Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a model for assessing population-related pharmacogenomics.
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.
Gandara
David R
DR
University of California Davis Cancer Center, 4501 X St, Suite 3017, Sacramento, CA 95817-2229, USA. david.gandara@ucdmc.ucdavis.edu
Kawaguchi
Tomoya
T
Crowley
John
J
Moon
James
J
Furuse
Kiyoyuki
K
Kawahara
Masaaki
M
Teramukai
Satoshi
S
Ohe
Yuichiro
Y
Kubota
Kaoru
K
Williamson
Stephen K
SK
Gautschi
Oliver
O
Lenz
Heinz Josef
HJ
McLeod
Howard L
HL
Lara
Primo N
PN
Coltman
Charles Arthur
CA
Fukuoka
Masahiro
M
Saijo
Nagahiro
N
Fukushima
Masanori
M
Mack
Philip C
PC
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
D000972:Antineoplastic Agents, Phytogenic; D016190:Carboplatin; D017239:Paclitaxel