切换至 "中华医学电子期刊资源库"

中华乳腺病杂志(电子版) ›› 2017, Vol. 11 ›› Issue (04) : 238 -242. doi: 10.3877/cma.j.issn.1674-0807.2017.04.010

综述

CYP2D6 基因多态性对乳腺癌治疗中他莫昔芬药物疗效的影响
单明1, 康文莉2, 张国强1,()   
  1. 1.150086 哈尔滨医科大学附属肿瘤医院乳腺外科
    2.150088哈尔滨黑龙江省农垦总局总医院肿瘤内科
  • 收稿日期:2016-04-11 出版日期:2017-08-01
  • 通信作者: 张国强
  • 基金资助:
    黑龙江省自然科学基金面上项目(H201333);黑龙江省青年科学基金项目(QC2015113)

Impact of CYP2D6 gene polymorphism on efficacy of tamoxifen in breast cancer treatment

Ming Shan, Wenli Kang, Guoqiang Zhang()   

  • Received:2016-04-11 Published:2017-08-01
  • Corresponding author: Guoqiang Zhang
引用本文:

单明, 康文莉, 张国强. CYP2D6 基因多态性对乳腺癌治疗中他莫昔芬药物疗效的影响[J/OL]. 中华乳腺病杂志(电子版), 2017, 11(04): 238-242.

Ming Shan, Wenli Kang, Guoqiang Zhang. Impact of CYP2D6 gene polymorphism on efficacy of tamoxifen in breast cancer treatment[J/OL]. Chinese Journal of Breast Disease(Electronic Edition), 2017, 11(04): 238-242.

乳腺癌是女性常见的恶性肿瘤,在中国女性中发病率也最高。 并且,乳腺癌是一种激素依赖性肿瘤,其发生、发展受到体内雌激素水平的影响。 乳腺癌的内分泌治疗是乳腺癌综合治疗的重要手段之一,而他莫昔芬(TAM)在20 世纪90 年代已经被证实是ER 阳性乳腺癌患者最主要的内分泌治疗药物,但临床上ER 阳性乳腺癌患者中仍有部分对其耐药。 TAM 竞争性结合ER,其在人体内的代谢产物必须经过肝脏细胞色素P450 的代谢,才能转化成为有活性的代谢产物,从而产生较强的抗雌激素作用。 CYP2D6 是P450 代谢酶中一种重要的氧化代谢酶,更是TAM 起效的关键因素。 研究显示,TAM耐药机制在很大程度上与CYP2D6 基因变异有关,且两者之间的相关性越来越受到重视。 而人群中存在100 多种CYP2D6 基因,呈多态性分布,导致其活性存在明显的不同。 因此,从临床合理用药方面而言,利用基因型分析来推断个体化的药物应用,是目前精准医学的重要任务。

