期刊
JOURNAL OF CLINICAL ONCOLOGY
卷 27, 期 21, 页码 3540-3546出版社
AMER SOC CLINICAL ONCOLOGY
DOI: 10.1200/JCO.2008.20.8793
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资金
- NCI NIH HHS [CA35090, CA22433, U10 CA045808, U10 CA045377, U10 CA046282, CA35192, U10 CA042777, U10 CA058882, N01 CA035176, CA74647, CA46282, U10 CA012644, CA45377, N01 CA063844, CA14028, U10 CA074811, N01 CA035119, U10 CA014028, CA5686, N01 CA067575, U10 CA035192, N01 CA045807, CA35128, U10 CA058416, U10 CA074647, CA67663, U10 CA045807, CA58658, U10 CA037981, U10 CA027057, U10 CA016385, CA38926, U10 CA058861, N01 CA035431, CA58416, U10 CA020319, CA46113, U10 CA046441, U10 CA035090, U10 CA035176, CA58861, CA45461, N01 CA046441, U10 CA067663, U10 CA067575, CA74811, N01 CA027057, U10 CA035128, CA11083, CA12644, CA20319, U10 CA011083, CA52654, CA42777, U10 CA035119, U10 CA035431, U10 CA022433, N01 CA032102, CA37981, U10 CA046113, CA35261, CA45808, U10 CA045461, U10 CA035261, U10 CA063844, U10 CA180846, U10 CA052654, U10 CA032102, CA58882, CA16385] Funding Source: Medline
- NIGMS NIH HHS [GM63340, U01 GM063340] Funding Source: Medline
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.
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