Division of Medical Oncology and Hematology, Princess Margaret Hospital and University of Toronto, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
Breast Cancer Res Treat. 2010 Aug;122(3):609-17. doi: 10.1007/s10549-010-0902-3. Epub 2010 May 8.
Pharmacological evidence shows that cytochrome P450 2D6 (CYP2D6) function is important in the conversion of tamoxifen to its active metabolites. Many retrospective analyses have assessed the role of both CYP2D6 genotype and concurrent administration of drug inhibitors of CYP2D6 on outcome of tamoxifen therapy. These studies have frequently been of small size and their data highly variable. A published data meta-analysis of trials evaluating outcomes of tamoxifen therapy in early breast cancer was undertaken. Hazard ratios (HRs) were extracted for disease-free survival (DFS) and overall survival (OS). Pooled estimates were computed using inverse-variance and random-effect modeling. Data from 10 studies assessing CYP2D6 genotype were included in a meta-analysis. There was significant heterogeneity in the definition of comparison groups between studies. When compared to reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR 2.07, 95% CI 0.96-4.49, P = 0.06) but not OS (HR 1.36, 95% CI 0.73-2.52, P = 0.34). Pooling of data from two studies evaluating CYP2D6 drug inhibitors showed that concomitant administration of these with tamoxifen was associated with a non-significant association with DFS (HR 1.37, 95% CI 0.69-2.73, P = 0.37). Analysis of the effect of CYP2D6 drug inhibitors on OS was not possible. The effect of CYP2D6 genotype on breast cancer seems to be relatively small and may not warrant testing of CYP2D6 genotype in all women with hormone receptor positive breast cancer. The effect of CYP2D6 genotype on outcome in low-risk patients may not be clinically relevant, while the upfront use of aromatase inhibitors is a reasonable alternative to tamoxifen in high-risk post-menopausal women, irrespective of CYP2D6 genotype. There are limited data supporting the association of potent inhibitors of CYP2D6 and detrimental outcome, but avoidance of such drugs seems reasonable.
药物学证据表明细胞色素 P450 2D6（CYP2D6）的功能对于他莫昔芬转化为其活性代谢物非常重要。许多回顾性分析评估了 CYP2D6 基因型和同时使用 CYP2D6 药物抑制剂对他莫昔芬治疗结果的作用。这些研究通常规模较小，数据差异较大。对评估早期乳腺癌他莫昔芬治疗结果的试验进行了已发表数据的荟萃分析。提取无病生存率（DFS）和总生存率（OS）的风险比（HR）。使用逆方差和随机效应模型计算合并估计值。纳入了 10 项评估 CYP2D6 基因型的研究数据进行荟萃分析。研究之间比较组的定义存在显著的异质性。与 CYP2D6 功能降低相比，正常功能与 DFS 改善趋势相关（HR 2.07，95%CI 0.96-4.49，P=0.06），但与 OS 无关（HR 1.36，95%CI 0.73-2.52，P=0.34）。对两项评估 CYP2D6 药物抑制剂的研究的数据进行汇总显示，同时使用这些药物与他莫昔芬联合使用与 DFS 无显著相关性（HR 1.37，95%CI 0.69-2.73，P=0.37）。无法分析 CYP2D6 药物抑制剂对 OS 的影响。CYP2D6 基因型对乳腺癌的影响似乎相对较小，可能不需要对所有激素受体阳性乳腺癌女性进行 CYP2D6 基因型检测。CYP2D6 基因型对低危患者的影响可能在临床上无意义，而在高危绝经后妇女中，芳香酶抑制剂的一线使用是替代他莫昔芬的合理选择，而与 CYP2D6 基因型无关。有有限的数据支持强效 CYP2D6 抑制剂与不良结局之间的关联，但避免使用此类药物似乎是合理的。
