期刊
CANCER
卷 124, 期 12, 页码 2498-2506出版社
WILEY
DOI: 10.1002/cncr.31307
关键词
breast cancer; breast and ovarian cancer susceptibility gene (BRCA)-mutant; DNA repair; hereditary; poly(adenosine diphosphate-ribose) polymerase (PARP)
类别
资金
- Cancer Center Support Grant from the National Cancer Institute [P30 CA014520]
Individuals with breast and ovarian cancer susceptibility gene 1 (BRCA1) or BRCA2 germline mutations have a significantly increased lifetime risk for breast and ovarian cancers. BRCA-mutant cancer cells have abnormal homologous recombination (HR) repair of DNA. In these tumors, the base excision repair (BER) pathway is important for cell survival. The poly(adenosine diphosphate-ribose) polymerase (PARP) enzymes play a key role in BER, and PARP inhibitors are effective in causing cell death in BRCA-mutant cells while sparing normal cells-a concept called synthetic lethality. PARP inhibitors are the first cancer therapeutics designed to exploit synthetic lethality. Recent clinical trials in BRCA-mutant, metastatic breast cancer demonstrated improved outcomes with single-agent PARP inhibitors (olaparib and talazoparib) over chemotherapy. However, resistance to PARP inhibitors remains a challenge. Primarily due to myelosuppression, the combination of PARP inhibitors with chemotherapy has been difficult. Novel combinations with chemotherapy, immunotherapy, and other targeted therapies are being pursued. In this review, the authors discuss current knowledge of PARP inhibitors in BRCA-mutant breast cancer and potential future directions for these agents. (C) 2018 American Cancer Society.
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