Tan David S P, Kaye Stanley B
From the National University Cancer Institute, Singapore; National University Hospital, Singapore; The Royal Marsden Hospital NHS Foundation Trust, London, United Kingdom.
Am Soc Clin Oncol Educ Book. 2015:114-21. doi: 10.14694/EdBook_AM.2015.35.114.
Retrospective studies have shown an improved prognosis, higher response rates to platinum-containing regimens, and longer treatment-free intervals between relapses in patients with BRCA 1 and BRCA 2 (BRCA1/2)-mutated ovarian cancer (BMOC) compared with patients who are not carriers of this mutation. These features of BMOC are attributed to homologous-recombination repair (HR) deficiency in the absence of BRCA1/2 function, which results in an impaired ability of tumor cells to repair platinum-induced double-strand breaks (DSBs), thereby conferring increased chemosensitivity and increased sensitivity to poly(ADP-ribose) polymerase (PARP) enzyme inhibition and other DNA-damaging chemotherapeutic agents such as pegylated liposomal doxorubicin (PLD). Therefore, the chemotherapeutic approach for patients with BMOC should focus on treatment with platinum-based chemotherapy at first-line and recurrent-disease settings and measures to increase the platinum-free interval following early platinum-resistant relapse (i.e., progression-free survival of less than 6 months from last platinum-based chemotherapy) by using nonplatinum cytotoxic agents, with the aim of reintroducing platinum again at a later date. The role of first-line intraperitoneal platinum-based therapy in the specific context of BMOC also merits further analysis. Other than platinum, alternative DNA-damaging agents (including PLD and trabectedin) also may have a therapeutic role in patients with recurrent BMOC. The recent approval of olaparib for clinical use in Europe and the United States will also affect chemotherapeutic strategies for these patients. Further work to clarify the precise relationship between BRCA1/2 mutation genotype and clinical phenotype is crucial to delineating the optimal therapeutic choices in the future for patients with BMOC.
回顾性研究表明，与未携带该突变的患者相比，携带乳腺癌1号基因（BRCA1）和乳腺癌2号基因（BRCA2，简称BRCA1/2）突变的卵巢癌患者（BMOC）预后改善、对含铂方案的缓解率更高，且复发之间的无治疗间隔更长。BMOC的这些特征归因于BRCA1/2功能缺失导致的同源重组修复（HR）缺陷，这使得肿瘤细胞修复铂诱导的双链断裂（DSB）的能力受损，从而增加了化疗敏感性以及对聚（ADP-核糖）聚合酶（PARP）酶抑制和其他DNA损伤化疗药物（如聚乙二醇化脂质体阿霉素，PLD）的敏感性。因此，BMOC患者的化疗方法应首先侧重于一线和复发性疾病情况下使用铂类化疗，以及通过使用非铂类细胞毒性药物来增加早期铂耐药复发（即从上一次铂类化疗开始无进展生存期少于6个月）后的无铂间隔，目的是在以后再次引入铂类药物。一线腹腔内铂类治疗在BMOC特定背景下的作用也值得进一步分析。除铂类药物外，其他DNA损伤药物（包括PLD和曲贝替定）在复发性BMOC患者中也可能具有治疗作用。奥拉帕尼最近在欧洲和美国获批用于临床也将影响这些患者的化疗策略。进一步阐明BRCA1/2突变基因型与临床表型之间的确切关系对于确定未来BMOC患者的最佳治疗选择至关重要。
