Impact of combined UGT2B17 and GSTA1 genotypes on exemestane pharmacogenetics

Exemestane (EXE) is an aromatase inhibitor used for the treatment of estrogen receptor–positive breast cancer. The metabolism of EXE includes reduction to form 17-β-hydroxy-EXE (17β-DHE) and subsequent UGT2B17-mediated glucuronidation to form 17-β-hydroxy-EXE-17-O-β-D-glucuronide (17β-DHE-Gluc), and GSTA1-mediated glutathione conjugation of EXE and 17β-DHE and subsequent sequential metabolism by γ-glutamyl transferases and dipeptidases to form 6-methylcysteinylandrosta-1,4-diene-3,17-dione (EXE-Cys) and 6-methylcysteinylandrosta-1,4-diene-17-β-hydroxy-3-one (17β-DHE-Cys). The aim of the present study was to determine the effects of UGT2B17 and GSTA1 genotype on the serum levels of EXE and its metabolites among subjects taking EXE. Genotypes of UGT2B17 and GSTA1 were determined by real-time polymerase chain reaction and serum EXE, 17β-DHE, 17β-DHE-Gluc, EXE-Cys, and 17β-DHE-Cys were quantified by ultra performance liquid chromatography-mass spectrometry. Shunting was observed between the 2 metabolic pathways of EXE, with serum EXE levels increased with increasing numbers of either the UGT2B17∗2 or GSTA1∗B alleles (P_trend< .0001). 17β-DHE-Gluc levels decreased (P_trend< .0001) and EXE-Cys levels increased (P_trend< .0001) with combined increasing numbers of the UGT2B17∗2 allele and decreasing numbers of the GSTA1∗B allele. Although GSTA1 genotype alone showed no effect on serum 17β-DHE-Gluc levels, the UGT2B17 (∗2/∗2) genotype was associated with a 10.4-fold decrease (P < .0001) in serum 17β-DHE-Gluc levels as compared with wild-type UGT2B17. The GSTA1 (∗B/∗B) genotype was associated with 1.4- (P < .0001) and 1.3-fold (P = .0005) decreases, whereas UGT2B17 (∗2/∗2) genotype was associated with 2.1- (P < .0001) and 2.3-fold (P < .0001) increases in EXE-Cys and 17β-DHE-Cys formation, respectively, as compared with their respective wild-type genotypes. These results suggest that GSTA1 and UGT2B17 genotypes play an important role in EXE metabolism variability and potentially in patient response to EXE. Significance Statement: To our knowledge, the present pharmacogenetic study is the first to examine interindividual variability in exemestane (EXE) metabolism for the 2 major phase II metabolism pathways of EXE. The UGT2B17 genotype was found to contribute to substantial interindividual variability in the metabolism of EXE, however, GSTA1 genotype was also significantly associated with altered EXE metabolism. Given their high polymorphic allele frequency, genotypes of UGT2B17 and GSTA1 potentially play important roles in interindividual variability in patient response including EXE efficacy and toxicity.