Overview
Hereditary cancers are often characterized by pathogenic/likely pathogenic (P/LP) variants associated with increased risk for certain cancers and transmission to offspring through the mother and/or father.1,2 They often have an early age of onset and exhibit an autosomal dominant inheritance pattern (ie, occur when the individual has a P/LP variant in only one copy of a gene). An individual suspected of being at risk for hereditary cancer should be offered genetic counseling.3,4 Assessment of an individual’s risk for familial or hereditary cancer is based on a thorough evaluation of the personal and family history.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric were developed with an intent to (1) serve as a resource for health care providers to identify individuals who may benefit from cancer risk assessment and genetic counseling and testing; (2) guide decisions related to genetic testing; and (3) facilitate a multidisciplinary approach in the comprehensive care of individuals at increased risk for hereditary colorectal, endometrial, and gastric cancer. The current NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric provide recommendations for the care of patients with high-risk syndromes, including Lynch syndrome (LS), adenomatous polyposis syndromes (eg, familial adenomatous polyposis, attenuated familial adenomatous polyposis, MUTYH-associated polyposis), and hamartomatous polyposis syndromes (eg, juvenile polyposis syndrome, Peutz-Jeghers syndrome [PJS], PTEN hamartoma tumor syndrome [PHTS]). These guidelines also provide recommended approaches to genetic counseling/testing in individuals with P/LP variants that predispose individuals to the aforementioned hereditary syndromes. Where possible, P/LP variants in more recently identified genes have been addressed to the extent possible given the limited information available.
This current manuscript describes the most recent NCCN Guidelines recommendations regarding hereditary syndromes and P/LP variants associated with endometrial cancer (EC), including the role of multigene panel testing (MGPT) in detection of these variants. This manuscript also describes updates to guidelines recommendations regarding colon cancer screening for individuals with CHEK2 P/LP variants.
Endometrial Cancer
Adenocarcinoma of the endometrium (also known as EC, or more broadly as uterine cancer or carcinoma of the uterine corpus) is the most common malignancy of the female genital tract in the United States. It is estimated that 67,880 new EC cases will occur in 2024, with 13,250 deaths resulting from the disease.5 There are >600,000 survivors of EC in the United States.6 An estimated 5% of EC cases are attributed to a hereditary syndrome.7 These include LS, PHTS, and PJS. An increase in MGPT has revealed other genes potentially associated with increased risk of EC (ie, BRCA1/2, POLD1, POLE).
Multigene Panel Testing
Next-generation sequencing (NGS) allows for the sequencing of multiple genes simultaneously. This is referred to as multigene panel testing (MGPT). The introduction of MGPT for hereditary forms of cancer has rapidly altered the clinical approach to testing patients who are at increased risk, and their families. MGPT simultaneously analyzes a set of genes that are associated with cancer phenotypes. MGPT may include syndrome-specific tests (ie, panels that test multiple genes associated with only one syndrome like LS or adenomatous polyposis), cancer-specific tests (ie, panels that test multiple genes associated with a specific type of cancer like EC), and comprehensive cancer panels (ie, panels that test many genes associated with multiple cancers or cancer syndromes).
MGPT can include only high-penetrance genes associated with a specific cancer, or both high- and moderate-penetrance genes, as well as genes with emerging evidence. Comprehensive cancer risk panels, which include a large number of genes associated with a variety of cancer types, are also available. The decision to use MGPT for patient care should be no different than the rationale for testing a single gene known to be associated with the development of a specific type of cancer. Testing is focused on identifying a P/LP variant known to be clinically actionable; that is, whether the treatment of an individual patient is altered based on the presence of a P/LP variant. MGPT may be most useful when a P/LP variant in more than one gene can explain a patient’s clinical and family history. In the cases where more than one P/LP variant could potentially influence a condition, MGPT may be more efficient and/or cost-effective.8 This approach may detect P/LP variants not found in single-gene testing.9 MGPT has comparable, or even higher, yield for LS, compared with tumor-based testing.10–12 Cost-effectiveness of this approach remains uncertain, as there are currently no recent studies in the United States evaluating current testing costs. MGPT may also be considered for those who tested negative (indeterminate) for one particular syndrome in the past, but whose personal and family history is strongly suggestive of an inherited susceptibility.13,14 Another instance where MGPT may be considered is for individuals meeting the NCCN testing criteria but who tested negative with previous limited testing (eg, single gene and/or absent deletion duplication analysis) and are interested in pursuing multigene testing. MGPT also provides the possibility of identifying P/LP variants in multiple actionable genes that would potentially impact screening and treatment of the individuals and family members who may otherwise be overlooked using cancer syndrome-specific panels.15,16 MGPT may also impact family planning in the setting of an identified P/LP variant that affects potential risk for a recessive disorder for offspring and may identify an unexpected finding such as a P/LP variant in a gene that does not currently explain the patient’s personal or family history of cancer.
