Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer

Abstract

Context Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer (OvCa) have produced conflicting results. Objective To determine the relationships between BRCA1/2 deficiency (i.e., mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole exome mutation rate in OvCa. Design, Setting, and Patients Observational study of multidimensional genomics and clinical data on 316 high-grade serous OvCa cases that were made public between 2009 and 2010 via The Cancer Genome Atlas project. Main Outcome Measures OS and PFS rates (primary outcomes) and chemotherapy response (secondary outcome). Results BRCA2 mutations (29 cases) were associated with significantly better OS (adjusted hazard ratio [HR], 0.33; 95% CI, 0.16–0.69, P=0.003; 5-year OS: 61% for BRCA2 mutated vs. 25% for BRCA wild-type [wt] cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22–0.74, P=0.004; 3-year PFS: 44% for BRCA2 mutated vs. 16% for BRCA wt cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) were associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2 mutated vs. 82% [P=0.02] and 80% [P=0.05] for BRCA wt and BRCA1 mutated cases, respectively) and longer platinum-free duration (median platinum-free duration: 18.0 months for BRCA2 mutated vs. 11.7 [P=0.02] and 12.5 [P=0.04] months for BRCA wt and BRCA1 mutated cases, respectively). Further investigation revealed that BRCA2 mutated, but not BRCA1 mutated cases, exhibited a “mutator phenotype” by containing significantly more mutations than BRCA wt cases across the whole exome (median mutation number per sample: 84 for BRCA2 mutated vs. 52 for BRCA wt cases, false-discovery rate <0.1). Conclusions BRCA2 mutation, but not BRCA1 deficiency, is associated with improved survival, chemotherapy response, and genome instability compared with BRCA wild-type.

The role of BRCA1 and BRCA2 in prostate cancer

“…[99][100][101] Previous studies in ovarian cancer suggested that mutations in both genes were associated with similar responses to platinum-based chemotherapy. 101 Recently, Yang et al 102 have reported a series of 316 ovarian cancer patients treated with surgery and adjuvant platinum-based chemotherapy in which BRCA2 mutations were associated with improved outcomes, while BRCA1-mutated or -hypermethylated tumours were not significantly different from BRCA wild-type cases. BRCA2 mutations were also associated with an increased rate of response to primary platinum chemotherapy.…”

Mapping genetic alterations causing chemoresistance in cancer: identifying the roads by tracking the drivers

“…234 Several studies have revealed ovarian cancer patients with BRCA1 as well as BRCA2 germline mutations to have a better chance of responding to platinumbased therapy as compared with patients wild type for BRCA1/2 in the primary setting as well as on tumour relapse. 233,[235][236][237][238] Most interestingly, there is experimental (BRCA2) but also results in human tumours (BRCA1 and BRCA2) revealing secondary mutations, restoring BRCA1/2 protein function, to be associated with acquired resistance toward platinum compounds. [239][240][241][242] The fact that mutations affecting both BRCA1 and BRCA2 seem to confer sensitivity to platinum compounds and to PARP inhibitors (see below) clearly implicates the Fanconi complex in drug sensitivity to these compounds.…”

Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas

“…30 Since that time, Soslow et al 23 validated the significance of different histologic patterns by describing variant morphologies (SET) in tumors with BRCA germline mutations that are associated with a better prognosis and a better response to chemotherapy. 3,4,[12][13][14][15][16][17][18][19] We previously reported on a separate cohort of high-grade serous carcinomas, showing an association between BRCA-positivity and variant histology (SET-like), younger age, a lower frequency of serous tubal intraepithelial carcinoma, and trends toward improved survival. 24 In this current study, we found that mutations in homologous recombination genes were 6 times more likely to be associated with nonclassic high-grade serous carcinoma histology (70%) than with classic high-grade serous carcinoma histology (28%) (P o0.001), and BRCA1 mutations were 10 times more likely to be associated with nonclassic high-grade serous carcinoma histology (P o 0.001) than classic histology.…”

“…10,11 The reliance on alternative end-joining repair pathways subsequently renders homologous recombination-deficient tumors more sensitive to chemotherapy as well as to PARPi. 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.…”

“…[6][7][8][9] Homologous recombination-deficient high-grade serous carcinomas (including BRCA1/2 mutations) depend on alternative, error-prone mechanisms for doublestrand break repair, such as the Polθ/PARP1-mediated alternative end-joining pathway for DNA repair, 10,11 and subsequently have been shown to have increased sensitivity to platinum chemotherapy and to poly ADP-ribose polymerase inhibitors (PARPi), and improved overall survival. 3,4,[12][13][14][15][16][17][18][19] Studies from The Cancer Genome Atlas Research Network (TCGA) demonstrated that nearly one-third of ovarian high-grade serous carcinomas had BRCA1-/2 alterations, which included 20% with either germline or somatic mutations in BRCA1/2 and an additional 11% with BRCA1 epigenetic silencing via hypermethylation. 20 Interestingly, they found that improved survival was limited to high-grade serous carcinomas with mutations in BRCA1/2, and was not seen in high-grade serous carcinomas with epigenetically silenced BRCA1.…”