NCCN Guidelines® Insights: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2024

Featured Updates to the NCCN Guidelines

Authors:
Mary B. Daly Fox Chase Cancer Center

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Tuya Pal Vanderbilt-Ingram Cancer Center

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Kara N. Maxwell Abramson Cancer Center at the University of Pennsylvania

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Jane Churpek University of Wisconsin Carbone Cancer Center

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Wendy Kohlmann Huntsman Cancer Institute at the University of Utah

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Zahraa AlHilli Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute

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Banu Arun The University of Texas MD Anderson Cancer Center

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Saundra S. Buys Huntsman Cancer Institute at the University of Utah

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Heather Cheng Fred Hutchinson Cancer Center

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Susan M. Domchek Abramson Cancer Center at the University of Pennsylvania

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Susan Friedman FORCE: Facing Our Risk of Cancer Empowered

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Veda Giri Yale Cancer Center/Smilow Cancer Hospital

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Michael Goggins The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Andrea Hagemann Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine

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Ashley Hendrix St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center

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Mollie L. Hutton Roswell Park Comprehensive Cancer Center

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Beth Y. Karlan UCLA Jonsson Comprehensive Cancer Center

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Nawal Kassem Indiana University Melvin and Bren Simon Comprehensive Cancer Center

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Seema Khan Robert H. Lurie Comprehensive Cancer Center of Northwestern University

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Katia Khoury O’Neal Comprehensive Cancer Center at UAB

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Allison W. Kurian Stanford Cancer Institute

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Christine Laronga Moffitt Cancer Center

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Julie S. Mak UCSF Helen Diller Family Comprehensive Cancer Center

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John Mansour UT Southwestern Simmons Comprehensive Cancer Center

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Kevin McDonnell City of Hope National Medical Center

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Carolyn S. Menendez Duke Cancer Institute

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Sofia D. Merajver University of Michigan Rogel Cancer Center

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Barbara S. Norquist Fred Hutchinson Cancer Center

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Kenneth Offit Memorial Sloan Kettering Cancer Center

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Dominique Rash UC San Diego Moores Cancer Center

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Gwen Reiser Fred & Pamela Buffett Cancer Center

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Leigha Senter-Jamieson The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

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Kristen Mahoney Shannon Mass General Cancer Center

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Kala Visvanathan The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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Jeanna Welborn UC Davis Comprehensive Cancer Center

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Myra J. Wick Mayo Clinic Comprehensive Cancer Center

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Marie Wood University of Colorado Cancer Center

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Matthew B. Yurgelun Dana-Farber/Brigham and Women’s Cancer Center

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Mary A. Dwyer National Comprehensive Cancer Network

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Susan D. Darlow National Comprehensive Cancer Network

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Full access

The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic focus primarily on assessment of pathogenic/likely pathogenic (P/LP) variants associated with increased risk of breast, ovarian, pancreatic, and prostate cancer, including BRCA1, BRCA2, CDH1, PALB2, PTEN, and TP53, and recommended approaches to genetic counseling/testing and care strategies in individuals with these P/LP variants. These NCCN Guidelines Insights summarize important updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome.

NCCN Continuing Education

Target Audience: This activity is designed to meet the educational needs of oncologists, nurses, pharmacists, and other healthcare professionals who manage patients with cancer.

Accreditation Statements

In support of improving patient care, National Comprehensive Cancer Network (NCCN) is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

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Physicians: NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 CreditTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Nurses: NCCN designates this educational activity for a maximum of 1.0 contact hour.

Pharmacists: NCCN designates this knowledge-based continuing education activity for 1.0 contact hour (0.1 CEUs) of continuing education credit. UAN: JA4008196-0000-23-010-H01-P

PAs: NCCN has been authorized by the American Academy of PAs (AAPA) to award AAPA Category 1 CME credit for activities planned in accordance with AAPA CME Criteria. This activity is designated for 1.0 AAPA Category 1 CME credit. Approval is valid until October 10, 2024. PAs should only claim credit commensurate with the extent of their participation.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: (1) review the educational content; (2) take the posttest with a 66% minimum passing score and complete the evaluation at https://education.nccn.org/node/92941; and (3) view/print certificate.

Pharmacists: You must complete the posttest and evaluation within 30 days of the activity. Continuing pharmacy education credit is reported to the CPE Monitor once you have completed the posttest and evaluation and claimed your credits. Before completing these requirements, be sure your NCCN profile has been updated with your NAPB e-profile ID and date of birth. Your credit cannot be reported without this information. If you have any questions, please email education@nccn.org.

Release date: October 10, 2023; Expiration date: October 10, 2024

Learning Objectives:

Upon completion of this activity, participants will be able to:

  • • Integrate into professional practice the updates to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic

  • • Describe the rationale behind the decision-making process for developing the NCCN Guidelines for Genetic/Familial High-Risk Assessment: 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 independent educational grant from Daiichi Sankyo. This activity is supported by independent medical education grants from Illumina, Inc. and Regeneron Pharmaceuticals, Inc.

Overview

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic were developed with an acute awareness of the preliminary nature of much of our knowledge regarding the clinical application of the rapidly emerging field of molecular genetics, and with an appreciation for the need for flexibility when applying these guidelines to individual families. These NCCN Guidelines are intended to serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; provide genetics health care professionals with an updated tool for the assessment of individual breast cancer, ovarian cancer, and pancreatic cancer risk and to guide decisions related to genetic testing; and facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary breast, ovarian, and pancreatic cancer. These NCCN Guidelines Insights describes key updates regarding: (1) a new section for transgender, nonbinary and gender diverse people who have a hereditary predisposition to cancer focused on risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer; and (2) testing criteria and management associated with TP53 P/LP variants and Li-Fraumeni syndrome (LFS).