A major dilemma regarding MGPT is that there are limited data and a lack of clear guidelines regarding the degree of cancer risk associated with some of the genes assessed in MGPT and how to communicate and manage risk for individuals with P/LP variants in these genes.14,17,18 This issue is compounded by the low prevalence of many P/LP variants, leading to difficulty in conducting adequately powered studies.17 Some MGPT include low- or moderate-penetrance genes, for which there are little available data regarding degree of cancer risk and guidelines for risk management.13,18–21 Further, as is the case with high-risk genes, it is possible that the risks associated with moderate-risk genes may not be due entirely to that gene alone, but may be influenced by gene/gene or gene/environment interactions. It is important to note that a germline MGPT result alone does not inform treatment decision-making for EC. For example, presence of a P/LP variant in a Lynch-associated mismatch repair (MMR) gene is not sufficient to initiate immune checkpoint inhibitor therapy. Tumor-based testing for MMR deficiency determined by PCR, NGS, or immunohistochemistry (IHC) are required for determining eligibility for immune checkpoint inhibitor therapy based on presence of dMMR.22
MGPT increases the likelihood of detecting variants of uncertain significance (VUS).13,18,21,23–28 The proportion of patients with one or more VUS is higher among members of racial/ethnic minority groups, particularly with utilization of large multigene panels, potentially increasing the burden of uncertain results on these populations.29–32 For example, the greater incidence of VUS in these patient groups may propagate inequities in the quality of preventive care such as recommendations of unnecessary bilateral mastectomy or high-risk screening, as well as related harms. Additionally, as these patient groups are underrepresented in clinical laboratory databases, this may lead to a greater wait time for VUS reclassification and a potential increase in the number of families for whom variant tracking may be considered.30,31 The increased possibility of detecting a VUS adds to the complexity of counseling following MGPT. Inclusion of more diverse populations in research studies may lead to lower VUS rates.30,32 In addition, many VUS previously identified through hereditary cancer testing have been reclassified and downgraded to benign or likely benign categories.23,33 Nonetheless, clinical phenotypic correlation is warranted with further discussion with the testing laboratory if evidence supports potential pathogenicity of a VUS. Patient and provider guidelines for follow-up of VUS have been developed.34,35
There are other issues to consider regarding MGPT. First, commercially available tests may differ significantly on a number of factors, such as number of genes analyzed, turnaround time, and insurance coverage, among others. Tests requiring a longer turnaround time may not be suitable for patients who need rapid results to inform surgical decision-making. The specific laboratory and multigene test should be chosen carefully.13 Second, P/LP variants identified for more than one gene add complexity that may lead to difficulty in making risk management recommendations.14 A management plan should only be developed for identified P/LP variants that are clinically actionable; care should be taken to ensure that overtreatment or overscreening does not occur due to findings for which clinical management is uncertain, or findings that are incorrectly interpreted due to lack of evidence. Additionally, challenges can be present in the setting of an incidental P/LP variant identified by MGPT in which the personal and/or family history is not consistent with the established P/LP variant phenotype. Penetrance and subsequent management recommendations in this clinical scenario may be more uncertain.
MGPT for Endometrial Cancer
MGPT increases the potential for detecting a P/LP variant in patients with EC. In patients with EC, MGPT identifies a P/LP variant in 9.2% to 14.7%.36–41 In these studies, unselected populations yielded lower rates of positive results, compared with studies of patients selected based on personal or family history. Cancer risk genes other than those associated with LS have been found in 3.4% to 11.8% of patients with EC. See Table 1 for a summary of the studies that have evaluated P/LP variant rates in patients with EC.36–41
Summary of Studies That Evaluated P/LP Variant Rates in Patients With Endometrial Cancer
| Study (Population) | Number of Patients With EC Tested | Number of Genes Tested in Panel | Total Number of P/LP Variants (%)a | Number of P/LP Variants in LS Genes (%) |
|---|---|---|---|---|
| Ring et al,41 2016 (high-risk) | 381 | 25 | 35 (9.2%)b | 22 (5.8%) |
| Cadoo et al,40 2019 (unselected) | 156 | 75 | 22 (14%)c | 5 (3.2%) |
| Levine et al,39 2021 (unselected) | 961 | 47 | 97 (10.1%)d | 29 (3%) |
| Karpel et al,37 2022 (high-risk) | 224 | Varied | 33 (14.7%)e | 21 (9.4%) |
| Heald et al,38 2022 (high-risk) | 6,490 | Varied | 880 (13.6%)f | 532 (8.2%) |
| Gordhandas et al,36 2023 (unselected) | 1,625 | 76–90 | 216 (13%)g | 39 (2.4%) |
| Summary (high-risk) | 7,095 | Variedh | 938 (13.4%) | 8.1% high-risk (575/7,095) |
| Summary (unselected) | 2,742 | 47–90 | 335 (12%) | 2.7% unselected (73/2,742) |
Abbreviation: EC, endometrial cancer.
