Abstract 3604: Significant effect of polymorphisms in CYP2D6 and DT-1 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients

Abstract

Abstract PURPOSE: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism and elimination of its active forms. We investigated relations of polymorphisms in transporter genes as well as CYP2D6 to clinical outcome of patients with tamoxifen treatment. PATIENTS AND METHODS: We enrolled 282 hormone receptor-positive, invasive breast cancer patients receiving tamoxifen monotherapy. We investigated the effects of allelic variants of CYP2D6 and tag-SNPs of DT-1, DT-2 and DT-3 on recurrence-free survivals using Kaplan-Meier and Cox regression analyses. Plasma concentrations of tamoxifen metabolites were measured in 98 patients taking 20 mg/day of tamoxifen. RESULTS: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = 3.6×10−5; hazard ratio (HR) 9.52 [95% CI 2.79-32.45] in patients with 2 variant alleles vs without variant allele). Among 51 tag-SNPs in transporter genes, a significant association was found at SNPY in DT-1(P = 1.7×10−4; HR 10.64 [95% CI 1.44-78.88] in patients with AA vs GG genotypes). The number of risk alleles of CYP2D6 and DT-1 showed cumulative effects on recurrence-free survivals (P = 5.5×10−8). The patients carrying 4 risk alleles had 45.25-times higher risk compared to those with ≤1 risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = 4.3×10−6 and 5.2×10−4), whereas no significant difference was found among DT-1 genotype groups. CONCLUSION: Our results indicated that polymorphisms in CYP2D6 and DT-1 are important predictors for the prognosis of breast cancer patients treated with tamoxifen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3604.