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 (HR) 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 HR pathway. Results 31% of ovarian carcinomas had a deleterious germline (24%) and/or somatic (9%) mutation in one or more of the 13 HR genes: BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FAM175A, MRE11A, NBN, PALB2, RAD51C, and RAD51D. Non-serous ovarian carcinomas had similar rates of HR mutations to serous carcinomas (28% vs. 31%, p=0.6), including clear cell, endometrioid, and carcinosarcoma. The presence of germline and somatic HR mutations was highly predictive of primary platinum sensitivity (p=0.0002) and improved overall survival (p=0.0006), with median overall survival 66 months in germline HR mutation carriers, 59 months in cases with a somatic HR mutation, and 41 months for cases without an HR mutation. Conclusions Germline or somatic mutations in HR genes are present in almost one-third of ovarian carcinomas, including both serous and non-serous histologies. Somatic BRCA1/2 mutations and mutations in other HR genes have a similar positive impact on overall survival and platinum responsiveness as germline BRCA1/2 mutations. The similar rate of HR mutations in non-serous carcinomas supports their inclusion in PARP inhibitor clinical trials.

Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas

“…3,4,[12][13][14][15][16][17][18][19] Only one PARPi has been FDA approved for the treatment of ovarian cancer, olaparib, and this is only in the setting of BRCA mutation and at least three prior lines of chemotherapy. Our findings further support the work of Pennington et al, 21 suggesting that a broader population of women with ovarian cancer may benefit from PARPi therapy.…”

“…20 In addition, we confirmed the prevalence of mutations in homologous recombination pathway genes across tumor histotypes, ranging from 25 to 45% of cases. 21 However, it is possible that this number is an underestimate of the actual prevalence, owing to the fact that our targeted panel was not entirely inclusive of all genes involved in homologous recombination, 21 as well as the fact that we were conservative by including only loss-of-function mutations or missense mutations that had been reported previously. In addition, although we did not evaluate epigenetic mechanisms of inactivating homologous recombination genes, such as promoter methylation, it has been shown that patients with epigenetically silenced BRCA1 have similar survival to patients with wild-type BRCA1/2.…”

“…In addition, it has recently been shown that platinum sensitivity and improved survival in high-grade serous carcinomas is not just limited to patients with BRCA1/2 mutations but also extends to patients with either germline or somatic mutations in many of the other genes involved in the homologous recombination DNA repair pathway. 21 Several studies have demonstrated specific morphologic features that are associated with BRCA mutations in high-grade serous carcinomas. The following features have been shown to be associated with BRCA1 germline mutations: serous or undifferentiated histology, prominent tumor-infiltrating lymphocytes, marked nuclear atypia with bizarre nuclei, and a high mitotic index.…”

ATM Mutations in Cancer: Therapeutic Implications

“…For example, a mutation of PALB2 has been described to sensitive pancreatic cancer to mitomycin C treatment by disrupting BRCA1 and BRCA2 interactions (4). Similarly, ATM mutations are predicted to result in increased sensitivity to platinum chemotherapy (6,67). However, a recent preclinical study in gynecologic cancer cell lines found that ATM inhibition enhanced the response to ionizing radiation, but did not enhance the in vitro killing of the cells by platinum drugs (68).…”

Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

“…4−6 Half of all high-grade serous ovarian carcinomas are estimated to have homologous recombination defi ciency, with about 15% of carcinomas harbouring a germline BRCA mutation, 6% a somatic BRCA mutation, and 20% a mutation in, or epigenetic silencing of, another homologous recombination gene. 7,8 Even without an identifi able mutation in BRCA or other known homologous recombination gene, many high-grade serous ovarian carcinomas show BRCA mutant-like genomic signatures, 6,9 which could serve as a downstream marker of homologous recombination defi ciency.…”