表1 2015 年St. Gallen 早期乳腺癌国际专家共识中ER 阳性/HER-2 阴性乳腺癌患者辅助治疗推荐[15]
图1 他莫昔芬体内代谢过程图 注:CYP 为细胞色素P450
表2 CYP2D6 基因型及其对应的蛋白表达和活性[28]
等位基因型 基因多态性导致编码蛋白的改变 效果
CYP2D6*1XN 多拷贝基因 酶活性增加
CYP2D6*2 R296C、S486T 酶活性正常
CYP2D6*2XN R296C、S486T、多拷贝基因 酶活性增加
CYP2D6*3、CYP2D6*8、CYP2D6*11 置换、剪切缺失、移码 酶无活性
CYP2D6*15、CYP2D6*18、CYP2D6*21 置换、剪切缺失、移码 酶无活性
CYP2D6*31、CYP2D6*38、CYP2D6*40 置换、剪切缺失、移码 酶无活性
CYP2D6*42、CYP2D6*44、CYP2D6*56 置换、剪切缺失、移码 酶无活性
CYP2D6*62 置换、剪切缺失、移码 酶无活性
CYP2D6*9 K281del 酶活性降低
CYP2D6*10 P34S、S486T 酶活性降低
CYP2D6*17 T107I、R296C、S486T 酶活性降低
CYP2D6*27 E410K 酶活性正常
CYP2D6*29 V136I、R296C、V338M、S486T 酶活性降低
CYP2D6*33 A237S 酶活性正常
CYP2D6*35A V11M、R296C、S486T 酶活性正常
CYP2D5*35X2 V11M、R296C、S486T、多拷贝基因 酶活性增加
CYP2D6*36 P34S、P469A、T470A、H478S、G479A、F481V、A482S、S486T 酶无活性
CYP2D6*39 S486T 酶活性正常
CYP2D6*41 R296C、剪切缺失、S486T 酶活性降低
CYP2D6*47 R25W、P34S、S486T 酶无活性
CYP2D6*48 A90V 酶活性正常
CYP2D6*49 P34S、F120I、S486T 酶活性降低
CYP2D6*50 E156A 酶活性降低
CYP2D6*51 R296C、E334A、S486T 酶无活性
CYP2D6*53 F120I、A122S 酶活性增加
CYP2D6*54 P54S、T261I、S486T 酶活性降低
CYP2D6*55 R296C、K404Q、S486T 酶活性降低
CYP2D6*57 P34S、R62W、P469A、T470A、H478S、G479A、F481V、A482S、S486T 酶无活性
CYP2D6*59 R296C、S486T 酶活性降低
CYP2D6*69 P34S、R296C、剪切缺失、S486T 酶活性降低
CYP2D6*72 P34S、E383K、S486T 酶活性降低
[29]
Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I[J]. Clin Pharmacokinet,2009,48(11):689-723.
[30]
McGraw J, Waller D. Cytochrome P450 variations in different ethnic populations[J]. Expert Opin Drug Metab Toxicol, 2012,8 (3):371-382.
[31]
Johnson AD,Wang D, Sadee W. Polymorphisms affecting gene regulation and mRNA processing: broad implications for pharmacogenetics[J].Pharmacol Ther,2005,106(1):19-38.
[32]
Pesenti C,Gusella M,Sirchia SM,et al. Germline oncopharmacogenetics,a promising field in cancer therapy[J]. Cell Oncol (Dordr), 2015,38(1):65-89.
[33]
Province MA, Goetz MP, Brauch H, et al. CYP2D6 genotype and adjuvant tamoxifen: meta-analysis of heterogeneous study populations[J]. Clin Pharmacol Ther,2014,95(2):216-227.
[34]
Hennig EE, Piatkowska M, Karczmarski J, et al. Limited predictive value of achieving beneficial plasma (Z)-endoxifen threshold level by CYP2D6 genotyping in tamoxifen-treated Polish women with breast cancer[J]. BMC Cancer,2015,15:570.
[35]
Jin Y, Desta Z, Stearns V, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment[J]. J Natl Cancer Inst,2005,97(1):30-39.
[36]
Del RM, Citi V, Crucitta S, et al. Pharmacogenetics of CYP2D6 and tamoxifen therapy: Light at the end of the tunnel? [J]. Pharmacol Res,2016,107:398-406.
[37]
Hertz DL, Deal A, Ibrahim JG, et al. Tamoxifen dose escalation in patients with diminished CYP2D6 activity normalizes endoxifen concentrations without increasing toxicity[J]. Oncologist,2016,21(7):795-803.
[38]
Dezentjé VO, Opdam FL, Gelderblom H, et al. CYP2D6 genotypeand endoxifen-guided tamoxifen dose escalation increases endoxifen serum concentrations without increasing side effects[J]. Breast Cancer Res Treat,2015,153(3):583-590.
[39]
Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes[J]. J Clin Oncol,2005,23(36):9312-9318.
[40]
Goetz MP,Knox SK,Suman VJ,et al. The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen[J]. Breast Cancer Res Treat,2007,101(1):113-121.
