Tamoxifen reduces the rate of breast cancer recurrence by approximately a half. Tamoxifen is metabolized to more active metabolites by enzymes encoded by polymorphic genes, including cytochrome P450 2D6 (CYP2D6). Tamoxifen is a substrate for ATP-binding cassette transporter proteins. We review tamoxifen's clinical pharmacology and use meta-analyses to evaluate the clinical epidemiology studies conducted to date on the association between CYP2D6 inhibition and tamoxifen effectiveness. Our findings indicate that the effect of both drug-induced and/or gene-induced inhibition of CYP2D6 activity is likely to be null or small, or at most moderate in subjects carrying two reduced function alleles. Future research should examine the effect of polymorphisms in genes encoding enzymes in tamoxifen's complete metabolic pathway, should comprehensively evaluate other biomarkers that affect tamoxifen effectiveness, such as the transport enzymes, and focus on subgroups of patients, such as premenopausal breast cancer patients, for whom tamoxifen is the only guideline endocrine therapy.
Future Oncology, 2014, Vol 10, Issue 1, p. 107-22
Biological Transport; Breast Neoplasms; Cytochrome P-450 CYP2D6; Female; Humans; Serotonin Uptake Inhibitors; Tamoxifen; Treatment Outcome; ATP-binding cassette transporter breast cancer breast cancer recurrence cytochrome P450 2D6 multiple drug resistance P-glycoprotein polymorphism selective serotonin reuptake inhibitor tamoxifen BREAST-CANCER PATIENTS RECEIVING ADJUVANT TAMOXIFEN SEROTONIN REUPTAKE INHIBITORS HARDY-WEINBERG EQUILIBRIUM RE CYP2D6 GENOTYPE GROUP 1-98 TRIAL RECURRENCE-FREE SURVIVAL HUMAN LIVER-MICROSOMES POSTMENOPAUSAL WOMEN GENETIC POLYMORPHISMS