Tamoxifen Metabolism Predicts Drug Concentrations and Outcome in Premenopausal Patients with Early Breast Cancer

Overview

Journal Pharmacogenomics J

Specialties Genetics
Molecular Biology
Pharmacology

Date 2014 Aug 6

PMID 25091503

Citations 71

Authors

P Saladores

T Murdter

D Eccles

B Chowbay

N K Zgheib

S Winter

B Ganchev

B Eccles

S Gerty

A Tfayli

J S L Lim

Y S Yap

R C H Ng

N S Wong

R Dent

M Z Habbal

E Schaeffeler

M Eichelbaum

W Schroth

M Schwab

H Brauch

Affiliations

Soon will be listed here.

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 (R(2): 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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