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Oncotarget. 2017 Jul 4;8(27):43653-43661. doi: 10.18632/oncotarget.17613.

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.

Author information

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.

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.

KEYWORDS:

BRCA; germline; olaparib; ovarian; somatic

PMID:
28525389
PMCID:
PMC5546431
DOI:
10.18632/oncotarget.17613
[Indexed for MEDLINE]
Free PMC Article

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