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|Title:||Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer|
|Citation:||Pharmacogenomics Journal, 2015; 15(1):84-94|
|Publisher:||Nature Publishing Group: Open Access Hybrid Model Option B|
|P Saladores, T Mürdter, D Eccles, B Chowbay, NK Zgheib, S Winter, B Ganchev, B Eccles, S Gerty, A Tfayli, JSL Lim, YS Yap, RCH Ng, NS Wong, R Dent, MZ Habbal, E Schaeffeler, M Eichelbaum, W Schroth, M Schwab and H Brauch|
|Abstract:||Tamoxifen is the standard-of-care treatment for estrogen receptor-positive premenopausal breast cancer. We examined tamoxifen metabolism via blood metabolite concentrations and germline variations of CYP3A5, CYP2C9, CYP2C19 and CYP2D6 in 587 premenopausal patients (Asians, Middle Eastern Arabs, Caucasian-UK; median age 39 years) and clinical outcome in 306 patients. N-desmethyltamoxifen (DM-Tam)/(Z)-endoxifen and CYP2D6 phenotype significantly correlated across ethnicities (R²: 53%, P<10⁻⁷⁷). CYP2C19 and CYP2C9 correlated with norendoxifen and (Z)-4-hydroxytamoxifen concentrations, respectively (P<0.001). DM-Tam was influenced by body mass index (P<0.001). Improved distant relapse-free survival (DRFS) was associated with decreasing DM-Tam/(Z)-endoxifen (P=0.036) and increasing CYP2D6 activity score (hazard ratio (HR)=0.62; 95% confidence interval (CI), 0.43–0.91; P=0.013). Low (<14 nM) compared with high (˃435 nM) endoxifen concentrations were associated with shorter DRFS (univariate P=0.03; multivariate HR=1.94; 95% CI, 1.04–4.14; P=0.064). Our data indicate that endoxifen formation in premenopausal women depends on CYP2D6 irrespective of ethnicity. Low endoxifen concentration/formation and decreased CYP2D6 activity predict shorter DRFS..|
|Rights:||© 2015 Macmillan Publishers Limited All rights reserved|
|Appears in Collections:||Pharmacology publications|
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