Posted September 23, 2013
David Bowtell, Ph.D., Kathryn Alsop, Ph.D., and Gillian Mitchell, M.B.B.S., Ph.D., Peter MacCullum Cancer Centre, East Melbourne, Australia
Inherited germline mutation in either the BRCA1 or BRCA2 gene is a well-defined risk factor for ovarian cancer. Germline BRCA1/2 mutations have been thought to be responsible for only about 10% of cases of ovarian cancer; however, this estimate was based on considering ovarian cancer as a single disease - we now know that ovarian cancer is a series of distinct diseases that should be evaluated separately. It was therefore important to characterize the clinical, pathological, family history, and molecular factors that predict whether a woman is carrying a BRCA1 or BRCA2 mutation, and to understand the effect of these mutations on treatment response. Drs. Gillian Mitchell and David Bowtell, recipients of a Department of Defense (DoD) Ovarian Cancer Research Program (OCRP) Fiscal Year 2007 (FY07) Translational Research Partnership Award, evaluated the frequency and impact of germline BRCA1/2 mutations in 1,001 population-based ovarian cancer cases. The research, led by then Ph.D. student Dr. Kathryn Alsop, leveraged existing samples and case information from the FY00 DoD OCRP-funded Australian Ovarian Cancer Study (AOCS). BRCA1/2 mutations were identified in 14% of the 1,001 samples from women with invasive non-mucinous ovarian tumors, similar to that reported previously by Canadian researchers. Importantly, the AOCS researchers found that BRCA1/2 germline mutations were enriched in high-grade serous cancers, where the combined frequency was 17.1%. In women under 50 years of age with high-grade serous ovarian cancer the rate was even higher at 22.2%. In many countries, including Australia, genetic testing guidelines have required that women with ovarian cancer have a significant family history of breast and/or ovarian cancer before they are offered genetic testing. However, almost half of the women carrying BRCA1/2 mutations in the AOCS study lacked a sufficiently strong family history of breast or ovarian cancer to trigger testing. These findings led to a revision in genetic testing guidelines in Australia in July 2013 to include all women under 70 years of age who are diagnosed with non-mucinous invasive ovarian cancer, regardless of family history.
The study also mapped responses of carriers and non-carriers to first line chemotherapy and during relapse, showing especially durable responses in most carriers to platinum-based chemotherapy as compared with other agents, and improved overall survival in carriers. The AOCS study highlighted the importance of persisting with platinum-based treatment in carriers until there is objective evidence of resistance, and recommended that testing be performed early in the disease trajectory so that knowledge of carrier status can be incorporated into treatment planning. The effect of BRCA mutation status on treatment responses and overall survival has significant implications for the interpretation of clinical trials in ovarian cancer and supports a recommendation for all trials to be stratified for BRCA mutation status.
Alsop K, Fereday S, Meldrum C, deFazio A, Emmanuel C, George J, Dobrovic A, Birrer MJ, Webb PM, Stewart C, Friedlander M, Fox S, Bowtell D, and Mitchell G. 2012. BRCA mutation frequency and patterns of treatment response in BRCA mutation-positive women with ovarian cancer: A report from the Australian Ovarian Cancer Study Group. Journal of Clinical Oncology 30(21):2654-2663.
Press release for updated genetic testing guidelines: