Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer

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dc.contributor.authorSaladores, P.
dc.contributor.authorMuerdter, T.
dc.contributor.authorEccles, D.
dc.contributor.authorChowbay, B.
dc.contributor.authorZgheib, N.
dc.contributor.authorWinter, S.
dc.contributor.authorGanchev, B.
dc.contributor.authorEccles, B.
dc.contributor.authorGerty, S.
dc.contributor.authorTfayli, A.
dc.contributor.authorLim, J.
dc.contributor.authorYap, Y.
dc.contributor.authorNg, R.
dc.contributor.authorWong, N.
dc.contributor.authorDent, R.
dc.contributor.authorHabbal, M.
dc.contributor.authorSchaeffeler, E.
dc.contributor.authorEichelbaum, M.
dc.contributor.authorSchroth, W.
dc.contributor.authorSchwab, M.
dc.contributor.authoret al.
dc.date.issued2015
dc.description.abstractTamoxifen 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..
dc.description.statementofresponsibilityP 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
dc.identifier.citationPharmacogenomics Journal, 2015; 15(1):84-94
dc.identifier.doi10.1038/tpj.2014.34
dc.identifier.issn1470-269X
dc.identifier.issn1473-1150
dc.identifier.urihttp://hdl.handle.net/2440/99364
dc.language.isoen
dc.publisherNature Publishing Group: Open Access Hybrid Model Option B
dc.rights© 2015 Macmillan Publishers Limited All rights reserved
dc.source.urihttps://doi.org/10.1038/tpj.2014.34
dc.subjectTamoxofin
dc.titleTamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer
dc.typeJournal article
pubs.publication-statusPublished

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