Pharmacogenetics of tamoxifen in relation to disease-free survival in a Dutch cohort of the tamoxifen exemestane adjuvant multinational (TEAM) trial.

Abstract

510 Background: Retrospective studies on the relationship between CYP2D6 genotype and tamoxifen efficacy show conflicting results (Dezentje et al., Clin Cancer Res 2009:15;15-21). Negative studies have been criticized because of heterogeneous populations, lack of controlling for possible confounders and of systematic documentation of treatment adherence and outcome measures. Well documented studies on homogeneous populations with a more comprehensive pathway approach are imperative. Methods: 747 Dutch patients who were randomized to receive tamoxifen followed by exemestane after 2.5 to 3 years within the TEAM Trial were genotyped for 29 germline genetic variants in 12 candidate genes encoding enzymes that are involved in the metabolic and pharmacodynamic pathway of tamoxifen. These variants were related to disease free survival (DFS) during tamoxifen use (censored at the time of switch to exemestane). A multivariable Cox regression was used to adjust for clinically relevant factors. Results: The clinical characteristics of the genotyped patients were similar to the entire Dutch TEAM cohort randomized to tamoxifen (n = 1,379). DFS was associated with UGT2B15*2 [Vt/Vt + Wt/Vt vs. Wt/Wt: HR = 0.51 (0.27-0.95); p = 0.034] and the estrogen receptor-1 polymorphism ESR1 PvuII [gene-dose effect: HR = 1.72 (1.10-2.69); p = 0.017]. In the univariable analysis CYP2C19*2 was associated with DFS [Vt/Vt vs Wt/Vt + Wt/Wt: HR = 3.85 (1.64-9.05); p = 0.002]. However, this association lost significance when adjusted for the ESR1 PvuII polymorphism. No association was found between the CYP2D6 genotypes and DFS. Conclusions: This translational study suggests that common and therefore relevant polymorphisms in UGT2B15 and the estrogen receptor-1 impact DFS in breast cancer patients treated with adjuvant tamoxifen. The previously reported association between CYP2D6 genotype and tamoxifen efficacy was not confirmed in our study. No significant financial relationships to disclose.