Cancer Risk Reduction Strategies for Transgender, Nonbinary, and Gender Diverse People With Hereditary Cancer Syndromes

Risk reduction strategies for ovarian (including ovarian, fallopian tube, and peritoneal cancer), uterine, prostate, and breast cancer for transgender, nonbinary, and gender diverse people who have a hereditary predisposition to cancer are now described in these NCCN Guidelines (see TNBGD-2 and TNBGD-3, pages 1006 and 1007, and in the full version of these guidelines at www.nccn.org). This addition is part of an ongoing NCCN initiative that began in 2020, which states that the guidelines recommendations should fully address the needs of individuals of all sexual orientations and gender identities. The terms transgender, nonbinary and gender diverse include a wide variety of physical and psychological states referring to individuals whose gender identity differs from the biologic sex assigned at birth. According to a recent Gallup poll, transgender individuals represent 0.7% of all US adults and 2.1% of those born from 1997 to 2003.1 A 2022 Pew Research Center survey of US adults showed that 5.1% of individuals aged <30 years identify as transgender or nonbinary.2

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Transgender, nonbinary, and gender diverse people encounter many challenges to health care, including stigmatization, discrimination, abuse, and possible higher rates of mortality due to lack of access to appropriate preventive care and guidance.3 In addition, these individuals face health disparities associated with cancer. Most electronic health data, including SEER data, census data, and electronic health records (EHRs), do not incorporate gender identity, thus hindering the collection of health data in these populations and denying appropriate screening invitations to these individuals. A narrative review showed that transgender women may have lower prostate cancer incidence relative to cisgender men,4 but this analysis was based on only 2 studies.5,6 For breast cancer, incidence is greater among transgender women than cisgender men, but lower among transgender men than cisgender women.4

Many transgender individuals pursue gender affirming hormonal and/or surgical treatments at some point in their lives, which may impact their cancer risks, although management of their risk is challenging as a result of limited data on the impact of these treatments on cancer risk in transgender individuals. A retrospective cohort study conducted in the Netherlands showed that estrogen therapy may be associated with increased risk of breast cancer in transgender women, compared with cisgender men (standardized incidence ratio [SIR], 46.7; 95% CI, 27.2–75.4).7 However, the incidence of breast cancer in transgender women receiving hormone treatment was not significantly greater than breast cancer incidence in cisgender women (SIR, 0.3; 95% CI, 0.2–0.4). Testosterone, a gender-affirming hormone therapy that may be used by transgender men, has been shown to reduce breast glandular tissue and increase connective tissue in these individuals.8,9

There are no prospective data on appropriate prevention and/or screening options for transgender, nonbinary, or gender diverse individuals, regardless of whether they are at average risk or hereditary risk. Therefore, recommendations for risk reduction must be made on a case-by-case basis depending on variables involved, which include age, family history, presence of a pathogenic variant in relevant genes, and duration of use of gender-affirming hormone therapy. One way to approach risk reduction choices is to focus on those organs at risk based on biologic sex at birth. Specifically, organs at risk in individuals assigned female at birth include the ovaries and uterus, and organs at risk in those assigned male at birth include the prostate. Breast cancer risk should be considered elevated regardless of whether an individual is assigned male or female at birth. See TNBGD-2 and TNBGD-3 (pages 1006 and 1007) for a complete list of cancer risk reduction strategies for transgender individuals with a hereditary risk for these cancers.

Individuals pursuing gender-affirming care should be followed at centers of excellence with access to a multidisciplinary team that understands their unique needs and provides a safe and welcoming environment. The team should include surgeons, primary care specialists, oncologists, radiologists, pathologists, endocrinologists, pediatricians, psychologists, genetic counselors, and social workers, all of whom are trained in the appropriate care of the transgender population and can address medical, psychologic, and social care needs. There is a need for formal education in the care of transgender, nonbinary, and gender diverse individuals at every level of the health care system. There is also a need for research regarding the impact of gender-affirming hormones and puberty-blocking agents and how they interact with hereditary susceptibility to cancer syndromes so that optimal prevention strategies for these populations may be developed. Finally, a national registry on the health outcomes of transgender, nonbinary, and gender diverse populations is needed to fill the gaps in the magnitude and management of risks associated with gender-affirming treatment in the setting of hereditary cancer susceptibilities. As in all research involving human participants, care must be taken to preserve the privacy and protection of this vulnerable population.

Li-Fraumeni Syndrome

Li-Fraumeni syndrome (LFS) is a rare hereditary cancer syndrome that is frequently associated with germline TP53 P/LP variants.10 The classic form of LFS is highly penetrant and characterized by a wide spectrum of neoplasms occurring at a young age and throughout the lifespan. An observational cohort study including 480 carriers with a TP53 P/LP variant enrolled in NCI’s longitudinal LFS study showed that LFS is associated with a greater incidence of cancer than the general population (SIR, 23.9; 95% CI, 21.9–26.0), with the highest comparative incidence from childhood to age 30 years.11 An analysis from the NCI LFS study (n=286) showed a cumulative lifetime cancer incidence of nearly 100%.12 Soft tissue sarcomas, osteosarcomas (except Ewing sarcoma), premenopausal breast cancer, adrenocortical tumors, and brain tumors are referred to as the “core” cancers of LFS because they account for the majority of cancers observed in individuals with germline TP53 P/LP variants. In one study, of 91 carriers of a germline TP53 P/LP variant, at least one of these cancers was found in one or more members of all families with a germline TP53 P/LP variant.13 Certain cancers are strongly associated with LFS, such as hypodiploid acute lymphoblastic leukemia,1416 choroid plexus tumor,17 and anaplastic rhabdomyosarcoma.18,19 Beyond the core cancers, LFS has also been associated with other leukemias, colon cancer, gastric cancer, bronchoalveolar and other lung cancers, prostate cancer, melanoma, and other central nervous system tumors.10,11,13,2029 However, it is important to mention that estimations of cancer risks associated with LFS are limited at least to some degree by selection bias, because dramatically affected kindreds are more likely to be identified and become the subject of further study. In addition, most data are from LFS cohorts composed of self-identified white individuals.

