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.

Source

Kathryn Alsop, David Bowtell, Alexander Dobrovic, Sian Fereday, Stephen Fox, Joshy George, Cliff Meldrum, Gillian Mitchell, The Peter MacCallum Cancer Centre, East Melbourne; Anna DeFazio, Catherine Emmanuel, Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute and Westmead Hospital, Sydney; Kathryn Alsop, David Bowtell, Alexander Dobrovic, Stephen Fox, Joshy George, Gillian Mitchell, University of Melbourne, Parkville; Penelope M. Webb, Queensland Institute of Medical Research, Brisbane; Colin Stewart, King Edward Memorial Hospital, Perth; Michael Friedlander, Prince of Wales Hospital, Randwick, Australia; Michael J. Birrer, Massachusetts General Hospital, Boston, MA.

Abstract

PURPOSEThe frequency of BRCA1 and BRCA2 germ-line mutations in women with ovarian cancer is unclear; reports vary from 3% to 27%. The impact of germ-line mutation on response requires further investigation to understand its impact on treatment planning and clinical trial design. PATIENTS AND METHODSWomen with nonmucinous ovarian carcinoma (n = 1,001) enrolled onto a population-based, case-control study were screened for point mutations and large deletions in both genes. Survival outcomes and responses to multiple lines of chemotherapy were assessed.ResultsGerm-line mutations were found in 14.1% of patients overall, including 16.6% of serous cancer patients (high-grade serous, 22.6%); 44% had no reported family history of breast or ovarian cancer. Patients carrying germ-line mutations had improved rates of progression-free and overall survival. In the relapse setting, patients carrying mutations more frequently responded to both platin- and nonplatin-based regimens than mutation-negative patients, even in patients with early relapse after primary treatment. Mutation-negative patients who responded to multiple cycles of platin-based treatment were more likely to carry somatic BRCA1/2 mutations. CONCLUSIONBRCA mutation status has a major influence on survival in ovarian cancer patients and should be an additional stratification factor in clinical trials. Treatment outcomes in BRCA1/2 carriers challenge conventional definitions of platin resistance, and mutation status may be able to contribute to decision making and systemic therapy selection in the relapse setting. Our data, together with the advent of poly(ADP-ribose) polymerase inhibitor trials, supports the recommendation that germ-line BRCA1/2 testing should be offered to all women diagnosed with nonmucinous, ovarian carcinoma, regardless of family history.

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