Functional polymorphisms in UDP-glucuronosyl transferases and recurrence in tamoxifen-treated breast cancer survivors

Abstract

Background: Tamoxifen is oxidized by cytochrome-P450 enzymes (e.g., CYP2D6) to two active metabolites, which are eliminated via glucuronidation by UDP-glucuronosyl transferases (UGT). We measured the association between functional polymorphisms in key UGTs (UGT2B15*2, UGT2B7*2, and UGT1A8*3) and the recurrence rate among breast cancer survivors. Methods: We used the Danish Breast Cancer Cooperative Group registry to identify 541 cases of recurrent breast cancer among women with estrogen receptor-positive tumors treated with tamoxifen for at least 1 year (ERp/TAMp), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER -/TAM -). We matched one control to each case on ER status, menopausal status, stage, calendar period, and county. UGT polymorphisms were genotyped from archived primary tumors. We estimated the recurrence OR for the UGT polymorphisms by using logistic regression models, with and without stratification on CYP2D6*4 genotype. Results: No UGT polymorphism was associated with breast cancer recurrence in either the ERp/TAMp or ER -/TAM - groups [in the ERp/TAMp group, compared with two normal alleles: adjusted OR for two UGT2B15*2 variant alleles = 1.0 (95% CI, 0.70-1.5); adjusted OR for two UGT2B7*2 variant alleles = 0.96 (95% CI, 0.65-1.4); adjusted OR for one or two UGT1A8*3 variant alleles = 0.95 (0.49-1.9)]. Associations were similar within strata of CYP2D6*4 genotype. Conclusions: Functional polymorphisms in key tamoxifen-metabolizing enzymes were not associated with breast cancer recurrence risk. Impact: Our results do not support the genotyping of key metabolic enzyme polymorphisms to predict response to tamoxifen therapy. ©2011 AACR.