Given the broad tumor types seen in LFS families, a number of different sets of criteria have been used to help identify individuals who have a high likelihood of having LFS, including classic, Chompret, Eeles, and Birch criteria. For the purposes of the NCCN Guidelines, 2 of these criteria, classic and Chompret, are used to facilitate the identification of individuals who are candidates for testing for TP53 P/LP variants.

Classic LFS criteria include, based on a study by Li and Fraumeni et al30 involving 24 LFS kindreds, a member of a kindred with a known TP53 P/LP variant; a combination of an individual diagnosed at age ≤45 years with a sarcoma and a first-degree relative diagnosed with cancer at age ≤45 years; and an additional first- or second-degree relative in the same lineage with cancer diagnosed at age <45 years or a sarcoma diagnosed at any age (see CRIT-7, page 1002). Classic LFS criteria have been estimated to have a high positive predictive value (estimated at >50%, and >70% in some studies) as well as a high specificity, although the sensitivity is relatively low (estimated at 40%).10,13,31 Because individuals with TP53 P/LP variants are likely to have cancers beyond the LFS core cancers, the classic criteria will miss a significant portion of families.23,32

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Other groups have broadened the classic LFS criteria to facilitate identification of individuals with LFS.33,34 For example, criteria for TP53 testing proposed by Chompret et al34 recommend testing in patients with multiple primary tumors of at least 2 “core” tumor types (ie, sarcoma, breast cancer, adrenocortical carcinoma, brain tumors) diagnosed at before 36 years of age or patients with adrenocortical carcinoma diagnosed at any age, regardless of family history (see CRIT-7, page 1002). The Chompret criteria have an estimated positive predictive value of 20% to 35%13,34 and, when incorporated as part of TP53 testing criteria in conjunction with classic LFS criteria, have been shown to improve the sensitivity to 95% (ie, the Chompret criteria added to classic LFS criteria detected 95% of patients with TP53 P/LP variants).13 Although not part of the original published criteria set forth by Chompret et al,34 the panel recommends adopting the 2015 Revised Chompret Criteria, including testing individuals with choroid plexus carcinoma or rhabdomyosarcoma of embryonal anaplastic subtype diagnosed at any age and regardless of family history (for inclusion in criterion 3), based on reports of considerable incidence of TP53 P/LP variants found in patients with these rare forms of cancer.13,21,3537 The panel supports the broader age cutoffs proposed by Tinat et al,37 based on a study in a large number of families, which detected germline TP53 P/LP variants in affected individuals with later tumor onsets.35 These age cutoffs are: (1) individuals diagnosed with LFS spectrum cancer before 46 years of age who also have at least one first-degree or second-degree relative with a LFS spectrum cancer diagnosed before 56 years of age or with multiple tumors; and (2) individual with multiple tumors from a LFS spectrum cancer, with the first diagnosed before 46 years of age.37

Patients with early-onset breast cancer (age of diagnosis ≤30 years) who were assigned female at birth, with or without family history of core tumor types, are another group for whom TP53 gene P/LP variant testing may be considered.36 Several studies have investigated the likelihood of a germline TP53 P/LP variant in this population.13,35,3841 Among females aged <30 years with breast cancer and without a family history, the incidence of TP53 P/LP variants has been reported to be 3% to 8%.13,39,41,42 Some studies have also suggested that amplification of HER2 may arise in conjunction with germline TP53 P/LP variants.4345 TP53 P/LP variants are a common finding across cancer types on tumor-only genomic testing,46,47 but usually do not warrant consideration of germline testing.48 A recent analysis showed that the germline conversion rate (defined as the fraction of patients with a TP53 P/LP variant on tumor-only testing that is determined to be germline on blood or saliva-based genetic testing) of TP53 P/LP variants was only 0.9% for tumors from patients of all ages and 5.1% for patients aged <30 years.48 In the absence of paired germline analysis, germline testing should be offered if the personal or family history provides sufficient clinical suspicion of a germline P/LP variant. Consistent with ESMO recommendations,49 the panel also recommends that germline testing be offered to all patients who were diagnosed with any cancer before 30 years of age.

Lastly, when TP53 is included on multigene germline panels, the NCCN testing criteria for LFS are often not met. It has been argued that a spectrum of heritable TP53-related cancer syndromes exist.50 One study described families with TP53 P/LP variants falling into a spectrum from classic LFS to attenuated families who do not meet criteria. These definitions will help future LFS research describe the populations being studied, but at this time LFS management is recommended for all individuals with TP53 P/LP variants regardless of the presentation in the family.51

If a TP53 P/LP variant is found in blood, saliva, or buccal samples, especially in individuals whose personal or family history does not meet LFS criteria, this warrants consideration of testing of an alternative tissue, usually cultured skin fibroblasts, and close relatives to try to distinguish between germline, constitutional mosaicism, and somatic findings, such as clonal hematopoiesis (CH) or tumor contamination of peripheral blood. For patients who have a personal history of cancer, the panel also recommends looking for signs of tumor somatic interference and technical limitations (see LIFR-A 1 and LIFR-A 2 in the complete version of these NCCN Guidelines, available at www.nccn.org).

