CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial
CYP2D6 Genotype and Tamoxifen Response in Postmenopausal Women with Endocrine-Responsive Breast Cancer: The Breast International Group 1-98 Trial
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DOI：
10.1093/jnci/djs125
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发表时间：
2012-03-21
影响因子：
10.3
通讯作者：
Viale, Giuseppe
中科院分区：
文献类型：
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作者：
Regan, Meredith M.;Leyland-Jones, Brian;Viale, Giuseppe
背景：他莫昔芬辅助治疗对绝经后内分泌反应性乳腺癌有效。细胞色素P450 2D6 （CYP2D6）酶将他莫昔芬代谢为临床活性代谢物，CYP2D6多态性可能对他莫昔芬的疗效产生不利影响。在这项研究中，我们研究了CYP2D6多态性的临床相关性。方法：我们从1998年3月至2003年5月参加随机III期双盲乳腺国际组（BIG） 1-98试验的8010名绝经后激素受体阳性乳腺癌妇女中4861人获得肿瘤组织和分离DNA，并接受他莫昔芬和/或来曲唑治疗。提取的DNA采用基于聚合酶链反应的方法对9个CYP2D6单核苷酸多态性进行基因分型。使用基因型组合将CYP2D6代谢表型分为贫代谢、中等代谢和广泛代谢（分别为PM、IM和EM； n = 4393例患者）。根据随机内分泌治疗和既往化疗评估CYP2D6代谢表型与乳腺癌无癌间隔（称为复发）和治疗性潮热的关系。采用Cox比例风险模型计算风险比（hr）和95%置信区间（ci）。所有统计检验均为双侧检验。结果在接受他莫昔芬单药治疗且无化疗史的患者中，CYP2D6代谢表型与乳腺癌无癌间期无相关性（P = 0.35）。与EM表型相比，PM或IM表型的乳腺癌复发风险降低无统计学意义（PM或IM vs EM，复发HR = 0.86, 95% CI = 0.60 ~ 1.24）。CYP2D6代谢表型与他莫昔芬诱导的潮热相关（P = 0.020）。与EM表型相比，PM和IM表型均增加了他莫昔芬诱导的潮热的风险（PM vs EM，潮热HR = 1.24, 95% CI = 0.96至1.59;IM vs EM，潮热HR = 1.23, 95% CI = 1.05至1.43）。结论CYP2D6酶活性降低的表型与疾病控制不相关，但与潮热增加有关，与假设相反。本研究的结果不支持使用潮热的存在与否或CYP2D6的药理学检测来决定是否用他莫昔芬治疗绝经后乳腺癌患者。
Background Adjuvant tamoxifen therapy is effective for postmenopausal women with endocrine-responsive breast cancer. Cytochrome P450 2D6 (CYP2D6) enzyme metabolizes tamoxifen to clinically active metabolites, and CYP2D6 polymorphisms may adversely affect tamoxifen efficacy. In this study, we investigated the clinical relevance of CYP2D6 polymorphisms.Methods We obtained tumor tissues and isolated DNA from 4861 of 8010 postmenopausal women with hormone receptor positive breast cancer who enrolled in the randomized, phase III double-blind Breast International Group (BIG) 1-98 trial between March 1998 and May 2003 and received tamoxifen and/or letrozole treatment. Extracted DNA was used for genotyping nine CYP2D6 single-nucleotide polymorphisms using polymerase chain reaction based methods. Genotype combinations were used to categorize CYP2D6 metabolism phenotypes as poor, intermediate, and extensive metabolizers (PM, IM, and EM, respectively; n = 4393 patients). Associations of CYP2D6 metabolism phenotypes with breast cancer-free interval (referred to as recurrence) and treatment-induced hot flushes according to randomized endocrine treatment and previous chemotherapy were assessed. Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.Results No association between CYP2D6 metabolism phenotypes and breast cancer-free interval was observed among patients who received tamoxifen monotherapy without previous chemotherapy (P = .35). PM or IM phenotype had a non-statistically significantly reduced risk of breast cancer recurrence compared with EM phenotype (PM or IM vs EM, HR of recurrence = 0.86, 95% CI = 0.60 to 1.24). CYP2D6 metabolism phenotype was associated with tamoxifen-induced hot flushes (P = .020). Both PM and IM phenotypes had an increased risk of tamoxifen-induced hot flushes compared with EM phenotype (PM vs EM, HR of hot flushes = 1.24, 95% CI = 0.96 to 1.59; IM vs EM, HR of hot flushes = 1.23, 95% CI = 1.05 to 1.43).Conclusions CYP2D6 phenotypes of reduced enzyme activity were not associated with worse disease control but were associated with increased hot flushes, contrary to the hypothesis. The results of this study do not support using the presence or absence of hot flushes or the pharmacogenetic testing of CYP2D6 to determine whether to treat postmenopausal breast cancer patients with tamoxifen.