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Background We sought to determine the prevalence of germline pathogenic variants (gPVs) in unselected patients with endometrial cancer (EC), define biallelic gPVs within tumors, and describe their associations with clinicopathologic features. Methods Germline assessment of at least 76 cancer predisposition genes was performed in patients with EC undergoing clinical tumor-normal Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) sequencing from January 1, 2015, to June 30, 2021. In patients with gPVs, biallelic alterations in ECs were identified through analysis of loss of heterozygosity and somatic PVs. Clinicopathologic variables were compared using nonparametric tests. Results Of 1625 patients with EC, 216 (13%) had gPVs, and 15 patients had 2 gPVs. There were 231 gPVs in 35 genes (75 [32%] high penetrance; 39 [17%] moderate penetrance; and 117 [51%] low, recessive, or uncertain penetrance). Compared with those without gPVs, patients with gPVs were younger (P = .002), more often White (P = .009), and less obese (P = .025) and had differences in distribution of tumor histology (P = .017) and molecular subtype (P Conclusions Of unselected patients with EC, 13% had gPVs, with 63% of gPVs in high-penetrance genes (MMR and homologous recombination) exhibiting biallelic inactivation, potentially driving cancer development. This supports germline assessment in EC given implications for treatment and cancer prevention.

Supplementary Data from MAPK Pathway Genetic Alterations Are Associated with Prolonged Overall Survival in Low-Grade Serous Ovarian Carcinoma

Purpose:To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC).Experimental Design:Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected.Results:Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation.Conclusions:This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC.See related commentary by Veneziani and Oza, p. 4357

Purpose: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSC). Experimental Design: Patients with LGSC tumors who underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations; copy-number alterations; and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected. Results: Following central pathology rereview, 119 patients with LGSC were identified for analysis. Of these, 110 (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; MAPK pathway alterations were found in 60% (n = 71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis more than 50 years (P = 0.02) and platinum-sensitive disease (P = 0.03). On multivariate analysis, MAPK pathway alterations (P = 0.02) and platinum sensitivity (P = 0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; seven pathogenic germline mutations were identified: MUTYH (n = 2), BAP1 (n = 1), RB1 (n = 1), CHEK2 (n = 1), APC (n = 1), and FANCA (n = 1). There were no germline BRCA1/2 mutations. One germline MUTYH-associated LGSC harbored loss-of-heterozygosity at the MUTYH locus, and the patient with the germline BAP1 mutation also harbored a somatic BAP1 frameshift mutation. Conclusions: This study showed that MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC. See related commentary by Veneziani and Oza, p. 4357

ObjectiveWe sought to describe clinicopathologic and treatment factors associated with oncologic outcomes in patients with early-stage ovarian clear cell carcinoma undergoing complete staging and in a sub-set of these patients undergoing fertility-conserving surgery.MethodsWe retrospectively identified patients with ovarian clear cell carcinoma initially treated at our institution from January 1, 1996 to March 31, 2020. Survival was estimated using Kaplan–Meier curves and compared by log-rank test. Survival-associated variables were identified by Cox proportional hazards regression.ResultsOf 182 patients, mismatch repair and p53 protein expression were assessed by immunohistochemistry on 82 and 66 samples, respectively. There were no significant differences in progression-free survival or overall survival between mismatch repair-deficient (n=6, including 4 patients with Lynch syndrome; 7.3%) and mismatch repair-proficient patients, whereas aberrant p53 expression (n=3; 4.5%) was associated with worse progression-free (pConclusionsIn patients with completely staged ovarian clear cell carcinoma, those with stage IA/IC1 disease have an excellent prognosis, regardless of chemotherapy. Aberrant p53 expression may portend worse outcomes. Additional investigation is warranted on the safety of fertility conservation in patients with stage IA/IC1 disease.

