Biological and clinical evidence for somatic mutations in BRCA1 and BRCA2 as predictive markers for olaparib response in high-grade serous ovarian cancers in the maintenance setting

// Brian A. Dougherty 1 , Zhongwu Lai 1 , Darren R. Hodgson 2 , Maria C.M. Orr 3 , Matthew Hawryluk 4 , James Sun 4 , Roman Yelensky 4 , Stuart K. Spencer 5 , Jane D. Robertson 5 , Tony W. Ho 6 , Anitra Fielding 7 , Jonathan A. Ledermann 8 and J. Carl Barrett 1 1 Innovative Medicines and Early Development, Oncology, AstraZeneca, Waltham, MA, USA 2 Innovative Medicines and Early Development, Oncology, AstraZeneca, Cambridge, UK 3 Personalized Healthcare and Biomarkers, AstraZeneca, Cambridge, UK 4 Foundation Medicine, Inc., Cambridge, MA, USA 5 Oncology Global Medicines Development, AstraZeneca, Cambridge, UK 6 Oncology Global Medicines Development, AstraZeneca, Gaithersburg, MD, USA 7 Oncology Global Medicines Development, AstraZeneca, Macclesfield, UK 8 UCL Cancer Institute, London, UK Correspondence to: Brian A. Dougherty, email: // Keywords : BRCA, somatic, germline, olaparib, ovarian Received : March 01, 2017 Accepted : April 26, 2017 Published : May 04, 2017 Abstract To gain a better understanding of the role of somatic mutations in olaparib response, next-generation sequencing (NGS) of BRCA1 and BRCA2 was performed as part of a planned retrospective analysis of tumors from a randomized, double-blind, Phase II trial (Study 19; D0810C00019; NCT00753545) in 265 patients with platinum-sensitive high-grade serous ovarian cancer. BRCA1/2 loss-of-function mutations were found in 55% (114/209) of tumors, were mutually exclusive, and demonstrated high concordance with Sanger-sequenced germline mutations in matched blood samples, confirming the accuracy (97%) of tumor BRCA1/2 NGS testing. Additionally, NGS identified somatic mutations absent from germline testing in 10% (20/209) of the patients. Somatic mutations had >80% biallelic inactivation frequency and were predominantly clonal, suggesting that BRCA1/2 loss occurs early in the development of these cancers. Clinical outcomes between placebo- and olaparib-treated patients with somatic BRCA1/2 mutations were similar to those with germline BRCA1/2 mutations, indicating that patients with somatic BRCA1/2 mutations benefit from treatment with olaparib.