Rutgers Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
Rutgers Cancer Institute of New Jersey, Rutgers, The State University of New Jersey, New Brunswick, NJ, USA.
Breast Cancer Res Treat. 2023 Jul;200(1):15-22. doi: 10.1007/s10549-023-06940-0. Epub 2023 May 2.
BRCA1 and BRCA2 are key tumor suppressor genes that are essential for the homologous recombination DNA repair pathway. Loss of function mutations in these genes result in hereditary breast and ovarian cancer syndromes, which comprise approximately 5% of cases. BRCA1/2 mutations are associated with younger age of diagnosis and increased risk of recurrences. The concept of synthetic lethality led to the development of PARP inhibitors which cause cell cytotoxicity via the inhibition of PARP1, a key DNA repair protein, in cells with germline BRCA1/2 mutations. Although still poorly understood, the most well-acknowledged proposed mechanisms of action of PARP1 inhibition include the inhibition of single strand break repair, PARP trapping, and the upregulation of non-homologous end joining. Olaparib and talazoparib are PARP inhibitors that have been approved for the management of HER2-negative breast cancer in patients with germline BRCA1/2 mutations. This review article highlights the clinical efficacy of PARP inhibitors in patients with HER2-negative breast cancer in early and advanced settings.
BRCA1 和 BRCA2 是关键的肿瘤抑制基因，对同源重组 DNA 修复途径至关重要。这些基因的功能丧失突变导致遗传性乳腺癌和卵巢癌综合征，约占病例的 5%。BRCA1/2 突变与更年轻的诊断年龄和更高的复发风险相关。合成致死性的概念导致了 PARP 抑制剂的发展，这些抑制剂通过抑制关键的 DNA 修复蛋白 PARP1，导致具有种系 BRCA1/2 突变的细胞发生细胞毒性。尽管仍然知之甚少，但 PARP1 抑制作用最被认可的作用机制包括抑制单链断裂修复、PARP 捕获和非同源末端连接的上调。奥拉帕利和他拉唑帕尼是 PARP 抑制剂，已被批准用于治疗携带种系 BRCA1/2 突变的 HER2 阴性乳腺癌患者。本文综述了 PARP 抑制剂在早期和晚期 HER2 阴性乳腺癌患者中的临床疗效。
