Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer
Date
2015
Authors
Saladores, P.
Muerdter, T.
Eccles, D.
Chowbay, B.
Zgheib, N.
Winter, S.
Ganchev, B.
Eccles, B.
Gerty, S.
Tfayli, A.
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Journal article
Citation
Pharmacogenomics Journal, 2015; 15(1):84-94
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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
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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..
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