tailoring adjuvant endocrine therapy for postmenopausal breast cancer a cyp2d6 multiple-genotype-based modeling analysis and validation裁剪辅助内分泌治疗绝经后患乳腺癌的cyp2d6 multiple-genotype-based建模分析和验证.pdf

Tailoring Adjuvant Endocrine Therapy for Postmenopausal Breast Cancer: A CYP2D6 Multiple- Genotype-Based Modeling Analysis and Validation . . Ke-Da Yu , A-Ji Huang , Zhi-Ming Shao* Department of Oncology, Shanghai Medical College, Cancer Institute and Cancer Center, Institutes of Biomedical Science, Fudan University, Shanghai, People’s Republic of China Abstract Purpose: Previous 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. Methods: We 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. Results: The 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. Conclusions: Our m