aGenes (number of specific P/LP variants).
bMLH1 (3), MSH2 (5), EPCAM (2), MSH6 (6), PMS2 (6), CHEK2 (4), APC (1), ATM (1), BARD1 (1), BRCA1 (1), BRCA2 (1), BRIP1 (1), NBN (1), PTEN (1), RAD51C (1).
cMLH1 (1), MSH6 (2), PMS2 (2), APC (5), ATM (3), CHEK2 (2), MUTYH (3), MRE11A (1), RECQL4 (2), BRCA1 (1), SMARCA4 (1).
dMLH1 (2), MSH2 (6), MSH6 (10), PMS2 (11), BRCA1 (4), BRCA2 (6), CDKN2A (1), SDHA (1), BRIP1 (6), PALB2 (2), RAD51C (1), ATM (2), NBN (4), NF1 (2), CHEK2 (moderate penetrance; 13), CHEK2 (low penetrance; 4), RAD50 (3), MUTYH (recessive; 15), MSH3 (recessive; 3), NTHL1 (recessive; 3), HOXB13 (1).
eMLH1 (4), MSH2 (5), MSH6 (7), PMS2 (4), EPCAM (1), CHEK2 (6), BRCA2 (2), ATM (2), APC (2), RAD51C (1), BRCA1 (1).
fMSH6 (234), MSH2 (130), PMS2 (100), CHEK2 (94), MLH1 (68), BRCA2 (52), BRCA1 (42), ATM (38), PALB2 (22), BRIP1 (21), RAD50 (16), PTEN (13), TP53 (9), MITF (7), APC (5), WRN (4), RECQL4 (4), NBN (4), MUTYH (biallelic; 4), EPCAM (4), RAD51C (4), FANCC (4), NF1 (4).
gAPC (24), ATM (9), BARD1 (3), BLM (7), BRCA1 (10), BRCA2 (11), BRIP1 (2), CDKN2A (1), CHEK2 (27), ERCC3 (14), FANCA (11), FANCC (4), FH (6), FLCN (1), MITF (3), MLH1 (5), MRE11A (2), MSH2 (12), MSH6 (19), MUTYH (19), NBN (4), NTHL1 (6), PALB2 (3), PMS2 (4), RAD51B (1), RAD51D (2), RB1 (1), RECQL (5), RECQL4 (5), RET (1), RTEL1 (2), SDHA (2), SMARCA4 (1), TP53 (1), VHL (3).
hExcept for Ring et al,41 which tested 25 genes.
One study found limited evidence for endometrial tumor histology as a predictor of P/LP variants in non-LS genes.41 Patients with P/LP variants in non-LS genes were more likely to have endometrial carcinomas with serous histology (23% vs 6%; P=.02) than patients without a P/LP variant. The patients with non-LS P/LP variants and serous histology had mutations in BRCA2, BRIP1, and RAD51C. Additionally, of the patients with P/LP variants in non-LS genes, 39% were of nonendometrioid histology.41 Another study reported a significant difference in histology between ECs occurring in patients with P/LP variants compared with those without (P=.017); P/LP variants were present in 13.4% of endometrioid, 8.7% of serous, 23.9% of clear cell, 11.3% of carcinosarcoma, 15.2% of de- or undifferentiated, and 14.5% of mixed or high-grade carcinoma not otherwise specified tumors.36 One analysis showed that age of diagnosis was not associated with a greater likelihood of testing positive for a P/LP variant.38 One prospective multicenter study showed that 34.5% of patients with LS (n=10 of 29) would not have been identified without MGPT.39 Specifically, 6 patients did not have microsatellite instability (MSI)/IHC performed at all at their institution, and 4 who underwent tumor testing had IHC and/or methylation findings that would not have led to a recommendation for germline testing.
