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

Research output: Contribution to journalArticle

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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/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.

Original languageEnglish (US)
Pages (from-to)3540-3546
Number of pages7
JournalJournal of Clinical Oncology
Volume27
Issue number21
DOIs
StatePublished - Jul 20 2009

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Cytochrome P-450 CYP3A
Pharmacogenetics
Carboplatin
Paclitaxel
Non-Small Cell Lung Carcinoma
Population
Neutropenia
Febrile Neutropenia
Survival
Proportional Hazards Models
DNA Repair
Restriction Fragment Length Polymorphisms
Antineoplastic Agents
Disease-Free Survival
Anemia
Japan
Logistic Models
Genotype
Clinical Trials
Prospective Studies

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

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

In: Journal of Clinical Oncology, Vol. 27, No. 21, 20.07.2009, p. 3540-3546.

Research output: Contribution to journalArticle

Gandara, DR, Kawaguchi, T, Crowley, J, Moon, J, Furuse, K, Kawahara, M, Teramukai, S, Ohe, Y, Kubota, K, Williamson, SK, Gautschi, O, Lenz, HJ, McLeod, HL, Lara, PN, Coltman, CA, Fukuoka, M, Saijo, N, Fukushima, M & Mack, PC 2009, 'Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer: A model for assessing population-related pharmacogenomics', Journal of Clinical Oncology, vol. 27, no. 21, pp. 3540-3546. https://doi.org/10.1200/JCO.2008.20.8793
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. / Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer : A model for assessing population-related pharmacogenomics. In: Journal of Clinical Oncology. 2009 ; Vol. 27, No. 21. pp. 3540-3546.
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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/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.",
author = "Gandara, {David R.} and Tomoya Kawaguchi and John Crowley and James Moon and Kiyoyuki Furuse and Masaaki Kawahara and Satoshi Teramukai and Yuichiro Ohe and Kaoru Kubota and Williamson, {Stephen K.} and Oliver Gautschi and Lenz, {Heinz Josef} and McLeod, {Howard L.} and Lara, {Primo N.} and Coltman, {Charles Arthur} and Masahiro Fukuoka and Nagahiro Saijo and Masanori Fukushima and Mack, {Philip C.}",
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TY - JOUR

T1 - Japanese-US common-arm analysis of paclitaxel plus carboplatin in advanced non-small-cell lung cancer

T2 - A model for assessing population-related pharmacogenomics

AU - Gandara, David R.

AU - Kawaguchi, Tomoya

AU - Crowley, John

AU - Moon, James

AU - Furuse, Kiyoyuki

AU - Kawahara, Masaaki

AU - Teramukai, Satoshi

AU - Ohe, Yuichiro

AU - Kubota, Kaoru

AU - Williamson, Stephen K.

AU - Gautschi, Oliver

AU - Lenz, Heinz Josef

AU - McLeod, Howard L.

AU - Lara, Primo N.

AU - Coltman, Charles Arthur

AU - Fukuoka, Masahiro

AU - Saijo, Nagahiro

AU - Fukushima, Masanori

AU - Mack, Philip C.

PY - 2009/7/20

Y1 - 2009/7/20

N2 - 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.

AB - 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.

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