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 Credit^TM. 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

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.

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,^14–16 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.^{10,11,13,20–29} 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.^{13,21,35–37} 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.^{13,35,38–41} 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.^43–45 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.

NCCN CATEGORIES OF EVIDENCE AND CONSENSUS

Category 1: Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2A: Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.

Category 2B: Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.

Category 3: Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.

All recommendations are category 2A unless otherwise noted.

Clinical trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.

PLEASE NOTE

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to treatment. The NCCN Guidelines Insights highlight important changes in the NCCN Guidelines recommendations from previous versions. Colored markings in the algorithm show changes and the discussion aims to further the understanding of these changes by summarizing salient portions of the panel’s discussion, including the literature reviewed.

The NCCN Guidelines Insights do not represent the full NCCN Guidelines; further, the National Comprehensive Cancer Network® (NCCN®) makes no representations or warranties of any kind regarding their content, use, or application of the NCCN Guidelines and NCCN Guidelines Insights and disclaims any responsibility for their application or use in any way.

The complete and most recent version of these NCCN Guidelines is available free of charge at NCCN.org.

© 2023 National Comprehensive Cancer Network® (NCCN®), All rights reserved. The NCCN Guidelines and the illustrations herein may not be reproduced in any form without the express written permission of NCCN.