Germline Testing for Lynch Syndrome in Endometrial & Ovarian Cancers

endometrial cancer; ovarian cancer: endometrial cancer; ovarian cancerIn the era of advanced cancer genomics, our recognition of hereditary cancer mutations continues to increase. Certain inherited germline mutations dramatically increase the risk of endometrial cancer (EC) and ovarian cancer (OC). Approximately 5 percent of all ECs and 1 percent of OCs are because of a Lynch syndrome (LS) mutation (Clin Colon Rectal Surg 2012; doi: 10.1055/s-0032-1313780). Patients with LS are predisposed to develop cancer characterized by an inherited germline mutation in one of four tumor suppressor DNA mismatch repair (MMR) genes: mutL homolog 1 (MLH1); mutS homolog 2 (MSH2); mutS homolog 6 (MSH6); PMS1 homolog 2, mismatch repair system component (PMS2); and epithelial cell adhesion molecule (EPCAM). Each MMR gene mutation is associated with a different risk level for endometrial and ovarian carcinoma. Specifically, women with LS have a 24-51 percent lifetime risk of EC, compared with 2.9 percent in the general population. Lynch mutation carriers are also at increased risk for OC with a cumulative risk of 3-20 percent compared with the 1.3 percent risk of the general population. Most commonly, LS-associated OCs are nonserous and nonmucinous, with an enrichment in endometrioid histology. LS carriers are recommended to undergo risk-reducing surgery, such as total hysterectomy with or without BSO or bilateral salpingectomy directly after childbearing is completed. Due to these high cancer risks, women with LS should regularly be surveyed with the aim of early detection. Historically, LS has been identified through analysis of family histories that met Amsterdam II clinical criteria. Unfortunately, due to the low sensitivity, multiple organizations now recommend universal tumor testing with immunohistochemistry (IHC) for MMR protein expression or microsatellite instability (MSI) testing at the time of diagnosis of EC and/or OC. Barriers Exist on Multiple Levels However, there are many patients with LS who remain undiagnosed due to several levels of obstacles. First, the patient's clinician needs to consider the possibility of LS. Second, even when the clinicians have recognized the need for genetic testing, being able to convey the importance of that to patients and make it easier for them to seek genetic evaluation remains a challenge. Third, many clinical sites don't have access to testing tumors for deficient MMR (MMRd). Fortunately, new models for accessing genetic services exist so patients no longer must travel to a genetic specialty clinic. Additionally, many more insurances are covering genetic testing and the cost of testing has also lessened. Still, building the awareness, developing the systems, and providing the education to both health care practitioners and patients are critically warranted. Germline Screening in Endometrial Cancer In a recent study led by Barrington and colleagues, researchers in Ohio aimed to explore various testing strategies as part of a statewide LS screening initiative for ES with a targeted enrollment of 700 subjects (Gynecol Oncol 2020; https://doi.org/10.1016/j.ygyno.2020.05.432). Methodology included tumor IHC for MMR proteins (MLH1, PMS2, MSH6, MSH2), along with research-based tumor only next-generation sequencing. In the multi-institutional initiative, germline hereditary cancer panel gene testing has been performed in 295 subjects enrolled at three participating centers to date. The interim analysis in this EC cohort identified MMR gene mutations in nine patients, with a LS rate of 3.1 percent: five in PMS2, two in MSH2, one in MSH6, and one in MLH1. All LS tumors were endometrioid histology. In 29.8 percent of patients, IHC abnormalities were observed—none of which were serous cancers. Collective IHC and methylation testing forecasted 20 cases with MMR mutations, only seven of which proved to have LS. Importantly, eight of nine LS patients were not previously aware they had LS or of their families' elevated hereditary cancer risk. The researchers note that, while upfront germline testing offers a streamlined method to LS screening, it does not detect somatic/epigenetic MMR defects that may have clinical implications. They conclude that “tumor sequencing may provide the most comprehensive information, as it identifies both inherited and tumor-specific MMR abnormalities.” Screening Strategies for Ovarian Cancer The optimal screening strategy for identifying LS in women with OC has not been determined. Consequently, in a separate study presented at the 2020 Society of Gynecologic Oncology annual meeting, Kim and colleagues compared the performance characteristics of various strategies combining MMR IHC, MSI, and family history to determine the best strategy to identify LS in this population. Women with nonserous and/or nonmucinous OC (n=212) were prospectively recruited from three cancer centers in Ontario, Canada. Tumors were reflexively assessed for MMR deficiency (MMRd) by IHC and MSI. All underwent germline testing for LS and completed a family history assessment. The sensitivity, specificity, and positive and negative predictive values (PPV and NPV) were compared with the gold standard of a germline result. Complete germline data were available for 153 (72%). The findings revealed that 12 women (7.8%, n=153) had pathogenic germline variants: three MLH1, seven MSH6, one MSH2, and one PMS2. Sequential IHC (with MLH1 promoter methylation analysis) followed by MSI was found to be the best screening strategy with sensitivity of 91.7 percent, specificity of 89.4 percent, PPV of 42.3 percent, and NPV of 99.2 percent. With a sensitivity of 80 percent, MSI had the lowest performance characteristics. The authors noted that while the rate of MMRd in nonserous/nonmucinous OC was lower than expected, the mutation rate is significant. Consequently, the researchers advocated that “strong consideration should be given to making reflex tumor testing the standard of care for all patients who are newly diagnosed with nonserous and/or nonmucinous OC, with all MMRd and/or nonmethylated patients undergoing confirmatory testing for LS.” Utilizing a Genetics Navigator Although reflex IHC for MMR proteins to identify LS is strongly recommended, uptake of genetic counselling by those who meet referral criteria is low. In a related study, the Canadian researchers aimed to use a multipronged approach including a genetics navigator to increase uptake of genetic testing for LS in EC and nonserous/mucinous OC patients (Gynecol Oncol 2020; https://doi.org/10.1016/j.ygyno.2020.06.064). Women with newly diagnosed EC or OC were prospectively recruited from three cancer centers in Ontario, Canada. Family history questionnaires were utilized to evaluate LS-specific family history. Reflex IHC for MMR proteins was carried out. A genetics navigator started a genetic counseling referral on behalf of the treating clinician and facilitated genetic referrals to the nearest genetic counseling center. In total, 838 (643 EC, 167 OC, and 28 synchronous EC/OC) patients agreed to the study. Overall, 162 (19%) women were eligible for genetic assessment for LS: 36 based on family history alone, 78 based on IHC alone, 22 based on family history and IHC, and 26 based on clinical discretion. A total of 97 were offered and completed genetic testing. Thirty women (3.6% total cohort; 30.9% of those with genetic testing) were diagnosed with LS: five MLH1, nine MSH2, 13 MSH6, and three PMS2. These findings demonstrate that introduction of a genetic navigator into the genetics referral process resulted in a high rate of genetic counseling (>90%) in gynecologic cancer patients at risk for LS. While the MMRd was lowest in nonserous/mucinous OC, the rate of LS in women with OC was high compared to EC (33.3% OC, 12% EC, 36.4% EC/OC), warranting reflex MMR IHC for this population. Conclusion These studies demonstrate that many patients who develop LS cancers could be identified if we broaden our search for these germline mutations. In addition, identifying first-degree relatives through cascade testing offers an opportunity for cancer prevention through cancer screening and risk-reduction strategies. Thus, the potential for personalized prevention and individualized treatment is great in these populations. Dibash Kumar Das is a contributing writer.

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