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-glucuronosyltransferases (UGTs). 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 one year (ER+/TAM+), and 300 cases of recurrent breast cancer among women with estrogen receptor-negative tumors who were not treated with tamoxifen (ER−/TAM−). We matched 1 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 odds ratio for the UGT polymorphisms 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 ER+/TAM+ or ER-/TAM- groups [in the ER+TAM+ 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 for UGT2B7*2 variant alleles = 0.91 (95% CI: 0.65, 1.3); adjusted OR for 1 or 2 UGT1A8*3 variant alleles = 0.75 (0.41, 1.4)]. 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.

Individualization of tamoxifen therapy: Much more than just CYP2D6 genotyping

“…In addition, few studies have examined the association between polymorphic UGTs (e.g. UGT2B7 ⁄ 2, UGT2B15 ⁄ 2, UGT1A8 ⁄ 3) and clinical outcome, but most of them did not find a significant association [38,48,74]. The most common variant allele SULT1A1 ⁄ 2 has been associated with decreased enzyme activity, but neither Jin and colleagues [17] nor Gjerde and colleagues [18] showed an association between SULT1A1 genotype and concentrations of tamoxifen or its metabolites.…”

“…The variant allele UGT2B7 ⁄ 2 has been associated with reduced activity, while an increased glucuronidation activity has been found for UGT2B15 ⁄ 2. The variant allele UGT1A8 ⁄ 3 lacks activity [74]. However, genetic variants of UGT2B7 and UGT2B15 have not been correlated with systemic levels of 4-hydroxytamoxifen or endoxifen in tamoxifen-treated individuals [9].…”

Metabolism and Transport of Tamoxifen in Relation to its Effectiveness: New Perspectives on an Ongoing Controversy

“…The tamoxifen derivatives with hydroxyl groups attached to their four-carbon have the highest binding affinities to the ER. The UDP-glucuronosyltransferase enzymes (primarily UGT1A8, UGT1A10, UGT2B7 and UGT2B15) [13,14] and sulfotransferase enzymes (primarily SULT1A1) [15] catalyze the conversion of tamoxifen metabolites into excretable forms. All enzymes in tamoxifen's metabolic pathway are polymorphic.…”

Phase Two Steroid Metabolism and Its Roles in Breast and Prostate Cancer Patients

“…When probing the relevance of these polymorphisms in breast and prostate cancer two potential roles have been identified; the impact of polymorphisms upon the tissue metabolism of endogenous steroids and the potential impact of the polymorphisms upon the metabolism of chemical or endocrine directed therapy. The latter is considered important but it is outside the scope of this review and we direct the reader toward original papers dealing with this topic (44–46). In this section we will concentrate on the potential impact of polymorphisms in treatment-naïve settings.…”