Gandara David R, Kawaguchi Tomoya, Crowley John, Moon James, Furuse Kiyoyuki, Kawahara Masaaki, Teramukai Satoshi, Ohe Yuichiro, Kubota Kaoru, Williamson Stephen K, Gautschi Oliver, Lenz Heinz Josef, McLeod Howard L, Lara Primo N, Coltman Charles Arthur, Fukuoka Masahiro, Saijo Nagahiro, Fukushima Masanori, Mack Philip C
University of California Davis Cancer Center, 4501 X St, Suite 3017, Sacramento, CA 95817-2229, USA.
J Clin Oncol. 2009 Jul 20;27(21):3540-6. doi: 10.1200/JCO.2008.20.8793. Epub 2009 May 26.
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 CYP3A41B (P = .01), CYP3A53C (P = .03), ERCC1 118 (P < .0001), ERCC2 K751Q (P < .001), and CYP2C8 R139K (P = .01). Genotypic associations were observed between CYP3A41B 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 CYP3A41B 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.
目的 鉴于研究设计、入选标准、分期和治疗方案相似，探讨与人群相关的药物基因组学是否导致在日本和美国进行的临床试验中患者结局存在差异。方法 我们前瞻性地设计并开展了三项晚期非小细胞肺癌的III期试验（四臂合作研究、LC00 - 03和S0003），每项试验都有一个紫杉醇加卡铂的共同治疗组。从LC00 - 03和S0003中接受紫杉醇（225 mg/m²）和卡铂（浓度 - 时间曲线下面积，6）治疗的患者中收集基因组DNA。通过焦磷酸测序或聚合酶链反应 - 限制性片段长度多态性分析CYP3A4、CYP3A5、CYP2C8、NR1I2 - 206、ABCB1、ERCC1和ERCC2的基因变异。通过Cox模型评估生存结果，通过逻辑回归评估缓解和毒性情况。结果 在两项日本试验中临床结果相似，而在生存、中性粒细胞减少、发热性中性粒细胞减少和贫血方面与美国试验有显著差异。日本和美国患者在CYP3A41B（P = 0.01）、CYP3A53C（P = 0.03）、ERCC1 118（P < 0.0001）、ERCC2 K751Q（P < 0.001）和CYP2C8 R139K（P = 0.01）的基因型分布上存在显著差异。观察到CYP3A41B与无进展生存（风险比[HR]，0.36；95%可信区间，0.14至0.94；P = 0.04）以及ERCC2 K751Q与缓解（HR，0.33；95%可信区间，0.13至0.83；P = 0.02）之间存在基因型关联。对于4级中性粒细胞减少，ABCB1 3425C→T的HR为1.84（95%可信区间，0.77至4.48；P = 0.19）。结论 观察到日本和美国患者在参与紫杉醇处置或DNA修复的基因的等位基因分布上存在差异。在探索性分析中，观察到CYP3A41B和ERCC2 K751Q与患者结局存在基因型相关的关联。这种共同治疗组方法有助于对与人群相关的药物基因组学进行前瞻性研究，其中预计抗肿瘤药物处置存在种族差异。
