FJ Candido-dos-Reis, H Song, EL Goode, JM Cunningham, BL Fridley, MC Larson, K Alsop, E Dicks, P Harrington, SJ Ramus, A de Fazio, G Mitchell, S Fereday, KL Bolton, C Gourley, C Michie, B Karlan, J Lester, C Walsh, I Cass, H Olsson, M Gore, JJ Benitez, MJ Garcia, I Andrulis, AM Mulligan, G Glendon, I Blanco, C Lazaro, AS Whittemore, V McGuire, W Sieh, M Montagna, E Alducci, S Sadetzki, A Chetrit, A Kwong, SK Kjaer, A Jensen, E Høgdall, S Neuhausen, R Nussbaum, M Daly, MH Greene, PL Mai, JT Loud, K Moysich, AE Toland, D Lambrechts, S Ellis, D Frost, JD Brenton, M Tischkowitz, DF Easton, A Antoniou, G Chenevix-Trench, SA Gayther, D Bowtell, PDP Pharoah, for EMBRACE, kConFab Investigators, Australian Ovarian Cancer Study Group
Clin Cancer Res
PURPOSE: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. EXPERIMENTAL DESIGN: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. RESULTS: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%-31%] for non-carriers, 25% (95% CI, 22%-28%) for BRCA1 carriers, and 35% (95% CI, 30%-41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer-specific mortality. CONCLUSIONS: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers.