Abstract
PurposePrevious studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6.MethodsWe created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive metabolizer (EM) patients using annual hazard ratio (HR) data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS) using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates.ResultsThe 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%). In the validation study, we further demonstrated that the 9-year EFS of tamoxifen-treated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4%) and similar to that of patients receiving an AI (83.2%). Two-way sensitivity analyses demonstrated the robustness of the results.ConclusionsOur modeling analyses indicate that, among EM patients, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to evaluate the value of the CYP2D6 genotype in the selection of endocrine therapy.
Highlights
Adjuvant tamoxifen is a fundamental systemic therapy for patients with hormone receptor-positive breast cancer [1]
The cytochrome P450 2D6 (CYP2D6) gene is highly polymorphic, and its phenotypes are usually categorized into four groups: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), and ultra-rapid metabolizer (UM) [4,5,6]
Using the data from the ATAC trial, our model obtained a 9-year event-free survival (EFS) of 83.2% for those receiving an aromatase inhibitors (AIs) and 78.4% for those receiving tamoxifen. These simulated results were similar to the real 9-year EFS outcomes reported in the ATAC trail (83.0% and 78.2% for anastrozole and tamoxifen, respectively)
Summary
Adjuvant tamoxifen is a fundamental systemic therapy for patients with hormone receptor-positive breast cancer [1]. Two minor but extremely active metabolites of tamoxifen, 4-hydroxytamoxifen and 4-hydroxy-N-desmethyltamoxifen (endoxifen), have been indicated to be predominantly catalyzed by cytochrome P450 2D6 (CYP2D6) [2]. The plasma concentrations of endoxifen could be affected by the genotypes coding for the CYP2D6 enzyme [3]. The clinical efficacy of tamoxifen may vary according to CYP2D6 genotypes. The CYP2D6 gene is highly polymorphic, and its phenotypes are usually categorized into four groups: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM), and ultra-rapid metabolizer (UM) [4,5,6]. The role of tamoxifen in postmenopausal breast cancer patients has been challenged by aromatase inhibitors (AIs)
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