Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval
Poly(ADP)-Ribose Polymerase Inhibition: Frequent Durable Responses in BRCA Carrier Ovarian Cancer Correlating With Platinum-Free Interval
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DOI：
10.1200/jco.2009.26.9589
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发表时间：
2010-05-20
影响因子：
45.3
通讯作者：
Kaye, Stan B.
中科院分区：
文献类型：
--
作者：
Fong, Peter C.;Yap, Timothy A.;Kaye, Stan B.
目的通过使用聚（ADP）-核糖聚合酶（PARP）抑制剂治疗BRCA1/2突变携带者的合成致死策略，可以实现选择性肿瘤细胞的细胞毒性，其中肿瘤细胞具有缺陷的同源重组（HR）DNA修复。铂类化疗反应与 HR DNA 修复能力相关。奥拉帕尼是一种有效的口服 PARP 抑制剂，耐受性良好，在 BRCA1/2 突变携带者中具有抗肿瘤活性。 患者和方法 BRCA1/2 突变卵巢癌患者在 I 期试验的剂量递增和单阶段扩展中接受奥拉帕尼治疗。随后，抗肿瘤活性与铂类敏感性相关。结果 50 名患者接受治疗：48 名患有种系 BRCA1/2 突变；48 名患有生殖系 BRCA1/2 突变。其中一名患者存在意义不明的 BRCA2 种系序列变化，另一名患者有很强的 BRCA1/2 相关癌症家族史，但拒绝进行突变检测。 50名患者中，13名患有铂类敏感疾病，24名患有铂类耐药疾病，13名患有铂类难治性疾病（根据无铂类间隔）。 20 例（40%；95% CI，26% 至 55%）达到实体瘤疗效评估标准 (RECIST) 完全或部分缓解和/或肿瘤标志物 (CA125) 缓解，3 例 (6.0%) 维持 RECIST 疾病稳定超过 4 个月，总体临床获益率为 46%（95% CI，32% 至 61%）。中位缓解持续时间为 28 周。在铂敏感、耐药和难治亚组中，临床获益率和无铂间隔之间存在显着相关性（分别为 69%、45% 和 23%）。事后分析表明铂敏感性与奥拉帕尼反应程度之间存在关联（放射学变化，P = .001；CA125 变化，P = .002）。结论奥拉帕尼在 BRCA1/2 突变卵巢癌中具有抗肿瘤活性，这与铂敏感性相关。
PurposeSelective tumor cell cytotoxicity can be achieved through a synthetic lethal strategy using poly(ADP)-ribose polymerase (PARP) inhibitor therapy in BRCA1/2 mutation carriers in whom tumor cells have defective homologous recombination (HR) DNA repair. Platinum-based chemotherapy responses correlate with HR DNA repair capacity. Olaparib is a potent, oral PARP inhibitor that is well tolerated, with antitumor activity in BRCA1/2 mutation carriers.Patients and MethodsPatients with BRCA1/2-mutated ovarian cancer were treated with olaparib within a dose-escalation and single-stage expansion of a phase I trial. Antitumor activity was subsequently correlated with platinum sensitivity.ResultsFifty patients were treated: 48 had germline BRCA1/2 mutations; one had a BRCA2 germline sequence change of unknown significance, and another had a strong family history of BRCA1/2-associated cancers who declined mutation testing. Of the 50 patients, 13 had platinum-sensitive disease, 24 had platinum-resistant disease, and 13 had platinum-refractory disease (according to platinum-free interval). Twenty (40%; 95% CI, 26% to 55%) achieved Response Evaluation Criteria in Solid Tumors (RECIST) complete or partial responses and/or tumor marker (CA125) responses, and three (6.0%) maintained RECIST disease stabilization for more than 4 months, giving an overall clinical benefit rate of 46% (95% CI, 32% to 61%). Median response duration was 28 weeks. There was a significant association between the clinical benefit rate and platinum-free interval across the platinum-sensitive, resistant, and refractory subgroups (69%, 45%, and 23%, respectively). Post hoc analyses indicated associations between platinum sensitivity and extent of olaparib response (radiologic change, P = .001; CA125 change, P = .002).ConclusionOlaparib has antitumor activity in BRCA1/2 mutation ovarian cancer, which is associated with platinum sensitivity.