High prevalence of actionable germline variants in unselected endometrial cancer (EC) patients.

5577 Background: The use of upfront germline genetic testing for cancer patients to identify hereditary syndromes and to aid in treatment decision making has increased dramatically. Recent evidence suggests that such testing should be considered for all solid tumors. In EC, mismatch repair deficiency (MMRd) has emerged as an important molecular marker for treatment with checkpoint inhibitors. MMRd is the hallmark of Lynch syndrome (LS), the most common hereditary cause of EC. Therefore, identifying LS not only affords opportunities for cancer prevention but also for making treatment decisions for women who already have EC. Although tumor-based screening is highly effective, some LS diagnoses will be missed. Upfront multi-gene panel testing (MGPT) for EC has been evaluated as an alternative approach to identifying LS with the potential to simultaneously find actionable germline variants in other cancer susceptibility genes (CSGs). Our objective was to determine the frequency and types of actionable germline variants in a large, unselected group of women with EC. Methods: Prospective germline MGPT for 47 CSGs was performed for 961 unselected EC cases. Patients diagnosed from 2017-2020 were enrolled at nine different institutions. Clinicopathologic data were abstracted from patients’ records. Results: 101 likely pathogenic (LP) or pathogenic variants (PV) were identified in 98 women (10.2%). LP/PVs in LS genes were most common: 29 LS cases were identified (3.02%, 95% CI 2.1 - 4.3%). MGPT found 9 cases (one-third of LS cases) that were not identified by tumor screening: 6 were from institutions that do not perform tumor screening and 3 had normal immunohistochemistry. There were 72 LP/PVs found in 17 different CSGs. 21 patients (2.1%) had LP/PVs in high penetrance CSGs other than the LS genes, 19 of which were in genes associated with breast and/or ovarian cancer (4 in BRCA1, 6 in BRCA2, 6 in BRIP1, 2 in PALB2, 1 in RAD51C). BRCA1/2 PVs (1.04% of the study population, 95% CI 0.6 - 1.9%) were significantly more frequent in women with type II cancers than the rest of the cohort (P =.005, HR 2.00, 95% CI 1.16 - 4.75). 21 additional LP/PVs were found in moderate risk CSGs ( ATM, CHEK2, NBN, NF1). Conclusions: Upfront MGPT in an unselected EC population improved LS diagnosis and identified an additional 2% of patients with LP/PVs in highly penetrant CSGs. The enrichment of germline BRCA1/2 PVs in type II cancers is consistent with prior reports that non-endometrioid tumors are frequently deficient in homologous recombination. Germline BRCA mutation is a known predictive biomarker in ovarian cancer and an attractive therapeutic target in EC. Knowing germline status at the time of diagnosis facilitates further delineation of germline/phenotype associations, and it defines a genetic syndrome allowing for cancer prevention. Upfront MGPT in EC provides clinically impactful information and should be adopted into routine clinical care. Clinical trial information: NCT03460483.