Abstract 3675: Effects of cytochrome P450 2D6 polymorphisms on tamoxifen metabolism in a pooled analysis of breast cancer prevention trials designed to define the minimal active dose of the drug

Background Tamoxifen is the most widely used drug for the prevention and treatment of hormone-receptor positive breast cancer (BC). Nevertheless, its clinical effectiveness varies among individuals. Tamoxifen is extensively metabolized by cytochrome P450 (CYP) enzymes, and recent in vivo studies have shown that women with genetically impaired CYP2D6 have reduced production of endoxifen, the main active metabolite. This impairment has been linked to a higher risk of breast cancer recurrence. Despite these observations, the contribution of endoxifen to the overall drug effectiveness of tamoxifen remains uncertain. Methods and results This study presents a pooled analysis of four chemoprevention trials assessing three different low dose tamoxifen schedules: 1mg/day (n=52), 10 mg/week (n=152) and 5 mg/day (n=158). Each participant had signed an informed consent. Genomic DNA was extracted from whole blood by the QIAamp DNA Blood Kit (Qiagen, Valencia, CA, USA), and the CYP2D6 polymorphisms analyzed by the use of the INFINITI CYP450 2D6T Assay (AutoGenomics, Carlsbad, CA, USA). The following alleles were identified: Full enzyme activity: *1, *2; reduced activity: *9, *41 *29; no activity: *3, *4, *5, *6. A total of 336 out of the 362 study participants were genotyped. Circulating concentrations of tamoxifen and its metabolites were determined on cryo-conserved (−80°C) serum samples collected at different treatment intervals according to study design. The women were defined as extensive metabolizers (EM) if they had 2 fully active alleles; intermediate (IM) if they carried reduced alleles or one non-functional allele, while poor metabolizers (PM) carried two non-functional alleles. We found the following phenotype frequencies: 146/336 (43%) EM, 171/336 (51%) IM, 19/336 (6%) PM. When analyzing the effects of phenotypes on serum concentrations of tamoxifen and its metabolites we found a statistically significant effect of phenotype on tamoxifen and metabolites. EM had lower levels of tamoxifen (8,6 ng/mL; P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3675. doi:10.1158/1538-7445.AM2011-3675