Emerging evidence has identified additional genes that may be associated with increased risk for EC, and the panel has evaluated the strength of the evidence based on published reports. Although research has demonstrated a potential risk for EC associated with these P/LP variants, the value of including these genes for clinical testing (eg, as part of a multigene panel) remains uncertain. Nonetheless, the panel recognizes that many testing companies offer panels that include these genes, and that patients are being tested and may need guidance regarding subsequent screening and surveillance. Accordingly, while the panel recommends caution in recommending MGPT, guidance on the management of results is discussed subsequently. Germline MGPT should include at minimum the following genes associated with EC risk: MLH1, MSH2, MSH6, PMS2, EPCAM, PTEN, BRCA1, and BRCA2. Germline MGPT with the following genes that have also been associated with increased risk for EC may also be considered: POLD1, POLE. Selection of a panel and decision to retest a person with previous more limited genetic testing should be based on considerations such as age at presentation and personal and family history of cancer, as well as patient and provider preference.
The NCCN panel carefully reviewed available evidence to support upfront MGPT. The optimal approach for MGPT remains uncertain. The panel currently does not assert that MGPT is a logistically simpler approach to genetic evaluation, compared with selection based on personal and family history and tumor-based screening. In addition, there is currently a lack of evidence regarding the impact of MGPT on EC incidence and mortality, and on inequities in genetic evaluation and follow-up by race, ethnicity, and other social determinants of health.
The panel recommends consideration of germline MGPT for patients with EC aged ≥50 years who do not meet other testing criteria (category 2B), or based on comprehensive assessment of personal and family history of cancer. Syndrome-specific panels may be considered in the following scenarios: (1) there is an individual from a family with a known P/LP variant and there is no other reason for MGPT (eg, individual does not otherwise meet NCCN criteria); and (2) the patient’s family history is suggestive of a known hereditary syndrome. The NCCN panel recommends that MGPT be ideally offered in the context of professional genetic expertise, with pre- and posttest counseling being offered. It is unclear if there is sufficient capacity to deliver pretest informed consent and appropriate posttest genetic counseling to all individuals with a P/LP variant and/or VUS, as well as negative results. Therefore, the capacity to offer MGPT to all patients with and survivors of EC is uncertain. Tumor registry data from 2013 to 2019 indicate that genetic testing rates among patients with EC are 6.4%.42 Patients with a P/LP variant should be encouraged to participate in clinical trials or genetic registries.
Criteria for testing and genetic evaluation for hereditary syndromes associated with EC can be found in Figures 1 and 2. MGPT principles can be found on Figures 3–6.
HRS-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
HRS-3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
HRS-A 1 of 3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
HRS-A 2 of 3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
GENE-1. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
GENE-2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
Hereditary Syndromes Associated With EC
Lynch Syndrome
LS accounts for approximately 3% of all EC cases.43 LS results from a germline P/LP variant in 1 of 4 DNA MMR genes (MLH1, MSH2, MSH6, or PMS2).44 Additionally, deletions in the EPCAM gene, which lead to hypermethylation of the MSH2 promoter and subsequent MSH2 silencing, cause LS.45,46 Identification of LS is important both for individuals with cancer, because of high personal risk for metachronous LS cancers (ie, EC after colorectal cancer [CRC] or vice versa; second CRC after first CRC), and for their families because of an autosomal dominant mode of inheritance and potentially high penetrance. After identification of LS, surveillance (particularly for first or metachronous CRC or EC) offers an opportunity for early detection and prevention of cancer among patients with a P/LP variant. Further, cancer site-specific evaluation and heightened attention to symptoms is also advised for other cancers that occur with increased frequency in patients with a P/LP variant, including colorectal, endometrial, gastric, ovarian, pancreatic, ureter and renal pelvis, biliary tract, brain (glioblastoma), and small intestinal cancers, as well as sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas.
Individuals with LS and assigned female at birth may have a lifetime risk of up to 60% for EC, and EC is the second most common LS-associated cancer in those at risk.47–50 The estimated age of presentation and cumulative risk for diagnosis through age 80 years depends on the P/LP variant, ranging from an average age of 49 to 50 years and cumulative risk of 13%–26% for PMS2 to an average age of 49 years and cumulative risk of 34%–54% for MLH1 P/LP variant.47,51–57 See “Gene-Specific Lynch Syndrome Cancer Risks and Surveillance/Prevention Strategies” in the algorithm (available at NCCN.org) for the complete list of average age of presentation and cumulative risk for diagnosis through age 80 years for EC for patients with an MMR P/LP variant.
