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Yang D, Khan S, Sun Y, et al. Association of BRCA1 and BRCA2 Mutations With Survival, Chemotherapy Sensitivity, and Gene Mutator Phenotype in Patients With Ovarian Cancer. JAMA. 2011;306(14):1557–1565. doi:https://doi.org/10.1001/jama.2011.1456
Author Affiliations: Department of Pathology (Drs Yang, Khan, Sun, and Zhang); Department of Biostatistics (Dr Hess); Department of Gynecologic Oncology and Reproductive Medicine, Department of Cancer Biology, and Center for RNAi and Non-Coding RNA (Dr Sood), University of Texas MD Anderson Cancer Center, Houston; Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China (Dr Sun); and Institute for Systems Biology, Seattle, Washington (Dr Shmulevich). Dr Khan is now with the Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland.
Context Attempts to determine the clinical significance of BRCA1/2 mutations in ovarian cancer have produced conflicting results.
Objective To determine the relationships between BRCA1/2 deficiency (ie, mutation and promoter hypermethylation) and overall survival (OS), progression-free survival (PFS), chemotherapy response, and whole-exome mutation rate in ovarian cancer.
Design, Setting, and Patients Observational study of multidimensional genomics and clinical data on 316 high-grade serous ovarian cancer 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 = .003 and 5-year OS, 61% for BRCA2-mutated vs 25% for BRCA wild-type cases) and PFS (adjusted HR, 0.40; 95% CI, 0.22-0.74; P = .004 and 3-year PFS, 44% for BRCA2-mutated vs 16% for BRCA wild-type cases), whereas neither BRCA1 mutations (37 cases) nor BRCA1 methylation (33 cases) was associated with prognosis. Moreover, BRCA2 mutations were associated with a significantly higher primary chemotherapy sensitivity rate (100% for BRCA2-mutated vs 82% [P = .02] and 80% [P = .05] for BRCA wild-type and BRCA1-mutated cases, respectively) and longer platinum-free duration (median platinum-free duration, 18.0 months for BRCA2-mutated vs 11.7 [P = .02] and 12.5 [P = .04] months for BRCA wild-type and BRCA1-mutated cases, respectively). BRCA2-mutated, but not BRCA1-mutated cases, exhibited a “mutator phenotype” by containing significantly more mutations than BRCA wild-type cases across the whole exome (median mutation number per sample, 84 for BRCA2-mutated vs 52 for BRCA wild-type cases, false discovery rate <0.1).
Conclusion Among women with high-grade serous ovarian cancer, BRCA2 mutation, but not BRCA1 deficiency, was associated with improved survival, improved chemotherapy response, and genome instability compared with BRCA wild-type.
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