For the 2024 NCCN Guidelines update, the panel added a table describing workup and management depending on etiology of TP53 P/LP variant found on genetic testing (see LIFR-A 3 of 6, page 1003). The intent of this new table was to expand on potentially mosaic TP53 findings. A panel working group reviewed evidence and current practice in this area and determined that the NCCN Guidelines previously did not sufficiently point out the possibility of postzygotic (somatic or constitutional) mosaicism (PZM) versus abnormal clonal expansions (ACE; including clonal hematopoiesis of indeterminate potential [CHIP] and clonal cytopenias of undetermined significance [CCUS]) and did not provide adequate guidance regarding how to care for these patients. A review of 84 TP53-positive probands identified through multigene testing on blood or saliva from 2012 to 2019 showed constitutional mosaicism in 8.3%.52 Ancillary tissue testing and cascade testing of children in all PZM and ACE TP53 P/LP variant carriers is recommended, because this will further facilitate diagnosis and management.53 In addition, the clinical features that suggest CH versus PZM when a TP53 P/LP variant is in the range of 30% to 70% variant allele frequency, in a patient with no prior chemotherapy and no hematologic abnormality, continue to be unknown.

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LFS Surveillance

Discussions with patients about LFS management should address the limitations of screening for the many cancers associated with this syndrome. It is also important to address the psychosocial and quality-of-life aspects of this syndrome. Given the complexity of LFS management and that this disease is rare, individuals with LFS should be followed at centers with expertise in management of this syndrome. Personal and family history of cancer should be taken into consideration for screening (ie, specific screenings, 5–10 years before earliest diagnosis). It is also important for patients’ primary care providers and/or pediatricians to be informed about patients’ diagnoses of LFS. For the 2023 NCCN Guidelines update, the panel added a section on pediatric surveillance in LFS (see LIFR-A 6 of 6, page 1005). Patients should be advised about the risk to relatives, and genetic counseling for relatives is recommended.54

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Breast screening in adults with LFS is described in the guidelines (see LIFR-A 4 of 6, page 1004) and includes clinical examination, breast imaging (MRI and mammogram, as indicated), and breast awareness. Although there are no data regarding risk reduction surgery, individuals with LFS who were assigned female at birth have increased breast cancer risk that warrants consideration of risk-reducing mastectomy (RRM). Given the high risk of contralateral breast cancer in LFS, the option of contralateral RRM should be discussed with patients diagnosed with breast cancer.55 Counseling for risk-reducing surgeries may include discussion of extent of cancer risk reduction/protection, risks associated with surgeries, degree of age-specific cancer risk, reconstructive options, and competing risks from other cancers. Family history and life expectancy should also be considered.

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Use of a screening protocol that includes MRI may improve early cancer detection in individuals with LFS.54,56 Whole-body MRI for screening of cancers associated with LFS continues to be evaluated in multiple international trials. Use of whole-body MRI is appealing due to its wide anatomic coverage, the lack of radiation, and the potential to reduce the number of imaging studies that a patient undergoes.57 A meta-analysis including 578 individuals with TP53 P/LP variants across 13 prospective cohorts showed that baseline whole-body MRI identified cancer in 7% of the sample, with 83% of the cancers being localized and able to be treated with curative intent.58 In a prospective observational study, a clinical surveillance protocol for carriers of a TP53 P/LP variant from families affected by LFS was incorporated.59 Eleven-year follow-up of this study, which included 89 carriers of a TP53 P/LP variant, showed that this surveillance protocol may be beneficial, with 84% (16 of 19) of patients who were diagnosed with cancer while under surveillance being alive at final follow-up, compared with 49% (21 of 43) of patients who were not being surveilled and were diagnosed with cancer due to symptoms (P=.012).60 The 5-year overall survival was greater for patients undergoing surveillance (88.8%) compared with those not undergoing surveillance (59.6%; P=.013). Based on these study results, the panel recommends annual whole-body MRI.54

It is important to note that, to date, data on the effectiveness of whole-body MRI have come from centers performing a high volume of these cancer screenings. Also, whole-body MRI protocols may vary. The panel acknowledges that this surveillance method may not be uniformly available or affordable. Patients who do not have access to whole-body MRI should be encouraged to enroll in clinical trials and to work with their clinicians to develop an alternative screening program based on available cancer screening approaches. The panel also acknowledges that whole-body MRI screening of all individuals with LFS may result in false-positives and overdiagnosis.58,61 Furthermore, the utility of whole-body MRI has not been evaluated in individuals with a TP53 P/LP variant who do not have a classic family history of LFS, a group that is increasingly being identified through multigene testing. The brain may be examined as part of whole-body MRI or as a separate examination.

In addition to whole-body MRI, the panel recommends additional screening modalities for certain cancers. Individuals assigned female at birth should begin breast cancer screening with annual clinical breast examination and breast MRI at age 20 years, with the addition of annual mammograms at age 30 years. In all individuals with a TP53 P/LP variant, the panel recommends colonoscopy and upper endoscopy every 2 to 5 y starting at age ≤25 years in the context of prior abdominal radiation or family history. Dermatologic examinations are recommended. Finally, prostate cancer screening with prostate-specific antigen testing is recommended beginning at age 40 years.

Many of the other cancers associated with germline TP53 P/LP variants do not lend themselves to early detection. Thus, additional recommendations for adults with LFS are general and include comprehensive physical examinations (including neurologic examination) every 6 to 12 months, especially when there is a high index of suspicion for second malignancies in cancer survivors and rare cancers (see CRIT-7, page 1002). Clinicians should address screening limitations for other cancers associated with LFS. Education regarding signs and symptoms of cancer is important. Cancer screening in LFS should take into account prior treatment with radiation therapy.

Individuals with a TP53 P/LP variant are at increased risk of second malignant neoplasms.36,62 Radiosensitivity in individuals with a TP53 P/LP variant is not significantly different than in the general population,63,64 but carriers seem to be more susceptible to radioresistance.17,64,65 Although use of therapeutic radiotherapy should generally be avoided in individuals with a TP53 P/LP variant, clinical decision-making should take into account the availability of other curative treatment options.

