Saladores, P.Muerdter, T.Eccles, D.Chowbay, B.Zgheib, N.Winter, S.Ganchev, B.Eccles, B.Gerty, S.Tfayli, A.Lim, J.Yap, Y.Ng, R.Wong, N.Dent, R.Habbal, M.Schaeffeler, E.Eichelbaum, M.Schroth, W.Schwab, M.et al.2016-06-022016-06-022015Pharmacogenomics Journal, 2015; 15(1):84-941470-269X1473-1150http://hdl.handle.net/2440/99364Tamoxifen 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..en© 2015 Macmillan Publishers Limited All rights reservedTamoxofinJournal article003004494810.1038/tpj.2014.340003484597000132-s2.0-84921883295238352