The NCCN panel recommends that, for patients or families where colorectal or endometrial tumor is available, one of two options should be considered for testing among people meeting testing criteria: (1) tumor testing with IHC or MSI, or a comprehensive tumor NGS panel (that includes, at a minimum, the 4 MMR genes and EPCAM, BRAF [for CRC only], MSI, and other known familial cancer genes); or (2) germline MGPT that includes at least the 4 MMR genes and EPCAM. The NCCN panel recommends tumor testing with IHC and/or MSI be used as the primary approach for pathology laboratory–based universal screening. If no tumor is available, tumor material is insufficient, or the affected relative is unavailable, germline MGPT may be considered that includes the 4 MMR genes and EPCAM. MGPT is recommended for patients who are diagnosed with EC or CRC aged <50 years or with a strong family history.10,58
If abnormal MSI or IHC for one of the DNA MMR proteins is identified within a CRC or EC, then a differential diagnosis must be considered. “Tumor Testing Results and Additional Testing Strategies” in the algorithm (available at NCCN.org) identifies a range of test result scenarios, the differential diagnosis, and recommended follow-up. In some scenarios, such as with absent MSH2 expression by IHC, follow-up germline testing for the indicated genes is directly recommended. In other scenarios, additional testing of the tumor tissue is recommended. For example, for the common scenario of absent MLH1 expression by IHC in endometrial tumors, the panel recommends additional tumor testing for presence of MLH1 hypermethylation, which would be consistent with sporadic, rather than LS-associated, cancer.59–62
EC Risk Management
Surveillance/prevention strategies for EC in LS can be found on Figures 7–10. EC risk management should be individualized based on several considerations. Education that enhances recognition and prompt reporting of relevant symptoms (eg, dysfunctional uterine bleeding or postmenopausal bleeding) is advised to promote early EC detection. The evaluation of these symptoms should include an endometrial biopsy. EC screening does not have proven benefit in women with LS. However, endometrial biopsy is highly sensitive and specific as a diagnostic procedure. Screening through endometrial biopsy every 1 to 2 years starting at age 30 to 35 years may be considered.63–68
LS-B 4 of 5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
LS-C 4 of 5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
LS-D 4 of 5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
LS-E 4 of 5. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
Routine transvaginal ultrasound to screen for EC in postmenopausal individuals has not been shown to be sufficiently sensitive or specific to warrant a positive recommendation,64–69 but may be considered at the clinician’s discretion. However, transvaginal ultrasound is not recommended as a screening tool in premenopausal individuals due to the wide range of endometrial stripe thickness throughout the normal menstrual cycle.
Total hysterectomy has not been shown to reduce EC mortality, but can reduce the incidence of EC and is an option that may be considered for risk reduction.60,63,65,70–72 The timing of hysterectomy can be individualized based on whether childbearing is complete, comorbidities, family history, and LS P/LP variant, because risks for EC vary by mutated gene. For patients requiring a colorectal surgery such as for CRC resection, coordination with risk-reducing gynecologic surgery may be considered.
Given the higher risks of early EC and ovarian cancer in individuals with an MLH1 or MSH2 P/LP variant, total hysterectomy with bilateral salpingo-oophorectomy should be considered starting at age 40 years in these patients.47,52–54,73 For patients with an MSH6 P/LP variant, total hysterectomy with opportunistic bilateral salpingectomy may be considered starting at age 40 years, with delayed bilateral oophorectomy starting at age 50 years. Opportunistic salpingectomy is defined as elective removal of both fallopian tubes during another abdominal surgery (such as a gallbladder surgery, a hernia operation, cesarean birth or hysterectomy) as a measure to prevent cancer of the fallopian tube, ovary or peritoneum. In patients with a PMS2 P/LP variant, total hysterectomy with bilateral salpingo-oophorectomy may be considered starting at age 50 years, reflecting lower risk of endometrial and ovarian cancer in these patients, compared with patients with other LS genes (MLH1, MSH2, MSH6). The decision to have a bilateral salpingo-oophorectomy as a risk-reducing option by patients with an MSH6 or PMS2 P/LP variant who have completed childbearing should be individualized and done with consultation with a gynecologist with expertise in LS.
