Clinicopathologic and molecular predictors of survival in BRCA-deficient tubo-ovarian high-grade serous carcinoma

Abstract BRCA -associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA -deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (g BRCA pv), residual disease after primary surgery has limited prognostic effect in g BRCA pv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA -deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2 -deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA , RAD21 and MYC amplification define BRCA2 -deficient HGSC with exceptionally short survival. Patients with BRCA1 -deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1 -deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.