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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 _, Zhongwu Lai, Darren R. Hodgson, Maria C.M. Orr, Matthew Hawryluk, James Sun, Roman Yelensky, Stuart K. Spencer, Jane D. Robertson, Tony W. Ho, Anitra Fielding, Jonathan A. Ledermann and J. Carl Barrett

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Oncotarget. 2017; 8:43653-43661. https://doi.org/10.18632/oncotarget.17613

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Abstract

Brian A. Dougherty1, Zhongwu Lai1, Darren R. Hodgson2, Maria C.M. Orr3, Matthew Hawryluk4, James Sun4, Roman Yelensky4, Stuart K. Spencer5, Jane D. Robertson5, Tony W. Ho6, Anitra Fielding7, Jonathan A. Ledermann8 and J. Carl Barrett1

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.


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