NYU Cancer Institute, 160 34th St, New York, NY 10016, USA.
Mol Cancer Ther. 2011 Oct;10(10):2000-7. doi: 10.1158/1535-7163.MCT-11-0272. Epub 2011 Aug 11.
Epithelial ovarian cancer (EOC) patients with BRCA mutations (BRCA +) benefit from platinum-based treatment more than noncarriers. Impaired ability to repair DNA by homologous recombination increases their chemosensitivity. We investigated whether BRCA + predicts for improved outcome following pegylated liposomal doxorubicin (PLD) for recurrence. Recurrent EOC patients receiving second- or third-line PLD from 1998 to 2009 in 4 institutions (Tel Aviv, New York, Padua, and Jerusalem) were subjected to retrospective comparisons between 40 (25.8%) patients who were BRCA +, and 115 (74.2%) deemed nonhereditary (NH). Median age was 59 years (range 31-83); 111 (72%) had a platinum-free interval more than 6 months [PLD alone (n = 65) and PLD plus platinum (n = 90)]; 104 received PLD in second-line and 51 in third-line. BRCA + versus NH comparisons: median time to treatment failure (TTF) 15.8 months [95% confidence interval (CI): 11.4-21.6] versus 8.1 months (95% CI: 6.1-10.3; P = 0.009); overall survival (OS) 56.8 months (95% CI: 32.5-indeterminate) versus 22.6 months (95% CI: 17.0-34.1; P = 0.002). In multivariate Cox models BRCA status was significantly associated with TTF (HR = 1.66; 95% CI: 1.08-2.55; P = 0.02) and OS (adjusted HR 2.07; 95% CI: 1.18-3.60; P = 0.01). Adjusted HR relating platinum sensitivity to OS was 1.58 (95% CI: 0.93-2.68; P = 0.09); no significant association found with age at diagnosis, line of PLD or combinations, or institution. In this retrospective analysis, recurrent EOC BRCA mutation carriers treated with PLD had an improved outcome, and this result seemed to be independent of platinum sensitivity. Tumors arising in a background of defective BRCA function are more sensitive than other EOCs to DNA-damaging agents such as PLD, even after acquiring platinum resistance.
上皮性卵巢癌（EOC）患者的 BRCA 突变（BRCA +）比非携带者更能从铂类治疗中获益。同源重组修复 DNA 的能力受损会增加其化疗敏感性。我们研究了 BRCA + 是否可以预测聚乙二醇脂质体多柔比星（PLD）治疗复发时的预后改善。1998 年至 2009 年，4 家机构（特拉维夫、纽约、帕多瓦和耶路撒冷）的复发 EOC 患者接受二线或三线 PLD 治疗，40 名（25.8%）BRCA + 患者与 115 名（74.2%）非遗传性（NH）患者进行回顾性比较。中位年龄为 59 岁（范围 31-83）；111 名（72%）无铂间隔超过 6 个月[PLD 单药（n=65）和 PLD 联合铂类（n=90）]；104 名患者接受二线 PLD 治疗，51 名患者接受三线 PLD 治疗。BRCA +与 NH 比较：中位无进展生存期（TTF）为 15.8 个月[95%置信区间（CI）：11.4-21.6]与 8.1 个月（95%CI：6.1-10.3；P=0.009）；总生存期（OS）为 56.8 个月（95%CI：32.5-不确定）与 22.6 个月（95%CI：17.0-34.1；P=0.002）。多变量 Cox 模型中 BRCA 状态与 TTF（HR=1.66；95%CI：1.08-2.55；P=0.02）和 OS（调整 HR 2.07；95%CI：1.18-3.60；P=0.01）显著相关。与 OS 相关的铂敏感性调整 HR 为 1.58（95%CI：0.93-2.68；P=0.09）；未发现与诊断时年龄、PLD 线或组合或机构有关。在这项回顾性分析中，接受 PLD 治疗的复发性 EOC BRCA 突变携带者的预后得到改善，并且这一结果似乎独立于铂敏感性。在 BRCA 功能缺陷的背景下发生的肿瘤对 DNA 损伤剂（如 PLD）比其他 EOC 更敏感，即使在获得铂类耐药后也是如此。
