Clinical characteristics and survival outcomes in BRCA1-methylated epithelial ovarian cancer (Bmeth-OC): A pooled analysis of data for 1,278 patients across five studies

Background: BRCA1/2 mutations render ovarian cancers (OC) homologous recombination deficient (HRD) and thus sensitive to platinum and PARP inhibitors. Data on BRCA1 promoter methylation in OC, another potential biomarker of HRD, are conflicting and limited. Methods: We searched PubMed and ASCO/ESMO abstracts for studies with survival outcomes in Bmeth-OC. Individual patient data were obtained from 5 studies. Associations between clinical characteristics and Bmeth-OC were determined using the Cochran-Mantel-Haenszel test. Progression-free (PFS) and overall survival (OS) differences between Bmeth-OC and non-Bmeth-OC (and between Bmeth-OC, BRCA1/2-mutated OC and BRCA1/2-wild type non-Bmeth-OC where data available) were estimated with Kaplan-Meier analysis, adjusting for cohort. Results: We obtained data for 164 patients (pts) with Bmeth-OC and 1114 pts with non-Bmeth-OC (Bmeth-OC frequency = 12.8%). Median age was 59 (range 26-93) and median follow-up was 31 months (range 0-203). 72.7% of OCs were high grade serous. 91.3% of pts received adjuvant platinum-based chemotherapy. Bmeth-OC was associated with high grade (85.4% vs 80.7% of non-BmethOC, p = 0.016) and younger age ( < 59: 58.5% vs 47.1% of non-BmethOC, p = 0.012), but not stage, histology, cytoreduction or platinum sensitivity. There was no difference in median PFS (18.7 vs 19.1 months, p = 0.42) or OS (44.3 vs 46 months, p = 0.62) between Bmeth-OC and non-Bmeth-OC. BRCA1/2 mutation status was assessed in 3 cohorts (639 pts). BRCA2-mutated OC had a better median PFS and OS compared to BRCA1-mutated OC, Bmeth-OC, and BRCA1/2-wild type non-Bmeth-OC (PFS: 26 vs 17.6, 15.6, 15.8 months, p = 0.025; OS: 74.3 vs 49.3, 41.9, 44mths, p = 0.003).On multivariate Cox analysis including clinical variables, BRCA2 mutation but not BRCA1 mutation/methylation had a significant effect on OS/PFS (p = 0.001, HR = 0.44 95%CI [0.27-0.70]/p = 0.001, HR = 0.5 95%CI [0.33-0.77]). Conclusions: BRCA1 methylation occurs in OC in younger pts, but has no impact on survival. BRCA2 mutation, in contrast to BRCA1 mutation/methylation, is an independent prognostic factor for improved survival in OC.