Effects of CYP2D6 and UGT2B7 polymorphisms on Tamoxifen pharmacokinetics and treatment outcomes in Thai breast cancer patients

Abstract

Antiestrogen tamoxifen (TAM) is used as adjuvant treatment in estrogen receptor positive breast cancer. TAM is a prodrug which is converted to endoxifen (END), an active metabolite with approximately 100 times higher affinity with estrogen receptor than TAM, by CYP2D6 then is excreted via glucuronidation by UGT2B7, one of the enzymes in UGTs family. The objectives of this study were to evaluate the impacts of enzyme polymorphisms on TAM pharmacokinetics using TAM and END plasma concentrations. Fifty-nine female breast cancer patients were included in the study. Average age was 50+9.3 years old, 76% of them were premenopausal and 85% had estrogen receptor positive breast cancer. Allele frequency of CYP2D6*10 and UGT2B7*2 were 0.53 and 0.28, respectively. Patients with CYP2D6*10/*10 had lower END concentrations compare to CYP2D26*1/*10 and CYP2D6*1/*1 (14.7+14.7 vs 17.9+9.8 and 22.4+12.8 ng/ml, respectively, p = 0.045). Polymorphisms of UGT2B7 alone did not have any impact on TAM metabolism, however, among patients with CYP2D6 *10/*10 (n=20), one with UGT2B7*2/*2 tended to have higher END concentrations compared to patients with UGT2B7*1/*1 and UGT2B7*1/*2 (27.2+7.2 ng/ml vs 9.03+4.9 and15.6+19.7 ng/ml, respectively, p= 0.073). Regarding treatment outcomes, low END concentrations that might be related to worse results shown in mammography screening. In patients with END concentration less than 15.3 ng/ml, the percentage of mammogram result as BI-RADS>3 was higher when compared to patients with higher END concentrations (41.2 % vs 19%). Adverse events were also found more frequent in patients with higher END concentration (26.7% vs 3.4%, OR 10.18, p = 0.034). In summary, this study confirmed impacts of CYP2D6 and UGT2B7 polymorphisms on pharmacokinetics of TAM. END concentrations tended to be related to treatment outcomes of Thai breast cancer patients.