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

Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer
Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer
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 (>35?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.
1470-269X
84-94
Saladores, P.
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Mürdter, T.
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Eccles, Diana
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Chowbay, B.
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Zgheib, N.K.
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Winter, S.
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Ganchev, B.
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Eccles, Bryony
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Gerty, Sue
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Tfayli, A.
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Lim, J.S.L.
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Yap, Y.S.
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Ng, R.C.H.
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Wong, N.S.
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Dent, R.
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Habbal, M.Z.
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Schaeffeler, E.
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Eichelbaum, M.
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Schroth, W.
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Schwab, M.
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Brauch, H.
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Saladores, P.
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Mürdter, T.
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Eccles, Diana
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Chowbay, B.
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Zgheib, N.K.
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Winter, S.
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Ganchev, B.
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Eccles, Bryony
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Gerty, Sue
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Tfayli, A.
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Lim, J.S.L.
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Yap, Y.S.
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Ng, R.C.H.
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Wong, N.S.
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Dent, R.
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Habbal, M.Z.
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Schaeffeler, E.
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Eichelbaum, M.
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Schroth, W.
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Schwab, M.
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Brauch, H.
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Saladores, P., Mürdter, T., Eccles, Diana, Chowbay, B., Zgheib, N.K., Winter, S., Ganchev, B., Eccles, Bryony, Gerty, Sue, Tfayli, A., Lim, J.S.L., Yap, Y.S., Ng, R.C.H., Wong, N.S., Dent, R., Habbal, M.Z., Schaeffeler, E., Eichelbaum, M., Schroth, W., Schwab, M. and Brauch, H. (2015) Tamoxifen metabolism predicts drug concentrations and outcome in premenopausal patients with early breast cancer. The Pharmacogenomics Journal, 15 (1), 84-94. (doi:10.1038/tpj.2014.34). (PMID:25091503)

Record type: Article

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 (>35?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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Accepted/In Press date: 4 June 2014
e-pub ahead of print date: 5 August 2014
Published date: 2015
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 380264
URI: http://eprints.soton.ac.uk/id/eprint/380264
ISSN: 1470-269X
PURE UUID: 46116606-db48-4a33-ac6f-ee3e3071090a
ORCID for Diana Eccles: ORCID iD orcid.org/0000-0002-9935-3169

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Date deposited: 11 Aug 2015 10:03
Last modified: 15 Mar 2024 02:40

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Contributors

Author: P. Saladores
Author: T. Mürdter
Author: Diana Eccles ORCID iD
Author: B. Chowbay
Author: N.K. Zgheib
Author: S. Winter
Author: B. Ganchev
Author: Bryony Eccles
Author: Sue Gerty
Author: A. Tfayli
Author: J.S.L. Lim
Author: Y.S. Yap
Author: R.C.H. Ng
Author: N.S. Wong
Author: R. Dent
Author: M.Z. Habbal
Author: E. Schaeffeler
Author: M. Eichelbaum
Author: W. Schroth
Author: M. Schwab
Author: H. Brauch

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