CYP2D6多态性与乳腺癌患者他莫昔芬疗效的相关性

Correlation between polymorphism of CYP2D6 gene with effect of tamoxifen in patients with breast cancer

目的探讨CYP2D6基因多态性与乳腺癌患者他莫昔芬（TAM）及其活性代谢产物4-羟基他莫昔芬（4-OH-TAM）血清浓度的相关性，并探讨CYP2D6基因多态性与乳腺癌患者预后的相关性。方法收集2008年1月至2010年10月期间200例服用TAM的乳腺癌患者的口腔黏膜及血清标本，采用Real—timeRT—PCR法检测CYP21）6。10基因多态性，并分析其与临床病理特征和预后的关系。采用液相色谱一质谱方法（LC—MS）测定患者体内TAM及其活性代谢物4-OH—TAM的血清浓度。结果200例乳腺癌中检测到CYP2D6＊10／＊10纯合子94例（47％），CYP2D6wt／wt野生型48例（24％），CYP2D6wt／＊10杂合型58例（29％）。CYP2D6wt／wt野生型和wt／＊10杂合型两组4-OH—TAM的血清浓度都明显高于＊10／＊10纯合型（F=4．31，P=0．01）。CYP2D6＊10基因多态性与患者各项临床病理因素均无关（均P〉0．05）。Log—rank检验分析显示CYP2D6突变组患者平均无病生存时间（47．2个月）明显短于CYP2D6正常组患者（51．2个月），P=0．018。Cox回归分析显示CYP2D6基因型与患者无病生存时间明显相关（HR=2．755，95％CIi1．230～6．173，P=0．014）。结论CYP2D6＊10／＊10基因型与乳腺癌他莫昔芬的疗效相关，检测CYP2D6基因型可能有助于临床上有效选择他莫昔芬。

Objective To investigate the correlation of CYP2D6 gene polymorphism and serum tamoxifen （TAM） and its active metabolites （4-hydroxy tamoxifen, 4-OH-TAM） in terms of prognosis of breast cancer patients. Methods The oral mucosas and serum were obtained from 200 breast cancer patients receiving oral TAM from Jan 2008 to Oct 2010. Real-time RT-PCR was used to determine CYP2D6＊ 10 gene polymorphism. The relationship between CYP2D6＊ 10 gene polymorphism and clinicopathological features and prognosis was assessed by Chi-square test and Cox proportional model. Serum TAM and 4-OH-TAM concentration were determined by liquid chromatography-trap mass spectrometry （LC-MS）. Results Of 200 breast cancer patients, CYP2D6 ＊ 10/＊ 10 homozygotes were found in 94 cases （47%）, CYP2D6 wt/wt wild type in 48 cases （24%） and CYP2D6 wt/＊ 10 heterozygote in 58 cases （29%）. The concentration of serum 4-OH-TAM in patients with CYP2D6 wt/wt wild type and wt/＊ 10 heterozygote was significantly higher than that in patients with CYP2D6 ＊ 10/＊ 10 homozygote （F = 4. 31, P = 0. 01 ）. CYP2D6 gene polymorphism was not related to clinicopathological features （ P 〉 0.05 ）. Log- rank test showed that patient＇s disease-free survival with mutational CYP2D6 （mean, 47.2 months） was significantly shorter than that in patients without mutational CYP2D6 （mean, 51.2 months） （P = 0. 018 ）. Cox proportional model showed that CYP2D6 genotype was related to disease-free survival （ HR = 2. 755, 95% CI： 1. 230 - 6. 173, P = 0. 014）. Conclusions CYP2D6 ＊ 10/＊ 10 genotype is related to curative effect of TAM on breast cancer patients, detection of CYP2D6 ＊ 10/＊ 10 genotype helps improve the choice of TAM therapy.