Abstract A1: Impact of CYP2D6*10 and CYP3A5*3 polymorphisms on the pharmacokinetics of tamoxifen in Asian breast cancer patients

Background: Tamoxifen (TAM) is a selective estrogen receptor modulator employed in the treatment of breast cancer. It is a prodrug with a complex metabolic pathway involving several phase I and II metabolic enzymes. TAM is metabolized by cytochrome P450 (CYP) enzymes to N-desmethyltamoxifen (NDM), 4-hydroxytamoxifen (4OHT) and endoxifen (END) with 4OHT and END being the active metabolites of TAM. CYP2D6 and CYP3A4/5 comprises the major CYP isoforms mediating the metabolism of TAM although other CYP isoforms also play a role. Polymorphisms present in genes encoding these CYP enzymes may influence the metabolism and pharmacokinetics of TAM and its metabolites. Methods: A total of 116 Asian breast cancer patients were genotyped for CYP3A5∗3 polymorphism while 104 of these patients were genotyped for CYP2D6. Plasma levels of TAM and its 3 metabolites were obtained at steady state. The occurrence of hot flashes were monitored. Results: The allelic frequencies of CYP2D6∗10 and CYP3A5∗3 in the breast cancer patients were 0.52 and 0.71, respectively. The plasma END level (median; range) of patients with CYP2D6∗10/∗10 (8.85; 6.27-34.68) was significantly lower compared to patients with CYP2D6∗1/∗1 (19.55; 4.18-42.56; pCYP2D6∗1/∗10 (16.18; 9.48-33.24; pCYP2D6∗10 was 359.02 ng/ml (124.7–590.65) and was significantly higher compared to patients with CYP2D6∗1/∗1 (239.27; 40.82-584.26; p=0.012). No associations were observed between the pharmacokinetics of TAM and CYP3A5∗3. Hot flashes, a common side-effect of TAM, occurred at an overall frequency of 0.208 in the patient population. Patients homozygous for the ∗10/∗10 genotype had the highest frequency of hot flashes compared to wild-type subjects (P>0.05). Conclusion: This exploratory study identified CYP2D6∗10 to be an important predictor of TAM pharmacokinetics in Asian breast cancer patients. Other polymorphisms present in CYP2D6 or genes encoding other enzymes involved in metabolism of TAM may be useful in explaining inter-individual variation in TAM pharmacokinetics. Citation Information: Clin Cancer Res 2010;16(7 Suppl):A1