CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations

M. A. Province, M. P. Goetz, H. Brauch, D. A. Flockhart, J. M. Hebert, R. Whaley, V. J. Suman, W. Schroth, S. Winter, H. Zembutsu, T. Mushiroda, W. G. Newman, M-T M. Lee, C. B. Ambrosone, M. W. Beckmann, J-Y Choi, A-S Dieudonné, P. A. Fasching, R. Ferraldeschi, L. GongE. Haschke-Becher, A Howell, L. B. Jordan, U. Hamann, K. Kiyotani, P. Krippl, D. Lambrechts, A Latif, U. Langsenlehner, W. Lorizio, P. Neven, A. T. Nguyen, B-W Park, C. A. Purdie, P. Quinlan, W. Renner, M. Schmidt, M. Schwab, J-G Shin, J. C. Stingl, P. Wegman, S. Wingren, A. H. B. Wu, E. Ziv, G. Zirpoli, A. M. Thompson, V. C. Jordan, Y. Nakamura, R. B. Altman, M. M. Ames, R. M. Weinshilboum, M. Eichelbaum, J. N. Ingle, T. E. Klein

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    Abstract

    The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20?mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.
    Original languageEnglish
    Pages (from-to)216-227
    Number of pages12
    JournalClinical Pharmacology & Therapeutics
    Volume95
    Issue number2
    Early online date23 Sep 2013
    DOIs
    Publication statusPublished - Feb 2014

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  • Cite this

    Province, M. A., Goetz, M. P., Brauch, H., Flockhart, D. A., Hebert, J. M., Whaley, R., Suman, V. J., Schroth, W., Winter, S., Zembutsu, H., Mushiroda, T., Newman, W. G., Lee, M-T. M., Ambrosone, C. B., Beckmann, M. W., Choi, J-Y., Dieudonné, A-S., Fasching, P. A., Ferraldeschi, R., ... Klein, T. E. (2014). CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations. Clinical Pharmacology & Therapeutics, 95(2), 216-227. https://doi.org/10.1038/clpt.2013.186