Perinatal epidemiology studies using healthcare utilization databases are often restricted to live births, largely due to the lack of established algorithms to identify non-live births. The study objective was to develop and validate claims-based algorithms for the ascertainment of non-live births.Using the Mass General Brigham Research Patient Data Registry 2000-2014, we assembled a cohort of women enrolled in Medicaid with a non-live birth. Based on ≥1 inpatient or ≥2 outpatient diagnosis/procedure codes, we identified and randomly sampled 100 potential stillbirth, spontaneous abortion, and termination cases each. For the secondary definitions, we excluded cases with codes for other pregnancy outcomes within ±5 days of the outcome of interest and relaxed the definitions for spontaneous abortion and termination by allowing cases with one outpatient diagnosis only. Cases were adjudicated based on medical chart review. We estimated the positive predictive value (PPV) for each outcome.The PPV was 71.0% (95% CI, 61.1-79.6) for stillbirth; 79.0% (69.7-86.5) for spontaneous abortion, and 93.0% (86.1-97.1) for termination. When excluding cases with adjacent codes for other pregnancy outcomes and further relaxing the definition, the PPV increased to 80.6% (69.5-88.9) for stillbirth, 86.6% (80.5-91.3) for spontaneous abortion and 94.9% (91.1-97.4) for termination. The PPV for the composite outcome using the relaxed definition was 94.4% (92.3-96.1).Our findings suggest non-live birth outcomes can be identified in a valid manner in epidemiological studies based on healthcare utilization databases.

5592 Background: Immune checkpoint inhibitors (ICI) targeting PD-1 have meaningful activity in microsatellite instability high (MSI-H), hypermutated or mismatch repair deficient (dMMR) advanced endometrial cancer (EC). We investigated if high-depth circulating cell free (cf)DNA sequencing can be used to assess MSI status and monitor ICI response in EC patients enrolled in a phase II trial (NCT03241745). Methods: Patients with recurrent/persistent MSI-H/dMMR/hypermutated EC with measurable disease and ≥1 prior lines of cytotoxic therapy were treated from 06/2018-01/2022 with nivolumab until progression of disease (PD) or unacceptable toxicity. Radiologic tumor response was assessed every 12 wks by RECIST 1.1 criteria.Pre-treatment ECs and matched normal blood-derived DNA were subjected to whole-exome sequencing (WES); cfDNA from plasma at baseline, 2 wks and every 6 wks thereafter was subjected to high-depth MSK-ACCESS sequencing (129 genes). MSI in WES and cfDNA was calculated by MSIsensor and ADMIE, respectively. Results: Ten patients with ≥10 ng cfDNA at baseline and 2 weeks after nivolumab initiation were included. Most (80%) had grade 3 endometrioid EC; 70% had MLH1 hypermethylated EC. Two patients had partial response (PR), 3 had stable disease (SD) and 5 had PD on nivolumab. A high-depth sequencing assay captured somatic mutations in cfDNA at baseline in all patients (median, 29.5; range, 2-75). Median circulating tumor (ct)DNA fraction in cfDNA was 13.1% at baseline (range, 0.0-86.0%). In 8 cases, ctDNA fraction was sufficient to perform MSI assessment. Liquid biopsy MSI status matched tumor MSI status assessed by WES: in 7 patients with MSI-H disease by tumor WES, cfDNA MSI status was also MSI-H ( > 0; range, 0.21-5.46); in 1 patient with MSI-low but hypermutated tumor, cfDNA MSI was 0.0. In all cases, changes in ctDNA fractions reflected ICI response. Median ctDNA fraction percent change from week 0 to week 8 was -51.6% (IQR, -6.2, -85.1) in patients with PR and SD vs +17.7% (IQR, -6.6, +356.6) in patients with PD (p = 0.08). In patients with PR, ctDNA fraction decreased at week 2 and stayed low at week 8 and weeks 32-55 of nivolumab in concordance with ongoing response. In 3 patients with SD, ctDNA fractions decreased by week 2. In 1 patient with SD at week 8 and PD at week 22, ctDNA fraction increased from week 8 to week 20. In 5 patients with PD, 4 had increased ctDNA fraction by week 8. The last patient had a stable ctDNA fraction but increasing allele frequency of 2 truncating B2M alterations, possibly associated with ICI resistance. Conclusions: In patients with advanced hypermutated ECs, cfDNA sequencing can be used to accurately detect MSI status. Early changes in ctDNA fraction may be associated with durable response to ICI or may anticipate radiological progression. Future studies may use ctDNA to assess mechanisms of ICI resistance and offer opportunities for adaptive therapy intervention. Clinical trial information: NCT03241745.