[41]
Schroth W, Antoniadou L, Fritz P, et al. Breast cancer treatment outcome with adjuvant tamoxifen relative to patient CYP2D6 and CYP2C19 genotypes[J]. J Clin Oncol,2007,25(33):5187-5193.
[42]
Bijl MJ, van Schaik RH, Lammers LA, et al. The CYP2D6*4 polymorphism affects breast cancer survival in tamoxifen users[J].Breast Cancer Res Treat,2009,118(1):125-130.
[43]
Ramóny Cajal T, Altés A, Paré L, et al. Impact of CYP2D6 polymorphisms in tamoxifen adjuvant breast cancer treatment [J].Breast Cancer Res Treat,2010,119(1):33-38.
[44]
Newman WG, Hadfield KD, Latif A, et al. Impaired tamoxifen metabolism reduces survival in familial breast cancer patients[J]. Clin Cancer Res,2008,14(18):5913-5918.
[45]
Xu Y, Sun Y, Yao L, et al. Association between CYP2D6 *10 genotype and survival of breast cancer patients receiving tamoxifen treatment[J]. Ann Oncol,2008,19(8):1423-1429.
[46]
Lim HS, Ju Lee H, Seok Lee K, et al. Clinical implications of CYP2D6 genotypes predictive of tamoxifen pharmacokinetics in metastatic breast cancer[J]. J Clin Oncol,2007,25(25):3837-3845.
[47]
熊萱, 张思超, 朱昶宇.中国人群CYP2D6 的基因多态性与乳腺癌患者他莫昔芬及其代谢物血药浓度关系的Meta 分析[J]. 中国生化药物杂志,2015,35(5):77-80.
[48]
谢新华, 韦尉东, 孔亚楠,等. 药物代谢酶细胞色素P4502D6 在他莫昔芬个体化治疗中的研究进展[J/CD]. 中华乳腺病杂志(电子版),2011,5(5):601-607.
[49]
Jung JA, Lim HS. Association between CYP2D6 genotypes and the clinical outcomes of adjuvant tamoxifen for breast cancer: a metaanalysis[J]. Pharmacogenomics,2014,15(1):49-60.
[50]
Sideras K, Ingle JN,Ames MM,et al. Coprescription of tamoxifen and medications that inhibit CYP2D6[J]. J Clin Oncol, 2010,28(16):2768-2776.
[51]
Rae JM, Drury S, Hayes DF, et al. CYP2D6 and UGT2B7 genotype and risk of recurrence in tamoxifen-treated breast cancer patients[J]. J Natl Cancer Inst,2012,104(6):452-460.
[52]
Goetz MP, Ingle JN. CYP2D6 genotype and tamoxifen: considerations for proper nonprospective studies[J]. Clin Pharmacol Ther, 2014,96(2):141-144.
[53]
Thompson AM, Johnson A, Quinlan P, et al. Comprehensive CYP2D6 genotype and adherence affect outcome in breast cancer patients treated with tamoxifen monotherapy[J]. Breast Cancer Res Treat, 2011,125(1):279-287.
[54]
Markkula A, Hjertberg M, Rose C, et al. No association found between CYP2D6 genotype and early breast cancer events in tamoxifentreated patients[J]. Acta Oncol,2014,53(2):195-200.
[55]
Bauerschlag DO, Maass N, Schem C. Standard of care and controversies in the adjuvant endocrine treatment of hormone-responsive early breast cancer[J]. Breast Care (Basel),2014,9(4):283-286.
[56]
Kimura M, Tominaga T, Kimijima I, et al. Phase III randomized trial of toremifene versus tamoxifen for Japanese postmenopausal patients with early breast cancer[J]. Breast Cancer,2014,21(3):275-283.
[57]
Ye QL,Zhai ZM. Toremifene and tamoxifen have similar efficacy in the treatment of patients with breast cancer: a meta-analysis of randomized trials[J]. Mol Biol Rep,2014,41(2):751-756.
[1]
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016[J]. CA Cancer J Clin,2016,66(1):7-30.
[2]
Chen W, Zheng R, Baade PD, et al. Cancer statistics in China,2015[J]. CA Cancer J Clin,2016,66(2):115-132.
