CYP2D6 genotype and optimization of breast cancer treatment

Abstract

A previous modeling analysis suggests that postmenopausal breast cancer women with wild-type CYP2D6 (non-CYP2D6*4-allele carriers) might actually have superior disease-free survival (DFS) outcomes when they take tamoxifen rather than an aromatase inhibitor (AI). The present study not only adjusts that original model by the comedication status of CYP2D6-inhibitors but also reconstructs a multiple-genotypebased model, so that an optimizing endocrine therapy for patients harboring wild-type CYP2D6 would be exactly determined. We created Markov models (a modified model and a reconstructed model) to determine whether tamoxifen or AIs maximized 5-year DFS for extensive-metabolizer patients. We also employed twoway sensitivity analyses to explore the impacts of hazard ratio (HR) of decreased metabolizers and frequency of each metabolizer on DFS by studying a range of estimates. In the comedication-adjusted model, the 5-year-DFS of tamoxifen-treated extensive-metabolizer patients was 84.7%, similar to or slightly superior to that for genotypically unselected patients receiving AIs (84.0%). Similarly, in the reconstructed model, the extensive-metabolizer patients also benefited more from tamoxifen than from AIs (5-year-DFS, 85.7% vs. 84.0%). Our reconstructed model with two parameters simplified the prediction of tamoxifen response and increased the reliability. Two-way sensitivity analyses demonstrated the robustness of these results. In conclusion, our modeling analyses indicate that among extensivemetabolizer patients, DFS outcomes of patients receiving tamoxifen are similar to even superior to those receiving AIs. The findings strongly suggest that postmenopausal patients who are concerned about the toxicity or cost of AIs could refer to the CYP2D6 genetic testing to pursue an optimal adjuvant endocrine treatment.