Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: A model for assessing population-related pharmacogenomics

David R. Gandara, Tomoya Kawaguchi, John Crowley, James Moon, Kiyoyuki Furuse, Masaaki Kawahara, Satoshi Teramukai, Yuichiro Ohe, Kaoru Kubota, Stephen K. Williamson, Oliver Gautschi, Heinz Josef Lenz, Howard L. McLeod, Primo N. Lara, Charles Arthur Coltman, Masahiro Fukuoka, Nagahiro Saijo, Masanori Fukushima, Philip C. Mack

Resultado de la investigación: Articlerevisión exhaustiva

173 Citas (Scopus)

Resumen

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/m2) 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.

Idioma originalEnglish (US)
Páginas (desde-hasta)3540-3546
Número de páginas7
PublicaciónJournal of Clinical Oncology
Volumen27
N.º21
DOI
EstadoPublished - jul 20 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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