[3]
Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials[J]. Lancet,2005,365(9472):1687-1717.
[4]
赵菲.2014 年美国临床肿瘤学会指南更新:激素受体阳性乳腺癌的辅助内分泌治疗[J/CD]. 中华乳腺病杂志(电子版),2014,8(5):373-374.
[5]
顾军, 于泽平.乳腺癌内分泌治疗的困惑与展望[J/CD]. 中华乳腺病杂志(电子版),2014,8(6):378-383.
[6]
Jeselsohn R, Buchwalter G, De Angelis C, et al. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer[J]. Nat Rev Clin Oncol,2015,12(10):573-583.
[7]
杨颖, 胡崇珠. 乳腺癌患者辅助内分泌治疗依从性研究进展[J/CD]. 中华乳腺病杂志(电子版),2014,8(6):48-53.
[8]
Jordan VC, Allen KE. Evaluation of the antitumour activity of the nonsteroidal antioestrogen monohydroxytamoxifen in the DMBA-induced rat mammary carcinoma model[J]. Eur J Cancer,1980,16(2):239-251.
[9]
Jordan VC. Tamoxifen as the first targeted long-term adjuvant therapy for breast cancer[J]. Endocr Relat Cancer,2014,21(3):R235-246.
[10]
No authors listed. Controlled trial of tamoxifen as adjuvant agent in management of early breast cancer. Interim analysis at four years by Nolvadex Adjuvant Trial Organisation[J]. Lancet, 1983,1(8319):257-261.
[11]
Fisher B, Redmond C, Wickerham DL, et al. Systemic therapy in patients with node-negative breast cancer. A commentary based on two National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials[J]. Ann Intern Med,1989,111(9):703-712.
[12]
No authors listed. Tamoxifen for early breast cancer:an overview of the randomised trials. Early Breast Cancer Trialists' Collaborative Group[J]. Lancet,1998,351(9114):1451-1467.
[13]
Early Breast Cancer Trialists' Collaborative Group (EBCTCG), Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level metaanalysis of randomised trials[J]. Lancet,2011,378(9793):771-784.
[14]
Davies C, Pan H, Godwin J, et al. Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer:ATLAS,a randomised trial[J]. Lancet,2013,381(9869):805-816.
[15]
Azim HA, Saadeldeen A. Commentary on “aTTom”: long-term effects of continuing adjuvant tamoxifen to 10 years[J]. Chin Clin Oncol,2014,3(1):7.
[16]
Coates AS, Winer EP, Goldhirsch A, et al. Tailoring therapiesimproving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015[J]. Ann Oncol,2015,26(8):1533-1546.
[17]
Gradishar WJ, Anderson BO, Balassanian R, et al. Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology[J]. J Natl Compr Canc Netw,2016,14(3):324-354.
[18]
Blackburn HL, Ellsworth DL, Shriver CD, et al. Role of cytochrome P450 genes in breast cancer etiology and treatment: effects on estrogen biosynthesis, metabolism, and response to endocrine therapy [J].Cancer Causes Control,2015,26(3):319-332.
[19]
Wu X, Hawse JR, Subramaniam M, et al. The tamoxifen metabolite,endoxifen, is a potent antiestrogen that targets estrogen receptor alpha for degradation in breast cancer cells[J]. Cancer Res, 2009,69(5):1722-1727.
[20]
de Vries Schultink AH, Zwart W, Linn SC, et al. Effects of pharmacogenetics on the pharmacokinetics and pharmacodynamics of tamoxifen[J]. Clin Pharmacokinet,2015,54(8):797-810.
[21]
Watanabe M, Watanabe N, Maruyama S, et al. Comparative metabolic study between two selective estrogen receptor modulators, toremifene and tamoxifen, in human liver microsomes [ J]. Drug Metab Pharmacokinet,2015,30(5):325-333.
