Germ-line BRCA mutations in high-grade ovarian cancer: A case for routine BRCA mutation screening after a diagnosis of invasive ovarian cancer.

Abstract

5026 Background: It has been accepted that 5-10% of all invasive epithelial ovarian cancer cases can be attributed to hereditary pathogenic mutations in cancer predisposition genes. Consequently genetic testing is mostly offered to those patients who also have a strong family history of relevant cancers or specific ancestry. We investigated the frequency and clinical characteristics, including the treatment response to platinum therapeutics, of germline BRCA1/2 pathogenic mutation carriers in a large population-based prospective cohort of Australian women with ovarian cancer. Methods: Participants were ascertained from the Australian Ovarian Cancer Study which recruited women presenting for surgery for ovarian cancer between 2002-2006. Women were eligible for BRCA1/2 genotyping if diagnosed with invasive epithelial ovarian, peritoneal or fallopian tube tumors. Mucinous histology was excluded from analysis. Full BRCA1 and BRCA2 analysis was done by gene sequencing and multiplex ligation-dependent probe amplification. Germline status was related to tumor features, clinical response and potential familiality in first degree relatives, including incidences of early onset breast cancer. Results: 134 pathogenic germline mutations were identified within the cohort, for an overall mutation frequency of 13.3% in the Australian ovarian cancer population. 113 (84.3%) mutations were associated with serous histology. 57% of mutation carriers had no evidence of familiality. Mutation carriers were more responsive to primary platinum treatment than non-carriers (87.4% had >6 months progression free survival, versus 68.4%), and were more likely to respond to platinum upon relapse (86% of mutation positive women responded to secondary platinum after relapsing <6 months after primary platinum treatment versus 60% of mutation negative women). Conclusions: Pathogenic BRCA1/2 mutations are common in invasive ovarian cancer and are associated with improved overall survival and response to systemic chemotherapy. BRCA testing should be implemented for all ovarian cancer patients as mutation status has important prognostic and therapeutic clinical utility.