast cancer, sarcoma, and
TP53 CH may be referred to Hematology.66,67 adrenocortical tumors. The presence of a TP53 P/LP variant
on a germline genetic test may indicate a diagnosis of
Summary LFS. However, somatic TP53 variants frequently con-
Risk reduction strategies for ovarian cancer, uterine can- found germline testing results, making their interpreta-
cer, prostate cancer, and breast cancer for transgender, tion challenging.
nonbinary, and gender diverse people who have a heredi-
tary predisposition to cancer, an area in which guidance
To participate in this journal CE activity, go to
and research are needed, have been added to the NCCN
https://education.nccn.org/node/92941
Guidelines for Genetic/Familial High-Risk Assessment:

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1010 © JNCCN—Journal of the National Comprehensive Cancer Network | Volume 21 Issue 10 | October 2023