There is little evidence regarding care of TP53 P/LP variant carriers with PZM or hypomorphic variants. Until more data are available on these carriers, they should be cared for as LFS, as opposed to patients with TP53 CH, which should not be managed as LFS (see LIFR-A 3 of 6, page 1003). Instead, given that the TP53 mutation is considered a high-risk clinical feature in CH, patients with TP53 CH may be referred to Hematology.66,67

Summary

Risk reduction strategies for ovarian cancer, uterine cancer, prostate cancer, and breast cancer for transgender, nonbinary, and gender diverse people who have a hereditary predisposition to cancer, an area in which guidance and research are needed, have been added to the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. To date, this is the first guidance geared toward care of transgender, nonbinary, and gender diverse people in the NCCN Guidelines. Additionally, updates to these guidelines include new guidance regarding workup and management depending on the etiology of the TP53 P/LP variant found on genetic testing, as well as pediatric surveillance in LFS. LFS is a highly penetrant cancer syndrome associated with a high lifetime risk for many cancers, including breast cancer, sarcoma, and adrenocortical tumors. The presence of a TP53 P/LP variant on a germline genetic test may indicate a diagnosis of LFS. However, somatic TP53 variants frequently confound germline testing results, making their interpretation challenging.

References

  • 1.

    Jones JM. LGBT identification in U.S. ticks up to 7.1%. Gallup. Accessed June 1, 2023. Available at: https://news.gallup.com/poll/389792/lgbt-identification-ticks-up.aspx

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Brown A. About 5% of young adults in the U.S. say their gender is different from their sex assigned at birth. Pew Research Center. Accessed June 1, 2023. Available at: https://www.pewresearch.org/short-reads/2022/06/07/about-5-of-young-adults-in-the-u-s-say-their-gender-is-different-from-their-sex-assigned-at-birth/

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Sutherland N, Espinel W, Grotzke M, et al. Unanswered questions: hereditary breast and gynecological cancer risk assessment in transgender adolescents and young adults. J Genet Couns 2020;29:625633.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Leone AG, Trapani D, Schabath MB, et al. Cancer in transgender and gender-diverse persons: a review. JAMA Oncol 2023;9:556563.

  • 5.

    Silverberg MJ, Nash R, Becerra-Culqui TA, et al. Cohort study of cancer risk among insured transgender people. Ann Epidemiol 2017;27:499501.

  • 6.

    de Nie I, de Blok CJM, van der Sluis TM, et al. Prostate cancer incidence under androgen deprivation: nationwide cohort study in trans women receiving hormone treatment. J Clin Endocrinol Metab 2020;105:e32933299.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    de Blok CJM, Wiepjes CM, Nota NM, et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ 2019;365:l1652.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Grynberg M, Fanchin R, Dubost G, et al. Histology of genital tract and breast tissue after long-term testosterone administration in a female-to-male transsexual population. Reprod Biomed Online 2010;20:553558.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Slagter MH, Gooren LJ, Scorilas A, et al. Effects of long-term androgen administration on breast tissue of female-to-male transsexuals. J Histochem Cytochem 2006;54:905910.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews. Accessed June 1, 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1311/

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    de Andrade KC, Khincha PP, Hatton JN, et al. Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol 2021;22:17871798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Mai PL, Best AF, Peters JA, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 2016;122:36733681.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009;27:12501256.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 2013;45:242252.

  • 15.

    Kamihara J, Rana HQ, Garber JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat 2014;35:654662.

  • 16.

    Qian M, Cao X, Devidas M, et al. TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J Clin Oncol 2018;36:591599.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Tabori U, Shlien A, Baskin B, et al. TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. J Clin Oncol 2010;28:19952001.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Ognjanovic S, Linabery AM, Charbonneau B, et al. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer 2009;115:42184226.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Hettmer S, Archer NM, Somers GR, et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer 2014;120:10681075.

  • 20.

    Garber JE, Goldstein AM, Kantor AF, et al. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 1991;51:60946097.

  • 21.

    Krutilkova V, Trkova M, Fleitz J, et al. Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations. Eur J Cancer 2005;41:15971603.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250:12331238.

  • 23.

    Varley JM, Evans DG, Birch JM. Li-Fraumeni syndrome—a molecular and clinical review. Br J Cancer 1997;76:114.

  • 24.

    Masciari S, Dewanwala A, Stoffel EM, et al. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med 2011;13:651657.

  • 25.

    Maxwell KN, Cheng HH, Powers J, et al. Inherited TP53 variants and risk of prostate cancer. Eur Urol 2022;81:243250.

  • 26.

    Curiel-Lewandrowski C, Speetzen LS, Cranmer L, et al. Multiple primary cutaneous melanomas in Li-Fraumeni syndrome. Arch Dermatol 2011;147:248250.

  • 27.

    Giavedoni P, Ririe M, Carrera C, et al. Familial melanoma associated with Li-Fraumeni syndrome and atypical mole syndrome: total-body digital photography, dermoscopy and confocal microscopy. Acta Derm Venereol 2017;97:720723.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Katona BW, Powers J, McKenna DB, et al. Upper gastrointestinal cancer risk and surveillance outcomes in Li-Fraumeni syndrome. Am J Gastroenterol 2020;115:20952097.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    MacFarland SP, Zelley K, Long JM, et al. Earlier colorectal cancer screening may be necessary in patients with Li-Fraumeni syndrome. Gastroenterology 2019;156:273274.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48:53585362.

  • 31.

    Nichols KE, Malkin D, Garber JE, et al. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 2001;10:8387.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Birch JM, Blair V, Kelsey AM, et al. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene 1998;17:10611068.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Chompret A. The Li-Fraumeni syndrome. Biochimie 2002;84:7582.

  • 34.

    Chompret A, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 2001;38:4347.

  • 35.

    Bougeard G, Sesboüé R, Baert-Desurmont S, et al. Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet 2008;45:535538.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 2015;33:23452352.

  • 37.

    Tinat J, Bougeard G, Baert-Desurmont S, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009;27:e108109; author reply e110.

  • 38.

