Somatic mutations in BRCA1 and BRCA2 could expand the number of patients that benefit from poly (ADP ribose) polymerase inhibitors in ovarian cancer

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.

Fig 1.

The relationship between (A) BRCA1 mutations and BRCA1 gene expression and between (B) BRCA2 mutations and BRCA2 gene expression is shown. The average δC_T of BRCA1 for BRCA1 mutants (3.26, n = 29) is not significantly different from the average δC_T of BRCA1 for BRCA1 nonmutants (3.33, n = 191; P value = 0.68). Likewise, the averages of δC_T of BRCA2 for BRCA2 mutants (2.92, n = 12) and nonmutants (2.90, n = 208) are not significantly different (P = .97).

Fig 2.

Kaplan-Meier curves showing that BRCA1 and BRCA2 mutations together in ovarian cancer tissue were associated with significantly improved progression-free survival (PFS) time after surgery as compared with BRCA1– and BRCA2–wild-type ovarian cancers. Median PFS for BRCA mutants and nonmutants were 20.1 (95% CI, 15.6 to 43.8) and 13.8 (95% CI, 11.9 to 16.3) months, respectively (P = .032). The patient with both a BRCA1 and a BRCA2 mutation was only counted once.

Fig 3.

Kaplan-Meier curves showing that BRCA½ deficiency in ovarian cancer tissue was associated with significantly improved progression-free survival (PFS) time after surgery as compared with other ovarian cancers. Median PFS for cancers with and without BRCA deficiency were 19.3 (95% CI, 15.7 to 31.6) and 13.8 (95% CI, 11.9 to 16.3) months, respectively (P = .026). The patient with both a BRCA1 and a BRCA2 mutation was only counted once.