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Tamoxifen is used to prevent and treat estrogen-dependent breast cancer. It is described as a prodrug since most of its antiestrogen effects are exerted through its hydroxylated metabolites 4-OH-tamoxifen and endoxifen. In prior work, we correlated optimal plasma levels of these metabolites with certain genotypes of  CYP2D6  and  SULT1A2 . This descriptive study examines correlations between concentrations of tamoxifen's glucuronide metabolites and genotypes  UGT1A4 Pro24Thr ,  UGT1A4 Leu48Val ,  UGT2B7 His268Tyr ,  UGT2B15 Asp85Y Tyr  UGT2B15 Lys523Thr  and  UGT2B17del  in 132 patients with estrogen receptor-positive breast cancer under treatment with tamoxifen. Patients were genotyped by real-time and conventional PCR-RFLP. The glucuronides 4-OH-tamoxifen-N-glucuronide, 4-OH-tamoxifen-O-glucuronide and endoxifen-O-glucuronide were isolated from blood plasma and quantified using a high-pressure liquid chromatography-tandem mass spectrometry system. Individuals who were homozygous for  UGT1A4 48VAL   showed significantly lower mean concentrations of both glucuronide metabolites compared to subjects genotyped as wt/wt plus wt/48Val (p=0.037 and p=0.031, respectively). Women homozygous for UGT2B7 268Tyr  also showed mean substrate/product ratios of 4-OH-tamoxifen/4-OH-tamoxifen-O-glucuronide and 4-OH-tamoxifen/4-OH-tamoxifen-N-glucuronide indicative of reduced glucuronidase activity compared to wt homozygotes or to heterozygotes for the polymorphism (p=0.005 and p=0.003, respectively). In contrast,  UGT2B15 Lys523Thr  and  UGT2B17del  were associated with possibly increased enzyme activity. Patients with at least one variant allele  UGT2B15 523Thr   showed significantly higher 4-OH-tamoxifen-O-glucuronide and endoxifen-glucuronide levels (p=0.023 and p=0.025, respectively) indicating a variant gene-dose effect. Higher 4-OH-tamoxifen-N-glucuronide levels observed in  UGT2B17del  genotypes (p=0.042) could be attributed to a mechanism that compensates for the greater expression of other genes in  UGT2B17  del/del individuals. Our observations suggest that patients carrying mutations  UGT1A4 48Val  ,  UGT2B7 268Tyr   or with wt genotypes for  UGT2B17 nodel   and  UGT2B15 523Lys   could be the best candidates for a good response to tamoxifen therapy in terms of eliciting effective plasma active tamoxifen metabolite levels. However, additional studies examining the effects of UGT genotype on overall patient response to TAM are needed to further examine the role of UGT polymorphisms in the therapeutic efficacy of TAM.

Impacts of the Glucuronidase Genotypes UGT1A4, UGT2B7, UGT2B15 and UGT2B17 on Tamoxifen Metabolism in Breast Cancer Patients