    Ginsburg OM, Akbari MR, Aziz Z, et al. The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. Fam Cancer 2009;8:563567.

  • 39.

    Lalloo F, Varley J, Moran A, et al. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 2006;42:11431150.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Lee DS, Yoon SY, Looi LM, et al. Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res 2012;14:R66.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Mouchawar J, Korch C, Byers T, et al. Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res 2010;70:47954800.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    McCuaig JM, Armel SR, Novokmet A, et al. Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer 2012;11:607613.

  • 43.

    Hu C, Polley EC, Yadav S, et al. The contribution of germline predisposition gene mutations to clinical subtypes of invasive breast cancer from a clinical genetic testing cohort. J Natl Cancer Inst 2020;112:12311241.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Packwood K, Martland G, Sommerlad M, et al. Breast cancer in patients with germline TP53 pathogenic variants have typical tumour characteristics: the cohort study of TP53 carrier early onset breast cancer (COPE study). J Pathol Clin Res 2019;5:189198.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Melhem-Bertrandt A, Bojadzieva J, Ready KJ, et al. Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 2012;118:908913.

  • 46.

    Leroy B, Anderson M, Soussi T. TP53 mutations in human cancer: database reassessment and prospects for the next decade. Hum Mutat 2014;35:672688.

  • 47.

    Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013;502:333339.

  • 48.

    Kuzbari Z, Bandlamudi C, Loveday C, et al. Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations. Ann Oncol 2023;34:215227.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Mandelker D, Donoghue M, Talukdar S, et al. Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group. Ann Oncol 2019;30:12211231.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Foulkes WD, Polak P. Li-Fraumeni syndrome in the cancer genomics era. J Natl Cancer Inst 2021;113:16151617.

  • 51.

    Kratz CP, Freycon C, Maxwell KN, et al. Analysis of the Li-Fraumeni spectrum based on an international germline TP53 variant data set: an International Agency for Research on Cancer TP53 database analysis. JAMA Oncol 2021;7:18001805.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Schwartz AN, Hyman SR, Stokes SM, et al. Evaluation of TP53 variants detected on peripheral blood or saliva testing: discerning germline from somatic TP53 variants. JCO Precis Oncol 2021;5:16771686.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Castillo D, Yuan TA, Nehoray B, et al. Clonal hematopoiesis and mosaicism revealed by a multi-tissue analysis of constitutional TP53 status. Cancer Epidemiol Biomarkers Prev 2022;31:16211629.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Kratz CP, Achatz MI, Brugières L, et al. Cancer screening recommendations for individuals with Li-Fraumeni Syndrome. Clin Cancer Res 2017;23:e3845.

  • 55.

    Siegel A, Bremer RC, Klein WMP, et al. Uptake and timing of bilateral and contralateral risk-reducing mastectomy in women with Li-Fraumeni syndrome. Breast Cancer Res Treat 2022;191:159167.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Mai PL, Khincha PP, Loud JT, et al. Prevalence of cancer at baseline screening in the National Cancer Institute Li-Fraumeni syndrome cohort. JAMA Oncol 2017;3:16401645.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Greer MC, Voss SD, States LJ. Pediatric cancer predisposition imaging: focus on whole-body MRI. Clin Cancer Res 2017;23:e613.

  • 58.

    Ballinger ML, Best A, Mai PL, et al. Baseline surveillance in Li-Fraumeni syndrome using whole-body magnetic resonance imaging: a meta-analysis. JAMA Oncol 2017;3:16341639.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011;12:559567.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol 2016;17:12951305.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Asdahl PH, Ojha RP, Hasle H. Cancer screening in Li-Fraumeni syndrome. JAMA Oncol 2017;3:16451646.

  • 62.

    Shin SJ, Dodd-Eaton EB, Gao F, et al. Penetrance estimates over time to first and second primary cancer diagnosis in families with Li-Fraumeni syndrome: a single institution perspective. Cancer Res 2020;80:347353.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    McEvoy M, Robison N, Manley P, et al. Successful treatment of recurrent Li-Fraumeni syndrome-related choroid plexus carcinoma. J Pediatr Hematol Oncol 2017;39:e473475.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Thariat J, Chevalier F, Orbach D, et al. Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53- related cancer syndromes. Lancet Oncol 2021;22:e562574.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Kappel S, Janschek E, Wolf B, et al. TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li-Fraumeni family. Breast Cancer Res Treat 2015;151:671678.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66.

    Weeks LD, Niroula A, Neuberg D, et al. Prediction of risk for myeloid malignancy in clonal hematopoiesis. NEJM Evid. Published online April 1, 2023. doi:10.1056/evidoa2200310

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Abelson S, Collord G, Ng SWK, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 2018;559:400404.

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All recommendations are category 2A unless otherwise noted.

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PLEASE NOTE

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  • 1.

    Jones JM. LGBT identification in U.S. ticks up to 7.1%. Gallup. Accessed June 1, 2023. Available at: https://news.gallup.com/poll/389792/lgbt-identification-ticks-up.aspx

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Brown A. About 5% of young adults in the U.S. say their gender is different from their sex assigned at birth. Pew Research Center. Accessed June 1, 2023. Available at: https://www.pewresearch.org/short-reads/2022/06/07/about-5-of-young-adults-in-the-u-s-say-their-gender-is-different-from-their-sex-assigned-at-birth/

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3.

    Sutherland N, Espinel W, Grotzke M, et al. Unanswered questions: hereditary breast and gynecological cancer risk assessment in transgender adolescents and young adults. J Genet Couns 2020;29:625633.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Leone AG, Trapani D, Schabath MB, et al. Cancer in transgender and gender-diverse persons: a review. JAMA Oncol 2023;9:556563.

  • 5.

    Silverberg MJ, Nash R, Becerra-Culqui TA, et al. Cohort study of cancer risk among insured transgender people. Ann Epidemiol 2017;27:499501.

