CYP2D6 genotype related to tamoxifen efficacy: An analysis with exclusion of potential false CYP2D6 genotype assignment caused by loss of heterozygosity in tumor tissue.

Abstract

597 Background: The clinical importance of CYP2D6 genotype as predictor of tamoxifen efficacy is still unclear. Recent genotyping studies on CYP2D6 using DNA derived from tumor blocks have been criticized because loss of heterozygosity (LOH) in tumors may lead to false genotype assignment. Methods: Postmenopausal early breast cancer patients who were randomized to receive tamoxifen, followed by exemestane in the Tamoxifen Exemestane Adjuvant Multinational trial (TEAM) were genotyped for 5 CYP2D6 variant alleles. CYP2D6 genotypes and phenotypes were related to disease free survival during tamoxifen use (DFS-t) in 731 patients. By analyzing three microsatellites flanking the CYP2D6 gene, patients whose genotyping results were potentially affected by LOH were excluded. Results: Analysis of the CYP2D6 alleles and the microsatellite markers demonstrated heterozygosity for at least one of the CYP2D6 alleles or microsatellite markers in 97.7% of patients with a specified CYP2D6 phenotype. The 14 patients (2.3%) with a homozygous CYP2D6 genotype in which no heterozygosity could be demonstrated for the microsatellite markers were excluded from the analysis. No association was found between the CYP2D6 genotype or predicted phenotype and DFS-t. Conclusions: In postmenopausal early breast cancer patients treated with adjuvant tamoxifen followed by exemestane neither CYP2D6 genotype nor phenotype was associated with DFS-t. This is in accordance with two recent studies in the BIG1-98 and ATAC trials. Our study is the first CYP2D6 association study using DNA from paraffin embedded tumor tissue in which potentially false interpretation of genotyping results because of LOH was excluded.