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 Gong, E 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
Clinical Pharmacology and Therapeutics 2014, 95 (2): 216-27
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.

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