CYP2D6 and UGT2B7 Genotype and Risk of Recurrence in Tamoxifen-Treated Breast Cancer Patients
CYP2D6 and UGT2B7 Genotype and Risk of Recurrence in Tamoxifen-Treated Breast Cancer Patients
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DOI：
10.1093/jnci/djs126
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发表时间：
2012-03-21
影响因子：
10.3
通讯作者：
Dowsett, Mitch
中科院分区：
文献类型：
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作者：
Rae, James M.;Drury, Suzy;Dowsett, Mitch
研究背景：在激素(雌激素和/或孕激素)受体阳性的乳腺癌患者中，辅助性他莫昔芬治疗可显著降低复发和死亡率。以前的研究表明，他莫昔芬需要通过细胞色素P450 2D6(细胞色素P450 2D6)代谢转化为艾多昔芬，患者才能从他莫昔芬治疗中受益。方法对参加随机双盲Arimidex、Tamoxifen、单独或联合(ATAC)临床试验的绝经后早期(I、II和IIIA期)激素受体阳性的乳腺癌患者的肿瘤标本进行CYP2D6变异基因分型(N=1203例患者：阿那曲唑[商品名：Arimidex]组，n=615例；他莫昔芬组(n=588例)和UDP-葡萄糖醛酸基转移酶-2B7(UGT2B7)，其基因产物使Enoxifen失活(N=1209例；阿那曲唑组n=606例；他莫昔芬组n=603例)。采用聚合酶链式反应Taq Man法进行基因分型。根据CYP2D6基因分型，患者可分为低代谢型(PM)、中间代谢型(IM)或广泛代谢型(EM)。我们通过使用Cox比例风险模型估计危险比(HR)和相应的95%可信区间(CI)，评估了CYP2D6和UGT2B7基因与远处复发(主要终点)和任何复发(次要终点)的相关性。结果经过10年的中位数随访，在接受他莫昔芬治疗的患者中，未发现有统计学意义的相关关系(PM和EM：远处复发的HR=1.25，95%CI=0.55~3.15，P=.64；任何复发的HR=0.99，95%CI=0.48~2.08，P=.99)。在接受他莫昔芬治疗的患者中，观察到UGT2B7基因与复发几乎为零相关。在接受阿那曲唑治疗的患者中，未观察到CYP2D6和UGT2B7基因与复发之间的关系。结论该结果不支持该结果预测绝经后乳腺癌患者辅助性三苯氧胺治疗的临床益处的假设。
Background Adjuvant tamoxifen therapy substantially decreases the risk of recurrence and mortality in women with hormone (estrogen and/or progesterone) receptor-positive breast cancer. Previous studies have suggested that metabolic conversion of tamoxifen to endoxifen by cytochrome P450 2D6 (CYP2D6) is required for patient benefit from tamoxifen therapy.Methods Tumor specimens from a subset of postmenopausal patients with hormone receptor-positive early-stage (stages I, II, and IIIA) breast cancer, who were enrolled in the randomized double-blind Arimidex, Tamoxifen, Alone or in Combination (ATAC) clinical trial, were genotyped for variants in CYP2D6 (N = 1203 patients: anastrozole [trade name: Arimidex] group, n = 615 patients; tamoxifen group, n = 588 patients) and UDP-glucuronosyltransferase-2B7 (UGT2B7), whose gene product inactivates endoxifen (N = 1209 patients; anastrozole group, n = 606 patients; tamoxifen group, n = 603 patients). Genotyping was performed using polymerase chain reaction based Taq Man assays. Based on the genotypes for CYP2D6, patients were classified as poor metabolizer (PM), intermediate metabolizer (IM), or extensive metabolizer (EM) phenotypes. We evaluated the association of CYP2D6 and UGT2B7 genotype with distant recurrence (primary endpoint) and any recurrence (secondary endpoint) by estimating the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) using Cox proportional hazards models. All statistical tests were two-sided.Results After a median follow-up of 10 years, no statistically significant associations were observed between CYP2D6 genotype and recurrence in tamoxifen-treated patients (PM vs EM: HR for distant recurrence = 1.25, 95% CI = 0.55 to 3.15, P= .64; HR for any recurrence = 0.99, 95% CI = 0.48 to 2.08, P= .99). A near-null association was observed between UGT2B7 genotype and recurrence in tamoxifen-treated patients. No associations were observed between CYP2D6 and UGT2B7 genotypes and recurrence in anastrozole-treated patients.Conclusion The results do not support the hypothesis that CYP2D6 genotype predicts clinical benefit of adjuvant tamoxifen treatment among postmenopausal breast cancer patients.