Department of Oncology, Shaare Zedek Medical Center, Jerusalem, Israel.
Department of Oncology, Kaplan Medical Center, Rehovot, Israel.
Breast. 2019 Oct;47:33-42. doi: 10.1016/j.breast.2019.06.007. Epub 2019 Jul 1.
Targeting of DNA repair is an important therapeutic approach in breast cancer, particularly for BRCA1/2 associated breast cancers and those characterized by a "BRCAness" phenotype including those with "triple negative" subtype. Various assays and scores have been developed to evaluate degree of homologous recombination deficiency in the hope that this would aid in predicting for susceptibility to DNA repair targeting agents, and yet, presence of a germline mutation in BRCA1/2 remains the strongest predictor for therapeutic efficacy of such agents. Pre-clinical studies suggested increased sensitivity to agents that damage DNA in a way that interferes with DNA replication forks and which subsequently require DNA repair by homologous recombination, such as platinum salts, and this data was further confirmed clinically. Recently published phase III data favor the use of PARP inhibitors amongst patients with BRCA1/2 associated advanced breast cancer. Novel chemotherapeutic agents targeting DNA damage repair are under evaluation as well as further combinations of PARP inhibitors with immuno-therapeutics and other biological agents.
针对 DNA 修复的靶向治疗是乳腺癌的一种重要治疗方法，特别是对于 BRCA1/2 相关的乳腺癌和具有“BRCAness”表型的乳腺癌，包括具有“三阴性”亚型的乳腺癌。已经开发了各种检测方法和评分标准，以评估同源重组缺陷的程度，希望这有助于预测对 DNA 修复靶向药物的敏感性，但 BRCA1/2 种系突变的存在仍然是此类药物治疗效果的最强预测因素。临床前研究表明，对以干扰 DNA 复制叉的方式损伤 DNA 的药物以及随后需要通过同源重组进行 DNA 修复的药物（如铂盐）更加敏感，这一数据在临床上得到了进一步证实。最近公布的 III 期数据支持在 BRCA1/2 相关晚期乳腺癌患者中使用 PARP 抑制剂。新型靶向 DNA 损伤修复的化疗药物以及 PARP 抑制剂与免疫疗法和其他生物制剂的联合应用正在评估中。
