Journal
PHARMACOGENOMICS JOURNAL
Volume 15, Issue 1, Pages 84-94Publisher
SPRINGERNATURE
DOI: 10.1038/tpj.2014.34
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Funding
- Robert Bosch Foundation, Stuttgart, Germany
- Deutsche Forschungsgemeinschaft (DFG), Germany [SCHR 1323/2-1, MU 1727/2-1]
- IZEPHA, Germany [21-0-0]
- German Cancer Consortium (DKTK)
- American University of Beirut Medical Practice Plan (AUBMPP)
- National Medical Research Council [NMRC/1159/2008, NMRCG13161]
- Cancer Research UK [19187] Funding Source: researchfish
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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 (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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