  • 6.

    de Nie I, de Blok CJM, van der Sluis TM, et al. Prostate cancer incidence under androgen deprivation: nationwide cohort study in trans women receiving hormone treatment. J Clin Endocrinol Metab 2020;105:e32933299.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    de Blok CJM, Wiepjes CM, Nota NM, et al. Breast cancer risk in transgender people receiving hormone treatment: nationwide cohort study in the Netherlands. BMJ 2019;365:l1652.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Grynberg M, Fanchin R, Dubost G, et al. Histology of genital tract and breast tissue after long-term testosterone administration in a female-to-male transsexual population. Reprod Biomed Online 2010;20:553558.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Slagter MH, Gooren LJ, Scorilas A, et al. Effects of long-term androgen administration on breast tissue of female-to-male transsexuals. J Histochem Cytochem 2006;54:905910.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Schneider K, Zelley K, Nichols KE, et al. Li-Fraumeni syndrome. In: Adam MP, Mirzaa GM, Pagon RA, et al, eds. GeneReviews. Accessed June 1, 2023. Available at: https://www.ncbi.nlm.nih.gov/books/NBK1311/

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    de Andrade KC, Khincha PP, Hatton JN, et al. Cancer incidence, patterns, and genotype-phenotype associations in individuals with pathogenic or likely pathogenic germline TP53 variants: an observational cohort study. Lancet Oncol 2021;22:17871798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Mai PL, Best AF, Peters JA, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer 2016;122:36733681.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Gonzalez KD, Noltner KA, Buzin CH, et al. Beyond Li Fraumeni syndrome: clinical characteristics of families with p53 germline mutations. J Clin Oncol 2009;27:12501256.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Holmfeldt L, Wei L, Diaz-Flores E, et al. The genomic landscape of hypodiploid acute lymphoblastic leukemia. Nat Genet 2013;45:242252.

  • 15.

    Kamihara J, Rana HQ, Garber JE. Germline TP53 mutations and the changing landscape of Li-Fraumeni syndrome. Hum Mutat 2014;35:654662.

  • 16.

    Qian M, Cao X, Devidas M, et al. TP53 germline variations influence the predisposition and prognosis of B-cell acute lymphoblastic leukemia in children. J Clin Oncol 2018;36:591599.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Tabori U, Shlien A, Baskin B, et al. TP53 alterations determine clinical subgroups and survival of patients with choroid plexus tumors. J Clin Oncol 2010;28:19952001.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Ognjanovic S, Linabery AM, Charbonneau B, et al. Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975–2005. Cancer 2009;115:42184226.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Hettmer S, Archer NM, Somers GR, et al. Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer 2014;120:10681075.

  • 20.

    Garber JE, Goldstein AM, Kantor AF, et al. Follow-up study of twenty-four families with Li-Fraumeni syndrome. Cancer Res 1991;51:60946097.

  • 21.

    Krutilkova V, Trkova M, Fleitz J, et al. Identification of five new families strengthens the link between childhood choroid plexus carcinoma and germline TP53 mutations. Eur J Cancer 2005;41:15971603.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990;250:12331238.

  • 23.

    Varley JM, Evans DG, Birch JM. Li-Fraumeni syndrome—a molecular and clinical review. Br J Cancer 1997;76:114.

  • 24.

    Masciari S, Dewanwala A, Stoffel EM, et al. Gastric cancer in individuals with Li-Fraumeni syndrome. Genet Med 2011;13:651657.

  • 25.

    Maxwell KN, Cheng HH, Powers J, et al. Inherited TP53 variants and risk of prostate cancer. Eur Urol 2022;81:243250.

  • 26.

    Curiel-Lewandrowski C, Speetzen LS, Cranmer L, et al. Multiple primary cutaneous melanomas in Li-Fraumeni syndrome. Arch Dermatol 2011;147:248250.

  • 27.

    Giavedoni P, Ririe M, Carrera C, et al. Familial melanoma associated with Li-Fraumeni syndrome and atypical mole syndrome: total-body digital photography, dermoscopy and confocal microscopy. Acta Derm Venereol 2017;97:720723.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Katona BW, Powers J, McKenna DB, et al. Upper gastrointestinal cancer risk and surveillance outcomes in Li-Fraumeni syndrome. Am J Gastroenterol 2020;115:20952097.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    MacFarland SP, Zelley K, Long JM, et al. Earlier colorectal cancer screening may be necessary in patients with Li-Fraumeni syndrome. Gastroenterology 2019;156:273274.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Li FP, Fraumeni JF Jr, Mulvihill JJ, et al. A cancer family syndrome in twenty-four kindreds. Cancer Res 1988;48:53585362.

  • 31.

    Nichols KE, Malkin D, Garber JE, et al. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol Biomarkers Prev 2001;10:8387.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Birch JM, Blair V, Kelsey AM, et al. Cancer phenotype correlates with constitutional TP53 genotype in families with the Li-Fraumeni syndrome. Oncogene 1998;17:10611068.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Chompret A. The Li-Fraumeni syndrome. Biochimie 2002;84:7582.

  • 34.

    Chompret A, Abel A, Stoppa-Lyonnet D, et al. Sensitivity and predictive value of criteria for p53 germline mutation screening. J Med Genet 2001;38:4347.

  • 35.

    Bougeard G, Sesboüé R, Baert-Desurmont S, et al. Molecular basis of the Li-Fraumeni syndrome: an update from the French LFS families. J Med Genet 2008;45:535538.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Bougeard G, Renaux-Petel M, Flaman JM, et al. Revisiting Li-Fraumeni syndrome from TP53 mutation carriers. J Clin Oncol 2015;33:23452352.

  • 37.

    Tinat J, Bougeard G, Baert-Desurmont S, et al. 2009 version of the Chompret criteria for Li Fraumeni syndrome. J Clin Oncol 2009;27:e108109; author reply e110.

