Department of Oncology, Strangeways Research Laboratory, University of Cambridge, 2 Worts Causeway, Cambridge, CB1 8RN, UK.
Breast Cancer Res. 2010;12(4):R64. doi: 10.1186/bcr2629. Epub 2010 Aug 23.
Tamoxifen is one of the most effective adjuvant breast cancer therapies available. Its metabolism involves the phase I enzyme, cytochrome P4502D6 (CYP2D6), encoded by the highly polymorphic CYP2D6 gene. CYP2D6 variants resulting in poor metabolism of tamoxifen are hypothesised to reduce its efficacy. An FDA-approved pre-treatment CYP2D6 gene testing assay is available. However, evidence from published studies evaluating CYP2D6 variants as predictive factors of tamoxifen efficacy and clinical outcome are conflicting, querying the clinical utility of CYP2D6 testing. We investigated the association of CYP2D6 variants with breast cancer specific survival (BCSS) in breast cancer patients receiving tamoxifen.
This was a population based case-cohort study. We genotyped known functional variants (n = 7; minor allele frequency (MAF) > 0.01) and single nucleotide polymorphisms (SNPs) (n = 5; MAF > 0.05) tagging all known common variants (tagSNPs), in CYP2D6 in 6640 DNA samples from patients with invasive breast cancer from SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity); 3155 cases had received tamoxifen therapy. There were 312 deaths from breast cancer, in the tamoxifen treated patients, with over 18000 years of cumulative follow-up. The association between genotype and BCSS was evaluated using Cox proportional hazards regression analysis.
In tamoxifen treated patients, there was weak evidence that the poor-metaboliser variant, CYP2D66 (MAF = 0.01), was associated with decreased BCSS (P = 0.02; HR = 1.95; 95% CI = 1.12-3.40). No other variants, including CYP2D64 (MAF = 0.20), previously reported to be associated with poorer clinical outcomes, were associated with differences in BCSS, in either the tamoxifen or non-tamoxifen groups.
CYP2D66 may affect BCSS in tamoxifen-treated patients. However, the absence of an association with survival in more frequent variants, including CYP2D64, questions the validity of the reported association between CYP2D6 genotype and treatment response in breast cancer. Until larger, prospective studies confirming any associations are available, routine CYP2D6 genetic testing should not be used in the clinical setting.
他莫昔芬是目前最有效的辅助乳腺癌治疗药物之一。其代谢涉及细胞色素 P4502D6（CYP2D6）的一期酶，该基因由高度多态性的 CYP2D6 基因编码。假设导致他莫昔芬代谢不良的 CYP2D6 变体将降低其疗效。目前有 FDA 批准的治疗前 CYP2D6 基因检测试剂盒。然而，来自已发表的研究评估 CYP2D6 变体作为他莫昔芬疗效和临床结果的预测因素的证据相互矛盾，质疑 CYP2D6 检测的临床实用性。我们研究了 CYP2D6 变体与接受他莫昔芬治疗的乳腺癌患者的乳腺癌特异性生存（BCSS）之间的关联。
这是一项基于人群的病例-队列研究。我们在 SEARCH（癌症遗传中的流行病学和风险因素研究）中对 6640 例浸润性乳腺癌患者的 DNA 样本中 CYP2D6 中的已知功能变体（n = 7；次要等位基因频率（MAF）> 0.01）和单核苷酸多态性（SNP）（n = 5；MAF > 0.05）进行了基因分型，以标记所有已知的常见变体（tagSNP）。在 3155 例接受他莫昔芬治疗的患者中，有 312 例死于乳腺癌，累积随访时间超过 18000 年。使用 Cox 比例风险回归分析评估基因型与 BCSS 之间的关联。
在接受他莫昔芬治疗的患者中，有微弱的证据表明，代谢不良的变体 CYP2D66（MAF = 0.01）与 BCSS 降低有关（P = 0.02；HR = 1.95；95%CI = 1.12-3.40）。其他变体，包括先前报道与临床结局较差相关的 CYP2D64（MAF = 0.20），在他莫昔芬组或非他莫昔芬组均与 BCSS 无差异。
CYP2D66 可能影响接受他莫昔芬治疗的患者的 BCSS。然而，更常见的变体（包括 CYP2D64）与生存无关，这质疑了 CYP2D6 基因型与乳腺癌治疗反应之间报告的关联的有效性。在有更大的、前瞻性研究证实任何关联之前，不应该在临床环境中常规使用 CYP2D6 基因检测。
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