Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer
Bryan T J Hennessy, Kirsten M Timms, Mark S Carey, Alexander Gutin, Larissa A Meyer, Darl D Flake 2nd, Victor Abkevich, Jennifer Potter, Dmitry Pruss, Pat Glenn, Yang Li, Jie Li, Ana Maria Gonzalez-Angulo, Karen Smith McCune, Maurie Markman, Russell R Broaddus, Jerry S Lanchbury, Karen H Lu, Gordon B Mills, Bryan T J Hennessy, Kirsten M Timms, Mark S Carey, Alexander Gutin, Larissa A Meyer, Darl D Flake 2nd, Victor Abkevich, Jennifer Potter, Dmitry Pruss, Pat Glenn, Yang Li, Jie Li, Ana Maria Gonzalez-Angulo, Karen Smith McCune, Maurie Markman, Russell R Broaddus, Jerry S Lanchbury, Karen H Lu, Gordon B Mills
Abstract
Purpose: The prevalence of BRCA(1/2) mutations in germline DNA from unselected ovarian cancer patients is 11% to 15.3%. It is important to determine the frequency of somatic BRCA(1/2) changes, given the sensitivity of BRCA-mutated cancers to poly (ADP ribose) polymerase-1 (PARP1) inhibitors and platinum analogs.
Patients and methods: In 235 unselected ovarian cancers, BRCA(1/2) was sequenced in 235, assessed by copy number analysis in 95, and tiling arrays in 65. 113 tumors were sequenced for TP53. BRCA(1/2) transcript levels were assessed by quantitative polymerase chain reaction in 220. When available for tumors with BRCA(1/2) mutations, germline DNA was sequenced.
Results: Forty-four mutations (19%) in BRCA1 (n = 31)/BRCA2 (n = 13) were detected, including one homozygous BRCA1 intragenic deletion. BRCA(1/2) mutations were particularly common (23%) in high-grade serous cancers. In 28 patients with available germline DNA, nine (42.9%) of 21 and two (28.6%) of seven BRCA1 and BRCA2 mutations were demonstrated to be somatic, respectively. Five mutations not previously identified in germline DNA were more commonly somatic than germline (four of 11 v one of 17; P = .062). There was a positive association between BRCA1 and TP53 mutations (P = .012). BRCA(1/2) mutations were associated with improved progression-free survival (PFS) after platinum-based chemotherapy in univariate (P = .032; hazard ratio [HR] = 0.65; 95% CI, 0.43 to 0.98) and multivariate (P = .019) analyses. BRCA(1/2) deficiency, defined as BRCA(1/2) mutations or expression loss (in 24 [13.3%] BRCA(1/2)-wild-type cancers), was present in 67 ovarian cancers (30%) and was also significantly associated with PFS in univariate (P = .026; HR = 0.67; 95% CI, 0.47 to 0.96) and multivariate (P = .008) analyses.
Conclusion: BRCA(1/2) somatic and germline mutations and expression loss are sufficiently common in ovarian cancer to warrant assessment for prediction of benefit in clinical trials of PARP1 inhibitors.
Conflict of interest statement
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Source: PubMed