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A certain minimum plasma concentration of ( Z )-endoxifen is presumably required for breast cancer patients to benefit from tamoxifen therapy. In this study, we searched for DNA variants that could aid in the prediction of risk for insufficient ( Z )-endoxifen exposure. A metabolic ratio (MR) corresponding to the ( Z )-endoxifen efficacy threshold level was adopted as a cutoff value for a genome-wide association study comprised of 287 breast cancer patients. Multivariate regression was used to preselect variables exhibiting an independent impact on the MR and develop models to predict below-threshold MR values. In total, 15 single-nucleotide polymorphisms (SNPs) were significantly associated with below-threshold MR values. The strongest association was with rs8138080 ( WBP2NL ). Two alternative models for MR prediction were developed. The predictive accuracy of Model 1, including rs7245, rs6950784, rs1320308, and the CYP2D6 genotype, was considerably higher than that of the CYP2D6 genotype alone (AUC 0.879 vs 0.758). Model 2, which was developed using the same three SNPs as for Model 1 plus rs8138080, appeared as an interesting alternative to the full CYP2D6 genotype testing. In conclusion, the four novel SNPs, tested alone or in combination with the CYP2D6 genotype, improved the prediction of impaired tamoxifen-to-endoxifen metabolism, potentially allowing for treatment optimization.

Non-CYP2D6 Variants Selected by a GWAS Improve the Prediction of Impaired Tamoxifen Metabolism in Patients with Breast Cancer