Germline mutation in BRCA1 or BRCA2 and ten-year survival for women diagnosed with epithelial ovarian cancer

The authors thank Craig Luccarini, the staff at the Eastern Cancer Registration and Information Centre (SEARCH); Alicia Barroso, Victoria Fernandez, Miguel Urioste; Spanish Network on Rare Diseases (CIBERER); Heather Thorne, Eveline Niedermayr, all the kConFab research nurses and staff, the heads and staff of the Family Cancer Clinics, the Clinical Follow-Up Study Members, and the kConFab Investigators (Peter MacCallum Cancer Center, East Melbourne, Australia: Stephen Fox, MD; Ian Campbell, PhD; Melissa Brown, PhD; Gerda Evans; Judy Kirk: Westmead Hospital, MD, PhD; Sunil Lakhani, MD; Geoff Lindeman, MD, PhD; Gillian Mitchell, MD, PhD; Kelly Phillips, MD; Melanie Price, PhD; Christobel Saunders, MD; Mandy Spurdle, PhD; Graeme Suthers, MD, PhD; Roger Milne, PhD) (kConFab/AOCS); Nayana Weerasooriya, Teresa Selander. A full list of principal investigators and participating centers for EMBRACE has been published (Hum Mol Genet 2010;19:2886-97). 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 Experimental Design: We used unpublished survival time data for 2,242 patients from two case-control studies and extended survival time data for 4,314 patients from previously reported studies.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.