Lack of Correlation between Genetic Polymorphisms in Tamoxifen Metabolizing Enzymes with Primary Endpoints in the IMPACT Trial.

Abstract

Abstract Background. Several studies aimed at correlating genetic variants in the enzymes responsible for tamoxifen metabolism and disposition with therapeutic outcomes have provided equivocal and conflicting data. The IMPACT trial compared the preoperative used of tamoxifen with anastrozole alone or in combination in postmenopausal breast cancer patients and provided strong evidence that tamoxifen-induced changes in the nuclear proliferation marker Ki67 can act as a surrogate marker of tamoxifen response. An advantage of this study design is that all patients contribute data to the end-point analyses which included changes in Ki67 and objective clinical response as defined by the WHO criteria. We therefore genotyped patients from IMPACT for variants in the enzyme (cytochrome p450 2D6 (CYP2D6)) responsible for the conversion of tamoxifen to its potent anti-estrogenic metabolite endoxifen, as well as the enzyme responsible for the detoxification and inactivation of endoxifen via conjugation (UDP-glucuronosyltransferase 2B7 (UGT2B7).Results: Depending on their CYP2D6 variant genotype, patients were assigned an 'activity score' based on predicted allele activities from 0 (no activity) to 2 (high activity). Patients were also tested for the UGT2B7*2 variant, which has lower enzymatic activity and is therefore correlated with higher serum endoxifen concentrations. Of the 135 patient samples available for genotype determinations, 123 and 134 we evaluable for CYP2D6 and UGT2B7, respectively. There was no evidence of an association between CYP2D6 score, as determined by genotype alone, with suppression of Ki67 after 2 or 12 weeks, or with objective clinical response after 16 weeks of therapy in the tamoxifen alone, anastrozole alone or combination groups. Furthermore, this lack of association was not altered by adjustment of the CYP2D6 score for concomitant medications, known to inhibit CYP2D6 and to correlate with lower serum endoxifen concentrations. Lastly, while a statistical test for a potential interaction between CYP2D6 genotype and UGT2B7 genotype was negative, there was a marginally statistically significant association between UGT2B7 genotype alone with suppression of Ki67 after 2 weeks in the tamoxifen only group.Conclusion: Although this was a small study, these data do not support the hypothesis that patients must have active CYP2D6 in order to benefit from tamoxifen therapy. Larger more definitive studies are underway to test the effects of drug metabolizing enzymes on anti-estrogen therapies. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2011.