Department of Oncology, Shanghai Medical College, Cancer Institute and Cancer Center, Fudan University, Shanghai, People's Republic of China.
PLoS One. 2010 Dec 20;5(12):e15649. doi: 10.1371/journal.pone.0015649.
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.
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.
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.
Our 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.
先前的研究表明，患有乳腺癌且 CYP2D6 为野生型的绝经后妇女，在接受他莫昔芬治疗而非芳香化酶抑制剂（AIs）时，可能具有相似或更优的无复发生存结局。本研究建立了一个基于 CYP2D6 多种基因型的模型，以确定携带野生型 CYP2D6 的患者的最佳内分泌治疗方案。
我们创建了一个 Markov 模型，使用 BIG 1-98 试验的年度风险比（HR）数据，来确定广泛代谢者（EM）患者使用他莫昔芬或 AIs 能否最大化 5 年无病生存（DFS）。然后，我们通过评估 ATAC 试验的 HR 数据，使用 9 年无事件生存（EFS）来复制该模型。此外，我们通过研究一系列估计值，进行双向敏感性分析，以研究降低代谢者（DM）的 HR 及其频率对生存的影响。
接受他莫昔芬治疗的 EM 患者 5 年 DFS 为 83.3%，与接受 AI 治疗的未经基因分型选择的患者（83.7%）相似。在验证研究中，我们进一步表明，接受他莫昔芬治疗的 EM 患者 9 年 EFS 为 81.4%，高于未经基因分型选择的接受他莫昔芬治疗的患者（78.4%），与接受 AI 治疗的患者（83.2%）相似。双向敏感性分析表明结果稳健。
我们的模型分析表明，在 EM 患者中，接受他莫昔芬治疗的患者的 DFS/EFS 结局与接受 AI 治疗的患者相似。需要进一步的前瞻性临床试验来评估 CYP2D6 基因型在选择内分泌治疗中的价值。
