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

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.

Figure 1. Mutual exclusivity of BRCA1 and BRCA2 mutations

The subset of samples with BRCA1/2 loss-of-function mutations (n=114) and with only VUS (n=13) are plotted by patient (column) and by gene and origin of gene mutation (row) as germline (gBRCA), somatic (sBRCA), or of unknown origin (uBRCA). Mutations are color coded by type (purple for frameshift or nonsense truncating, orange for splice site, green for clinically important missense, dark blue for homozygous deletions, light blue for insertions/rearrangements, gray for VUS) and zygosity (■ for homozygous, ◨ for heterozygous, □ for not in tumor, - for unknown, c for subclonal somatic). Note that while BRCA1/2 loss-of-function mutations (purple, orange, green, dark blue, light blue) are mutually exclusive, VUS (gray) can occur concomitantly with BRCA1/2 loss-of-function mutations. Not all VUS are represented because of co-occurrence with loss-of-function mutations or VUS in the same gene; a complete listing is found in Supplemental Table 1.

Figure 2. Progression-free survival of BRCA1/2 somatic- versus germline-mutated patients

Time for somatic-mutated (sBRCAm) and germline-mutated (gBRCAm) patients treated with olaparib (blue line) or placebo (black line) is plotted against the proportion of patients event-free.