For patients with an EPCAM P/LP variant, evidence for gynecologic cancer surveillance recommendations is lacking. Although cancer risks associated with EPCAM pathogenic mutation have historically been characterized similarly to MSH2-related risks, EC risk is variable and related to extent and location of the deletion of EPCAM and its proximity to the MSH2 promoter. Currently, the NCCN Guidelines recommend counseling and surveillance based on family history and shared decision-making for these patients. Risk-reducing surgery may be considered at a later age, similar to patients with a PMS2 P/LP variant.
An observational study showed that hormonal contraceptive use is associated with lower risk for endometrial cancer in patients with an MMR P/LP variant (hazard ratio [HR], 0.39; 95% CI, 0.23–0.64; P<.001).74 However, prospective data are needed before hormonal contraceptives are recommended for prevention of gynecologic cancers in patients with LS. In general, risk reduction agents should be considered, with detailed discussion between the physician and patient outlining the associated risks and benefits.
Peutz-Jeghers Syndrome
PJS is an autosomal dominant condition mainly characterized by hamartomatous gastrointestinal polyps.75 Besides being associated with an increased risk for CRC, PJS is also associated with increased risk for cancers of the breast, pancreas, stomach, small intestine, and lung.76–78 Risk of certain gynecologic cancers (ie, sex cord tumor with annular tubules, endometrial cancer, minimal deviation adenocarcinoma of the uterine cervix) is also increased in patients with PJS, as well as cancer of the testes (Sertoli cell tumors).76–78
Molecular testing and identification techniques (eg, multiplex PCR, Sanger sequencing, multiplex ligation-dependent probe amplification) have identified mutations in STK11/LKB1 in 66% to 94% of cases of PJS.79,80 Even with modern techniques, however, the detection rate of STK11/LKB1 P/LP variants in PJS has not approached100%. This leaves the possibility of PJS as being a heterogenous genetic disease with other potential P/LP variants playing a role in disease development.81
Patients who meet clinical criteria for PJS or have a P/LP variant in STK11 are recommended for referral to a specialized team and encouraged to participate in available clinical trials. The full NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric (available at NCCN.org) include PJS surveillance recommendations for both adults and children. The panel’s recommendations for screening of extracolonic cancers in patients with PJS are consistent with the recommendations from the United States Multi-Society Task Force on Colorectal Cancer regarding diagnosis and management of cancer risk for gastrointestinal hamartomatous polyposis syndromes.82
To monitor for gynecologic cancer, a pelvic examination and Papanicolaou test should be done annually, beginning at around ages 18 to 20 years. Annual pelvic ultrasound may be considered. Endometrial biopsy may be done if abnormal bleeding is present, and total hysterectomy (including the uterus and cervix) may be considered when childbearing is complete. In children, an annual physical examination for observation of precocious puberty is recommended beginning at around age 8 years. Surveillance strategies for PJS can be found in Figure 11 for pediatric surveillance and Figure 12 for adult surveillance.
PJS-2. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
PJS-3. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
PTEN Hamartoma Tumor Syndrome
The spectrum of disorders resulting from a germline P/LP variant in PTEN are referred to as PTEN hamartoma tumor syndrome (PHTS).83 The spectrum of PHTS includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related Proteus syndrome, adult Lhermitte-Duclos disease, Proteus-like syndrome,84–86 and autism spectrum disorders with macrocephaly.85–87 Cowden syndrome is rare, with an incidence of 1 in 200,000, although it is likely to be underestimated due to difficulties associated with making a clinical diagnosis of the disease.88,89 Cowden syndrome is an autosomal dominant disorder, and most cases are associated with a germline PTEN P/LP variant; however, one study found that germline KILLIN methylation may also be associated with this syndrome.90 The frequency of a germline PTEN P/LP variant in Cowden syndrome cases is high, at approximately 80%.91
PHTS is associated with multiple hamartomatous and/or cancerous lesions in various organs and tissues, including the colon, skin, mucous membranes, breast, thyroid, endometrium, and brain.85,92–95 Although not well defined, individuals with PHTS who were assigned female at birth may have a 5% to 22% risk for endometrial cancer.85,96–98 Although many females with Cowden syndrome/PHTS may also have uterine fibroids, this risk is not likely to be much greater than in females without Cowden syndrome/PHTS or PTEN P/LP variant.