[22]
Utkarsh D, Loretz C,Li AP. In vitro evaluation of hepatotoxic drugs in human hepatocytes from multiple donors: Identification of P450 activity as a potential risk factor for drug-induced liver injuries[J]. Chem Biol Interact,2016,255:12-22.
[23]
Regan MM, Leyland-Jones B,Bouzyk M,et al. CYP2D6 genotype and tamoxifen response in postmenopausal women with endocrine-responsive breast cancer: the breast international group 1-98 trial[J]. J Natl Cancer Inst,2012,104(6):441-451.
[24]
Okishiro M, Taguchi T, Jin KS, et al. Genetic polymorphisms of CYP2D6 10 and CYP2C19 2, 3 are not associated with prognosis,endometrial thickness, or bone mineral density in Japanese breast cancer patients treated with adjuvant tamoxifen[J]. Cancer, 2009,115(5):952-961.
[25]
Maximov PY, McDaniel RE, Fernandes DJ, et al. Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes[J]. Br J Pharmacol, 2014,171(24):5624-5635.
[26]
Martinez de Dueñas E, Ochoa Aranda E, Blancas Lopez-Barajas I, et al. Adjusting the dose of tamoxifen in patients with early breast cancer and CYP2D6 poor metabolizer phenotype[J]. Breast, 2014,23(4):400-406.
[27]
张欢,吴斌.CYP2D6 基因多态性在乳腺癌中的价值[J]. 肿瘤基础与临床,2015,28(2):180-184.
[28]
Sim SC, Ingelman-Sundberg M. The human cytochrome P450 (CYP)allele nomenclature website: a peer-reviewed database of CYP variants and their associated effects [J]. Hum Genet,2010,4(4):278-281.
[1] 李洋, 蔡金玉, 党晓智, 常婉英, 巨艳, 高毅, 宋宏萍. 基于深度学习的乳腺超声应变弹性图像生成模型的应用研究[J/OL]. 中华医学超声杂志(电子版), 2024, 21(06): 563-570.
[2] 河北省抗癌协会乳腺癌专业委员会护理协作组. 乳腺癌中心静脉通路护理管理专家共识[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 321-329.
[3] 刘晨鹭, 刘洁, 张帆, 严彩英, 陈倩, 陈双庆. 增强MRI 影像组学特征生境分析在预测乳腺癌HER-2 表达状态中的应用[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 339-345.
[4] 张晓宇, 殷雨来, 张银旭. 阿帕替尼联合新辅助化疗对三阴性乳腺癌的疗效及预后分析[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 346-352.
[5] 邱琳, 刘锦辉, 组木热提·吐尔洪, 马悦心, 冷晓玲. 超声影像组学对致密型乳腺背景中非肿块型乳腺癌的诊断价值[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 353-360.
[6] 程燕妮, 樊菁, 肖瑶, 舒瑞, 明昊, 党晓智, 宋宏萍. 乳腺组织定位标记夹的应用与进展[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 361-365.
[7] 涂盛楠, 胡芬, 张娟, 蔡海峰, 杨俊泉. 天然植物提取物在乳腺癌治疗中的应用[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 366-370.
[8] 朱文婷, 顾鹏, 孙星. 非酒精性脂肪性肝病对乳腺癌发生发展及治疗的影响[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 371-375.
[9] 周荷妹, 金杰, 叶建东, 夏之一, 王进进, 丁宁. 罕见成人肋骨郎格汉斯细胞组织细胞增生症被误诊为乳腺癌术后骨转移一例[J/OL]. 中华乳腺病杂志(电子版), 2024, 18(06): 380-383.
[10] 高杰红, 黎平平, 齐婧, 代引海. ETFA和CD34在乳腺癌中的表达及与临床病理参数和预后的关系研究[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 64-67.
[11] 韩萌萌, 冯雪园, 马宁. 乳腺癌改良根治术后桡神经损伤1例[J/OL]. 中华普外科手术学杂志(电子版), 2025, 19(01): 117-118.
[12] 张志兆, 王睿, 郜苹苹, 王成方, 王成, 齐晓伟. DNMT3B与乳腺癌预后的关系及其生物学机制[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 624-629.
[13] 王玲艳, 高春晖, 冯雪园, 崔鑫淼, 刘欢, 赵文明, 张金库. 循环肿瘤细胞在乳腺癌新辅助及术后辅助治疗中的应用[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 630-633.
[14] 赵林娟, 吕婕, 王文胜, 马德茂, 侯涛. 超声引导下染色剂标记切缘的梭柱型和圆柱型保乳区段切除术的效果研究[J/OL]. 中华普外科手术学杂志(电子版), 2024, 18(06): 634-637.
[15] 张龙, 孙善柯, 徐伟, 李文柱, 李俊达, 池涌泉, 何广胜, 成峰, 王学浩, 饶建华. 腹腔镜脾切除治疗血液系统疾病的临床疗效分析[J/OL]. 中华肝脏外科手术学电子杂志, 2024, 13(06): 870-875.
阅读次数
全文


摘要