Japanese-US Common-Arm Analysis of Paclitaxel Plus Carboplatin in Advanced Non-Small-Cell Lung Cancer: A Model for Assessing Population-Related Pharmacogenomics
Japanese-US Common-Arm Analysis of Paclitaxel Plus Carboplatin in Advanced Non-Small-Cell Lung Cancer: A Model for Assessing Population-Related Pharmacogenomics
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DOI：
10.1200/jco.2008.20.8793
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发表时间：
2009-07-20
影响因子：
45.3
通讯作者：
Mack, Philip C.
中科院分区：
文献类型：
--
作者：
Gandara, David R.;Kawaguchi, Tomoya;Mack, Philip C.
目的探讨在研究设计、合格标准、分期和治疗方案相似的情况下，人群相关药物基因组学是否有助于在日本和美国进行的临床试验之间患者结局的差异。（四组合作研究，LC 00 -03和S 0003），每一组均采用紫杉醇加卡铂的共同组。从LC 00 -03和S 0003中接受紫杉醇（225 mg/m2）和卡铂（浓度-时间曲线下面积，6）的患者中采集基因组DNA。通过焦磷酸测序或PCR限制性片段长度多态性分析CYP 3A 4、CYP 3A 5、CYP 2C 8、NR 1 I2 -206、ABCB 1、ERCC 1和ERCC 2的基因型变异体。结果进行了评估生存考克斯模型和logistic回归反应和toxicity.Results临床结果相似，在两个日本试验，并显着不同，从美国试验，生存，中性粒细胞减少，发热性中性粒细胞减少，贫血。日本和美国患者的CYP 3A 4 *1B（P = .01）、CYP 3A 5 *3C（P = .03）、ERCC 1 118（P < .0001）、ERCC 2 K751 Q（P <.001）和CYP 2C 8 R139 K（P = .01）基因型分布存在显著差异。CYP 3A 4 *1B与无进展生存期（风险比[HR]，0.36; 95% CI，0.14 - 0.94; P = .04）和ERCC 2 K751 Q与缓解（HR，0.33; 95% CI，0.13 - 0.83; P = .02）之间存在基因型相关性。对于4级中性粒细胞减少症，ABCB 1 3425 C-> T的HR为1.84（95%CI，0.77至4.48; P = 0.19）。结论在日本和美国患者中观察到参与紫杉醇处置或DNA修复的基因的等位基因分布差异。在一项探索性分析中，观察到CYP 3A 4 *1B和ERCC 2 K751 Q与患者结局的基因型相关性。这种共同臂的方法有利于人口相关的药物基因组学的前瞻性研究，其中种族差异的药物处置的预期。
Purpose To explore whether population-related pharmacogenomics contribute to differences in patient outcomes between clinical trials performed in Japan and the United States, given similar study designs, eligibility criteria, staging, and treatment regimens.Methods We prospectively designed and conducted three phase III trials (Four-Arm Cooperative Study, LC00-03, and S0003) in advanced-stage, non-small-cell lung cancer, each with a common arm of paclitaxel plus carboplatin. Genomic DNA was collected from patients in LC00-03 and S0003 who received paclitaxel (225 mg/m(2)) and carboplatin (area under the concentration-time curve, 6). Genotypic variants of CYP3A4, CYP3A5, CYP2C8, NR1I2-206, ABCB1, ERCC1, and ERCC2 were analyzed by pyrosequencing or by PCR restriction fragment length polymorphism. Results were assessed by Cox model for survival and by logistic regression for response and toxicity.Results Clinical results were similar in the two Japanese trials, and were significantly different from the US trial, for survival, neutropenia, febrile neutropenia, and anemia. There was a significant difference between Japanese and US patients in genotypic distribution for CYP3A4*1B (P = .01), CYP3A5*3C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A4*1B for progression-free survival (hazard ratio [HR], 0.36; 95% CI, 0.14 to 0.94; P = .04) and ERCC2 K751Q for response (HR, 0.33; 95% CI, 0.13 to 0.83; P = .02). For grade 4 neutropenia, the HR for ABCB1 3425C -> T was 1.84 (95% CI, 0.77 to 4.48; P = .19).Conclusion Differences in allelic distribution for genes involved in paclitaxel disposition or DNA repair were observed between Japanese and US patients. In an exploratory analysis, genotype-related associations with patient outcomes were observed for CYP3A4*1B and ERCC2 K751Q. This common-arm approach facilitates the prospective study of population-related pharmacogenomics in which ethnic differences in antineoplastic drug disposition are anticipated.