Screening recommendations for individuals with PHTS can be found in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (available at NCCN.org). Given that PHTS is rare, there are no data on screening for EC in these patients, though consideration of screening can begin as early as age 35 years. The panel recommends patient education regarding the symptoms of endometrial cancer including the necessity of a prompt response to symptoms such as abnormal bleeding. Prompt reporting promotes early detection of endometrial cancer. The evaluation of these symptoms should include an endometrial biopsy. Though EC screening does not have proven benefit in individuals with PHTS, endometrial biopsy is highly sensitive and specific as a diagnostic procedure. Therefore, screening through endometrial biopsy every 1 to 2 years may be considered. Routine transvaginal ultrasound to screen for EC in postmenopausal individuals has not been shown to be sufficiently sensitive or specific to warrant a positive recommendation but may be considered at the clinician’s discretion. However, transvaginal ultrasound is not recommended as a screening tool in premenopausal individuals due to the wide range of endometrial strip thickness throughout the normal menstrual cycle.
Although no data are available regarding risk reduction surgery in individuals with PHTS who were assigned female at birth, the option of risk-reducing mastectomy and hysterectomy should be discussed. Counseling for risk-reducing surgeries may include discussion of the extent of cancer risk reduction/protection, risks associated with surgeries, and reproductive options. Oophorectomy is not specifically recommended. It is also important to address the psychosocial and quality-of-life aspects of undergoing risk-reducing surgical procedures.
Other Genes Potentially Associated With EC Risk
POLD1/POLE
P/LP variants in the POLD1 and POLE genes are primarily associated with colonic polyposis and an increased risk for CRC.99–107 Limited evidence for an increased risk of extracolonic cancers such as EC have been reported in individuals with POLD1 and POLE P/LP variants.99,102,105–113 In a 2022 study, 9 of 17 (53%) individuals with POLD1 exonuclease domain variant and 5 of 43 (12%) individuals with POLE exonuclease domain variants were diagnosed with EC.102 A 2023 systematic review and meta-analysis found that 11 of 20 (55%) patients with a POLD1 P/LP variant had EC and 11 of 41 (27%) patients with a POLE P/LP variant had EC.99 Given the small sample sizes in the aforementioned studies, the panel believes that there is currently insufficient evidence to support risk management strategies for extracolonic cancers, including EC.
NCCN Guidelines recommendations for colon cancer risk management for patients with a POLD1 or POLE P/LP variant can be found in Figure 13.
GENE-11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
BRCA1 and BRCA2
It is widely accepted that BRCA1 and BRCA/2 P/LP variants are highly penetrant for breast and ovarian cancer. These pathogenic variants are associated with other cancers as well, such as cancers of the pancreas and prostate. Some studies have suggested an increased risk specifically of serous uterine cancer in patients with a P/LP BRCA1 or BRCA2 variant.114–118 Analyses from a multicenter prospective cohort study including 1,083 patients with a P/LP BRCA1 variant who underwent risk reducing salpingo-oophorectomy without hysterectomy showed an increased risk for serous and/or serous-like endometrial cancer.119 A Dutch cohort study including 5,980 patients with a P/LP BRCA1 or BRCA2 variant showed a 2- to 3-fold increased risk for endometrial cancer, with the highest risks for serous-like (HR, 10.48; 95% CI, 2.95–37.20) and p53-abnormal endometrial cancer (HR, 15.71; 95% CI, 4.62–53.40) in patients with a P/LP BRCA1 variant.118 A systematic review and meta-analysis including 11 studies with 13,871 patients with a P/LP BRCA1 or BRCA2 variant showed that the prevalence of EC was 0.62% in patients with a P/LP BRCA1 variant and 0.47% in patients with a P/LP BRCA2 variant (comparing BRCA1 to BRCA2, relative risk, 1.18; 95% CI, 0.7–2.0).120 For uterine papillary serous carcinoma, the prevalence rates were 0.20% for BRCA1 and 0.08% for BRCA2 (comparing BRCA1 to BRCA2, relative risk, 1.39; 95% CI, 0.5–3.7). It has been suggested that the increased risk for endometrial cancer observed in some patients with a BRCA1 or BRCA2 P/LP variant may be due to the use of tamoxifen therapy by these patients rather than the presence of a P/LP variant.121–123
The absolute risk of uterine cancer in patients with a P/LP BRCA1 or BRCA2 variant appears low overall, despite some evidence of increased risk. Information on management of gynecologic cancers in patients with a P/LP BRCA1 or BRCA2 variant can be found in the NCCN Guidelines for Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (available at NCCN.org).