  • 38.

    Ginsburg OM, Akbari MR, Aziz Z, et al. The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30. Fam Cancer 2009;8:563567.

  • 39.

    Lalloo F, Varley J, Moran A, et al. BRCA1, BRCA2 and TP53 mutations in very early-onset breast cancer with associated risks to relatives. Eur J Cancer 2006;42:11431150.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Lee DS, Yoon SY, Looi LM, et al. Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients. Breast Cancer Res 2012;14:R66.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Mouchawar J, Korch C, Byers T, et al. Population-based estimate of the contribution of TP53 mutations to subgroups of early-onset breast cancer: Australian Breast Cancer Family Study. Cancer Res 2010;70:47954800.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    McCuaig JM, Armel SR, Novokmet A, et al. Routine TP53 testing for breast cancer under age 30: ready for prime time? Fam Cancer 2012;11:607613.

  • 43.

    Hu C, Polley EC, Yadav S, et al. The contribution of germline predisposition gene mutations to clinical subtypes of invasive breast cancer from a clinical genetic testing cohort. J Natl Cancer Inst 2020;112:12311241.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Packwood K, Martland G, Sommerlad M, et al. Breast cancer in patients with germline TP53 pathogenic variants have typical tumour characteristics: the cohort study of TP53 carrier early onset breast cancer (COPE study). J Pathol Clin Res 2019;5:189198.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Melhem-Bertrandt A, Bojadzieva J, Ready KJ, et al. Early onset HER2-positive breast cancer is associated with germline TP53 mutations. Cancer 2012;118:908913.

  • 46.

    Leroy B, Anderson M, Soussi T. TP53 mutations in human cancer: database reassessment and prospects for the next decade. Hum Mutat 2014;35:672688.

  • 47.

    Kandoth C, McLellan MD, Vandin F, et al. Mutational landscape and significance across 12 major cancer types. Nature 2013;502:333339.

  • 48.

    Kuzbari Z, Bandlamudi C, Loveday C, et al. Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations. Ann Oncol 2023;34:215227.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 49.

    Mandelker D, Donoghue M, Talukdar S, et al. Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO Precision Medicine Working Group. Ann Oncol 2019;30:12211231.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Foulkes WD, Polak P. Li-Fraumeni syndrome in the cancer genomics era. J Natl Cancer Inst 2021;113:16151617.

  • 51.

    Kratz CP, Freycon C, Maxwell KN, et al. Analysis of the Li-Fraumeni spectrum based on an international germline TP53 variant data set: an International Agency for Research on Cancer TP53 database analysis. JAMA Oncol 2021;7:18001805.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    Schwartz AN, Hyman SR, Stokes SM, et al. Evaluation of TP53 variants detected on peripheral blood or saliva testing: discerning germline from somatic TP53 variants. JCO Precis Oncol 2021;5:16771686.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Castillo D, Yuan TA, Nehoray B, et al. Clonal hematopoiesis and mosaicism revealed by a multi-tissue analysis of constitutional TP53 status. Cancer Epidemiol Biomarkers Prev 2022;31:16211629.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Kratz CP, Achatz MI, Brugières L, et al. Cancer screening recommendations for individuals with Li-Fraumeni Syndrome. Clin Cancer Res 2017;23:e3845.

  • 55.

    Siegel A, Bremer RC, Klein WMP, et al. Uptake and timing of bilateral and contralateral risk-reducing mastectomy in women with Li-Fraumeni syndrome. Breast Cancer Res Treat 2022;191:159167.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 56.

    Mai PL, Khincha PP, Loud JT, et al. Prevalence of cancer at baseline screening in the National Cancer Institute Li-Fraumeni syndrome cohort. JAMA Oncol 2017;3:16401645.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 57.

    Greer MC, Voss SD, States LJ. Pediatric cancer predisposition imaging: focus on whole-body MRI. Clin Cancer Res 2017;23:e613.

  • 58.

    Ballinger ML, Best A, Mai PL, et al. Baseline surveillance in Li-Fraumeni syndrome using whole-body magnetic resonance imaging: a meta-analysis. JAMA Oncol 2017;3:16341639.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 59.

    Villani A, Tabori U, Schiffman J, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 2011;12:559567.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 60.

    Villani A, Shore A, Wasserman JD, et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: 11 year follow-up of a prospective observational study. Lancet Oncol 2016;17:12951305.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 61.

    Asdahl PH, Ojha RP, Hasle H. Cancer screening in Li-Fraumeni syndrome. JAMA Oncol 2017;3:16451646.

  • 62.

    Shin SJ, Dodd-Eaton EB, Gao F, et al. Penetrance estimates over time to first and second primary cancer diagnosis in families with Li-Fraumeni syndrome: a single institution perspective. Cancer Res 2020;80:347353.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 63.

    McEvoy M, Robison N, Manley P, et al. Successful treatment of recurrent Li-Fraumeni syndrome-related choroid plexus carcinoma. J Pediatr Hematol Oncol 2017;39:e473475.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 64.

    Thariat J, Chevalier F, Orbach D, et al. Avoidance or adaptation of radiotherapy in patients with cancer with Li-Fraumeni and heritable TP53- related cancer syndromes. Lancet Oncol 2021;22:e562574.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 65.

    Kappel S, Janschek E, Wolf B, et al. TP53 germline mutation may affect response to anticancer treatments: analysis of an intensively treated Li-Fraumeni family. Breast Cancer Res Treat 2015;151:671678.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 66.

    Weeks LD, Niroula A, Neuberg D, et al. Prediction of risk for myeloid malignancy in clonal hematopoiesis. NEJM Evid. Published online April 1, 2023. doi:10.1056/evidoa2200310

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 67.

    Abelson S, Collord G, Ng SWK, et al. Prediction of acute myeloid leukaemia risk in healthy individuals. Nature 2018;559:400404.

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