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Tamoxifen efficacy may be influenced by a number of factors, including CYP2D6 genotype, co-administration of drugs that inhibit CYP2D6, and adherence to tamoxifen therapy. CYP2D6 plays a major role in catalyzing the conversion of tamoxifen to its active metabolite endoxifen. Studies of the relevance of CYP2D6 genotyping have had conflicting results due to various limitations: differences in CYP2D6 allele coverage, phenotype classification and other confounding variables.
Using archival samples from two UK cohorts of tamoxifen-treated women with invasive breast cancer (Dundee, n = 391; Manchester, n = 227), we estimated the association of inferred CYP2D6 metabolic phenotypes with recurrence-free survival time (RFS) using Cox proportional hazard models, adjusted for nodal status and tumor size. Comprehensive CYP2D6 genotyping was performed using the AmpliChip CYP450 test.
Sixty percent of patients had at least one reduced-function CYP2D6 allele and 6% had no functional alleles. Analysis of the entire group revealed a nonsignificant trend for worse RFS in patients with any reduced function alleles - HR = 1.52 (CI = 0.98 to 2.36, P = 0.06). In the subset of postmenopausal women on tamoxifen monotherapy, the HR for recurrence for patients with reduced functional alleles was 1.96 (CI = 1.05 to 3.66, P = 0.036). When the analysis was limited to four common allelic variants of CYP2D6 , this difference was not apparent.
This study indicates that patients with two fully functional CYP2D6 alleles are more likely to experience the full therapeutic benefit of tamoxifen. The apparent adverse effect of reduced function alleles is best detected by a genotyping test with comprehensive CYP2D6 allele coverage that captures uncommon variants with decreased function.