CHEK2 P/LP Variants and Colon Cancer Risk
Germline P/LP variants in the cell cycle checkpoint kinase 2 (CHEK2) gene are associated with increased risk for breast cancer; however, the risk for CRC is more uncertain.124–129 Significant associations between CHEK2 P/LP variants and CRC risk have been identified in early meta-analyses (including studies published no later than 2012).125–127 One such meta-analysis of 7 studies, including 4,029 cases and 13,844 controls based on search criteria, found a significant association between the CHEK2 I157T variant and CRC risk.125 In another meta-analysis of 7 studies, analysis of 3,874 cases and 11,630 controls revealed a strong cumulative evidence of association between CHEK2 1100delC variant and risk of CRC (odds ratio [OR], 1.88; 95% CI, 1.29–2.73; P=.001); similar results were obtained for one other CHEK2 variant (rs17879961).127
An analysis that used corrected data from one of the studies included in a 2011 meta-analysis126 showed that CHEK2 1100delC variant was not associated with a significantly increased CRC risk in both familial CRC and sporadic CRC subgroups, when comparing with the control population.128 Further, in the larger unselected CRC group, a reduction in overall CRC risk was observed in these carriers. Larger retrospective studies published more recently also cast doubt on the association between CHEK2 P/LP variants and CRC risk. In a 2022 retrospective cohort of 3,783 patients with one or more CHEK2 P/LP variants, CHEK2 was not associated with CRC, and those patients with a CHEK2 P/LP variant were less likely to have been diagnosed with CRC, compared with patients who did not carry a CHEK2 P/LP variant (OR, 0.62; 95% CI, 0.51–0.76; P<.001). A similar result was reported when stratified by patients with CHEK2 1100delC, and CRC was less frequently diagnosed in patients with 1100delC compared with patients who did not carry a CHEK2 P/LP variant (OR, 0.69; 95% CI, 0.53–0.88; P<.002).130 A second large retrospective study of 6,255 individuals carrying a single truncating or missense P/LP variant in CHEK2 found no significant differences in the prevalence of CRC among individuals with truncating (2.2%) or missense (1.8%) P/LP variants compared with individuals who did not carry a CHEK2 P/LP variant (2.2%).129
A clinical practice resource published by the American College of Medical Genetics and Genomics in 2023 concluded that published data are at best supportive of a moderate association of CHEK2 P/LP variants with CRC risk. It also noted that, although an association with CRC is reported in some studies for both truncating and missense CHEK2 variants, the risk falls below the level of relative risk that they define as low increased risk.131 One model has suggested that earlier screening than the average-risk initiation may be justified for patients with CHEK2 1100delC and I157T based on reaching the same risk for CRC at an earlier age than observed among average-risk persons initiating screening at age 50 years, but this model was published prior to availability of the aforementioned large cohort studies showing no increased risk for CRC among patients with a CHEK2 P/LP variant.129,130,132
Taking this into consideration, for patients with a CHEK2 P/LP variant, the NCCN panel recommends screening and surveillance as per the NCCN Guidelines for Colon Cancer, NCCN Guidelines for Rectal Cancer, and NCCN Guidelines for Colorectal Cancer Screening (available at NCCN.org). For patients with a CHEK2 P/LP variant unaffected by CRC and without a first degree relative with CRC, the panel recommends general population screening. NCCN Guidelines recommendations for CRC risk management for patients with a CHEK2 P/LP variant can be found on Figure 14.
GENE-6. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric, Version 3.2024.
Citation: Journal of the National Comprehensive Cancer Network 22, 10; 10.6004/jnccn.2024.0061
Summary
With the rapid integration of MGPT as a standard approach to genetic testing for inherited cancer risk assessment, several challenges have come to light, including the potential to reveal genetic variations that have uncertainty regarding cancer risk and management decisions. As such, appropriate risk counseling and individualized guidance on screening and management by health care providers with expertise in genetics will remain critical to optimizing patient care. Surveillance and management recommendations for EC vary based on the hereditary syndrome and/or P/LP variant identified in the individual. As newer data on P/LP variants and their association with the risk of hereditary cancers including EC and CRC emerge, the NCCN panel expects that surveillance and management recommendations for individuals at high risk for these cancers and associated syndromes will also evolve. The panel recognizes the increased risk of EC in individuals with LS, PHTS or PJS; however, limited evidence exists for the association of P/LP variants in certain other genes such as POLE, POLD1, BRCA1, and BRCA2 with EC. Lastly, more recent data have revealed a lack of significant association between CHEK2 P/LP variants and risk of CRC, prompting the panel to recommend general population screening for patients with CRC who have these variants.
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