Germline and somatic mutations in homologous recombination genes predict platinum response and survival in ovarian, fallopian tube, and peritoneal carcinomas

Abstract

Purpose: Hallmarks of germline BRCA1/2-associated ovarian carcinomas include chemosensitivity and improved survival. The therapeutic impact of somatic BRCA1/2 mutations and mutations in other homologous recombination DNA repair genes is uncertain.

Experimental design: Using targeted capture and massively parallel genomic sequencing, we assessed 390 ovarian carcinomas for germline and somatic loss-of-function mutations in 30 genes, including BRCA1, BRCA2, and 11 other genes in the homologous recombination pathway.

Results: Thirty-one percent of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 homologous recombination genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Nonserous ovarian carcinomas had similar rates of homologous recombination mutations to serous carcinomas (28% vs. 31%, P = 0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic homologous recombination mutations was highly predictive of primary platinum sensitivity (P = 0.0002) and improved overall survival (P = 0.0006), with a median overall survival of 66 months in germline homologous recombination mutation carriers, 59 months in cases with a somatic homologous recombination mutation, and 41 months for cases without a homologous recombination mutation.

Conclusions: Germline or somatic mutations in homologous recombination genes are present in almost one third of ovarian carcinomas, including both serous and nonserous histologies. Somatic BRCA1/2 mutations and mutations in other homologous recombination genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of homologous recombination mutations in nonserous carcinomas supports their inclusion in PARP inhibitor clinical trials.

Figure 1

Mutation rates in HR genes. A, Overall, 115 of 367 subjects (31.3%) had deleterious mutations in 13 HR genes: 83 (22.6%) with germline HR mutations, 28 (7.6%) with somatic HR mutations, and 4 (1.1%) with both germline and somatic HR mutations. Mutations were detected in every HR gene tested. B, Eighty-seven subjects (24%) had 88 germline mutations in 11 HR genes. Germline HR mutations included 49 (13.4%) in BRCA1, 17 (4.6%) in BRCA2, and 22 (6%) in other HR genes, including BARD1, BRIP1, CHEK1, CHEK2, FAM175A, NBN, PALB2, RAD51C, and RAD51D. C, Thirty-two carcinomas (8.7%) had a total of 35 somatic mutations in 7 HR genes. Somatic HR mutations included 19 (5.2%) in BRCA1, 6 (1.6%) in BRCA2, and 10 (2.7%) in other HR genes, including ATM, BRIP1, CHEK2, MRE11A, and RAD51C.

Figure 2

HR gene mutation rates by histology. A, HR gene mutations were identified at similar frequencies in non-serous and serous carcinomas. Seventeen of 61 (28%) non-serous cases and 80 of 258 (31%) serous cases had a deleterious germline or somatic HR mutation (p=0.63). HR gene mutations were identified in almost every type of non-serous histology tested, including 5/19 (26%) clear cell, 7/26 (27%) endometrioid, 4/12 (33%) carcinosarcoma, and 1/1 (100%) malignant Brenner’s carcinoma. No mutations were identified in the one mucinous or two mixed histology carcinomas. B, Whereas serous carcinomas had a predominance of mutations in BRCA1 and BRCA2, the non-serous carcinomas had a much wider distribution of mutations in other HR genes. In non-serous carcinomas with HR mutations, 56% of mutations were in other HR genes, compared to only 21% of mutations in serous carcinomas (p=0.005).

Figure 3

Germline HR mutations and somatic HR mutations were each predictive of platinum sensitivity compared to cases without HR mutations: 49 of 61 (80%) cases with a germline mutation (p=0.008), and 22 of 24 (92%) carcinomas with a somatic mutation (p=0.003) were platinum sensitive (p=0.003). In contrast, only 95 of 158 (60%) carcinomas without an identified HR mutation had primary platinum sensitivity.

Figure 4

Overall survival by genetic status. A, The presence of an HR gene mutation was associated with an improved overall survival compared to cases without HR mutations (median overall survival 66 vs. 41 months, p=0.006, hazard ratio (HR) 0.6, 95% confidence interval (CI) 0.4 to 0.8). HR gene mutations were significantly related to overall survival after accounting for the covariates age, stage, and optimal cytoreduction (p=0.006). B, Overall survival in subjects with germline HR mutations was significantly better than subjects without HR mutations (median 66 months vs. 41 months, p=0.001). Overall survival in cases with somatic mutations (median 59 months) was similar to germline mutation carriers, but these differences did not reach statistical significance when compared to cases without HR mutations (p=0.09). C, Subjects with germline BRCA1/2 mutations had improved overall survival compared to subjects without HR mutations (median 70 months vs. 41 months, p=0.001, HR 0.5, 95% CI 0.4 to 0.8). Subjects with a germline mutation in HR genes other than BRCA1/2 or any HR somatic mutation (including BRCA1/2 mutations) also had improved survival (median 59 months, p=0.05, HR 0.7, 95% CI 0.5 to 1.0). D, Median overall survival in subjects with PTEN mutations was 25.5 months, significantly shorter than for cases with no HR or PTEN mutations (median 42 months, p=0.007, HR= 2.2, 95% CI 1.4 to 7.4), and cases with somatic HR mutations (median 59 months).