PARP inhibitors in breast cancer: Bringing synthetic lethality to the bedside.

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. Cancer 2018;124:2498-506. © 2018 American Cancer Society.

Turk AA ，Wisinski KB 《-》

Resurrection of PARP Inhibitors in Breast Cancer.

PARP enzymes are essential for DNA damage repair. Cancers with defective homologous recombination DNA repair, such has BRCA1- and BRCA2-mutated breast cancers, are targets for PARP inhibitors (PARPi) through the exploitation of synthetic lethality. A number of PARPi are currently undergoing clinical evaluation in breast cancer, with olaparib and talazoparib having demonstrated superior efficacy compared with standard chemotherapy in advanced germline BRCA-mutated cancer. This review describes the biological rationale for PARPi and presents the accumulating data on PARPi use in breast cancer.

Lyons TG ，Robson ME 《-》

Advances in PARP inhibitors for the treatment of breast cancer.

Dizdar O ，Arslan C ，Altundag K 《-》

Development of poly(ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated breast cancer.

Sulai NH ，Tan AR 《-》

New Targeted Agents in Gynecologic Cancers: Synthetic Lethality, Homologous Recombination Deficiency, and PARP Inhibitors.

Liu FW ，Tewari KS 《-》