Risk-reducing gynecologic surgery in non-BRCA cancer predisposition mutations: a multi-institutional study.

Prophylactic gynecologic surgery is increasingly performed for non-BRCA germline mutations despite limited evidence regarding pathologic findings and long-term outcomes. This study compares histopathologic findings at prophylactic surgery (serous tubal intra-epithelial carcinoma and/or high-grade serous carcinoma) and longitudinal oncologic outcomes between the largest reported cohort of low- and moderate-risk non-BRCA mutation carriers and a cohort of high-risk BRCA1/2 mutation carriers. This multi-institutional, institutional review board-approved retrospective study included patients with pathogenic germline variants in low- to moderate-risk genes (PALB2, RAD51C, RAD51D, BRIP1, CHEK2, BARD1, and ATM) or in BRCA1/2 who underwent risk-reducing salpingectomy or salpingo-oophorectomy, with or without hysterectomy, at three academic centers from 2013 to 2022; all specimens were processed using the Sectioning and Extensively Examining the FIMbriated End protocol. The primary end points were high-grade serous carcinoma and serous tubal intra-epithelial carcinoma at surgery. Age-adjusted Firth's penalized logistic regression was performed using R version 4.5.3, while time-to-event analyses were precluded by the absence of incident high-grade serous carcinoma during follow-up. The study included 207 patients undergoing prophylactic surgery for low- or moderate-risk mutations: PALB2 (42%), BRIP1 (31%), RAD51D (9%), RAD51C (8%), ATM (7%), and CHEK2 (3%). Three serous borderline tumors (1%) were identified, with the remainder (97%) being benign. Median follow-up was 17 months (range 0 to 115 months), at which time all patients had no evidence of disease. The BRCA1/2 cohort (n =388) showed pathologic findings in 18 of 388 (5%), including isolated serous tubal intra-epithelial carcinoma (0.7%) and high-grade serous carcinoma (2%). Median follow-up was 45 months (range 0 to 242 months). In total, 374 of 388 patients (96%) were alive without evidence of primary or recurrent/metastatic disease, and 1 of 388 (0.2%) was alive with disease. BRCA1/2 mutations were associated with increased odds of incidental high-grade serous carcinoma at the time of prophylactic surgery (odds ratio 9.42, 95% confidence interval 1.08 to 1222, p = .04) and higher odds of tubal intra-epithelial carcinoma (odds ratio 5.15, 95% confidence interval 0.53 to 689, p = .18). Occult high-grade serous carcinoma and serous tubal intra-epithelial carcinoma were absent among low- and moderate-risk non-BRCAmutation carriers, contrasting with the higher prevalence observed in BRCA1/2 carriers. These data support a more individualized, gene-specific approach to risk-reducing gynecologic surgery rather than extrapolation of BRCA-based management strategies to all hereditary cancer predisposition syndromes.