title: Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics.
abstract: 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.
authors.affiliation: University of California Davis Cancer Center, 4501 X St, Suite 3017, Sacramento, CA 95817-2229, USA. david.gandara@ucdmc.ucdavis.edu
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kawaguchi
authors.forename: John
authors.initials: J
authors.lastname: Crowley
authors.forename: James
authors.initials: J
authors.lastname: Moon
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Furuse
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kawahara
authors.forename: Satoshi
authors.initials: S
authors.lastname: Teramukai
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Ohe
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kubota
authors.forename: Stephen K
authors.initials: SK
authors.lastname: Williamson
authors.forename: Oliver
authors.initials: O
authors.lastname: Gautschi
authors.forename: Heinz Josef
authors.initials: HJ
authors.lastname: Lenz
authors.forename: Howard L
authors.initials: HL
authors.lastname: McLeod
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Charles Arthur
authors.initials: CA
authors.lastname: Coltman
authors.forename: Masahiro
authors.initials: M
authors.lastname: Fukuoka
authors.forename: Nagahiro
authors.initials: N
authors.lastname: Saijo
authors.forename: Masanori
authors.initials: M
authors.lastname: Fukushima
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
mesh_terms: D000740:Anemia; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000401:mortality; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000401:mortality; D009367:Neoplasm Staging; D009503:Neutropenia / Q000209:etiology*; D017239:Paclitaxel / Q000627:therapeutic use; D010597:Pharmacogenetics; D011013:Pneumonectomy; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011788:Quality of Life; D013534:Survival; D014481:United States
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D016190:Carboplatin; D017239:Paclitaxel