尿苷二磷酸葡萄糖醛酸转移酶1A1基因多态性与伊立替康联合替吉奥治疗晚期食管鳞癌所致不良反应的关系  

Correlation between nUGT1A1 gene polymorphisms and adverse events of irinotecan plus S-1 for patients with recurrent or metastatic esophageal squamous cell carcinoma:a prospective,open-label,randomized controlled trial(ESWN 01)

作　　者：王玺 刘莺 黄俊星[4] 路平[5] 巴一[6] 邬麟[7] 白玉贤[8] 张述[9] 冯继锋[10] 程颖[11] 李杰[12] 温璐[13] 袁响林[14] 马长武[15] 胡春宏[16] 樊青霞[17] 徐兵河 黄镜 Wang Xi;Liu Ying;Huang Junxing;Lu Ping;Ba Yi;Wu Lin;Bai Yuxian;Zhang Shu;Feng Jifeng;Cheng Ying;Li Jie;Wen Lu;Yuan Xianglin;Ma Changwu;Hu Chunhong;Fan Qingxia;Xu Binghe;Huang Jing(Department of Medical Oncology,National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100021,China;Daycare Center,Peking University Cancer Hospital&Institute,Beijing 100142,China;Department of Medical Oncology,Henan Cancer Hospital,Zhengzhou 450008,China;Departmentof Medical Oncology,Taizhou People′s Hospital,Taizhou 225300,China;Department of Medical Oncology,the First Affiliated Hospital of Xinxiang Medical University,Xinxiang 453100,China;Department of Medical Oncology,Tianjin Cancer Hospital,Tianjin 300060,China;Departmentof Medical Oncology,Hunan Cancer Hospital,Changsha 410006,China;Department of Medical Oncology,Harbin Medical University Cancer Hospital,Harbin 150040,China;Department of Medical Oncology,Shandong Cancer Hospital,Jinan 250117,China;Department of Medical Oncology,Jiangsu Cancer Hospital,Nanjing 210009,China;Department of Medical Oncology,Jilin Cancer Hospital,Changchun 130012,China;Department of Radiotherapy,Shanxi Cancer Hospital,Taiyuan 030013,China;Department of Medical Oncology,Shanxi Cancer Hospital,Taiyuan 030013,China;Department of Medical Oncology,Tongji Hospital,Wuhan 430030,China;Department of Medical Oncology,Chifeng Municipal Hospital,Chifeng 024000,China;Department of Oncology,the Second Xiangya Hospital of Central South University,Changsha 410011,China;Department of Oncology,the First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China)

机构地区：[1]国家癌症中心,国家肿瘤临床医学研究中心,中国医学科学院北京协和医学院肿瘤医院内科,100021 [2]北京大学肿瘤医院暨北京市肿瘤防治研究所日间化疗病区,100142 [3]郑州大学附属肿瘤医院,河南省肿瘤医院肿瘤内科,450008 [4]江苏省泰州市人民医院肿瘤内科,225300 [5]新乡医学院附属第一医院肿瘤内科,453100 [6]天津市肿瘤医院肿瘤内科,300060 [7]湖南省肿瘤医院肿瘤内科,长沙410006 [8]哈尔滨医科大学附属肿瘤医院肿瘤内科,150040 [9]山东省肿瘤医院肿瘤内科,济南250117 [10]江苏省肿瘤医院肿瘤内科,南京210009 [11]吉林省肿瘤医院肿瘤内科,长春130012 [12]山西省肿瘤医院放射治疗科,太原030013 [13]山西省肿瘤医院肿瘤内科,太原030013 [14]华中科技大学同济医学院附属同济医院肿瘤内科,武汉430030 [15]内蒙古自治区赤峰市医院肿瘤内科,024000 [16]中南大学湘雅二医院肿瘤内科,长沙410011 [17]郑州大学第一附属医院肿瘤内科,450052

出　　处：《中华肿瘤杂志》2021年第11期1177-1182,共6页Chinese Journal of Oncology

基　　金：中国癌症基金会北京希望马拉松专项基金(LC2017A02)。

摘　　要：目的探讨尿苷二磷酸葡萄糖醛酸转移酶1A1(UGT1A1)基因多态性与伊立替康联合替吉奥治疗晚期食管鳞癌所致不良反应的关系。方法选取ESWN 01研究中伊立替康联合替吉奥治疗组(伊立替康160 mg/m2,第1天;替吉奥胶囊80~120 mg/d,第1~10天;每14 d重复)的46例晚期食管鳞癌患者,观察化疗期间出现的剂量限制性不良反应,采用聚合酶链反应检测UGT1A1*6和UGT1A1*28基因型,分析UGT1A1基因多态性与不良反应的关系。结果 46例患者中,UGT1A1*6野生型(GG)、杂合突变型(GA)、纯合突变型(AA)患者分别为30、15和1例,UGT1A1*28野生型(TA6/6)、杂合突变型(TA6/7)、纯合突变型(TA7/7)患者分别为36、8和2例。仅有的1例UGT1A1*6纯合突变型患者出现3级迟发性腹泻,未出现骨髓抑制。2例UGT1A1*28纯合突变型患者,均发生3~4级中性粒细胞减少,其中1例发生3级迟发性腹泻。UGT1A1*28突变型(TA6/7和TA7/7)患者的客观缓解率为55.6%(5/9),高于野生型(TA6/6)患者[26.5%(9/34)]。结论中国食管鳞癌患者中,UGT1A1*6和UGT1A1*28纯合突变均十分少见(<5%)。给予伊立替康(160 mg/m2)联合替吉奥2周方案治疗后,纯合突变型食管鳞癌患者并不都发生严重的剂量限制性不良反应。但对UGT1A1*6和UGT1A1*28纯合突变型患者仍需密切监测严重迟发性腹泻和骨髓抑制的发生,并及时作出剂量调整。Objective To investigate the correlation between UGT1A1 polymorphisms and the irinotecan plus S-1 regimen-induced toxicities in Chinese advanced esophageal squamous cell carcinoma(ESCC)patients.Methods A total of 46 recurrent or metastatic ESCC patients selected from ESWN 01 trial were randomly assigned to irinotecan plus S-1 group[intravenous infusion of irinotecan(160 mg/m2)on day 1 and oral S-1(80-120 mg)on days 1-10,repeated every 14 days].Peripheral venous blood at baseline was collected and genomic DNA was extracted.The genetic polymorphisms of UGT1A1*6 and UGT1A1*28 were analyzed by polymerase chain reaction(PCR)amplification.Irinotecan plus S-1 regimen-induced toxicities of patients with different UGT1A1 polymorphisms were observed.The correlation between UGT1A1 polymorphisms and the adverse effects was analyzed.Results Among the 46 patients,the numbers of UGT1A1*6 wild type genotype(GG),mutant heterozygote(GA)and mutant homozygote(AA)were 30,15 and 1,while those with UGT1A1*28 wild type genotype(TA6/6),mutant heterozygote(TA6/7)and mutant homozygote(TA7/7)were 36,8 and 2,respectively.Only one patient with UGT1A1*6 AA genotype occurred grade 3 diarrhea,while one of the 2 patients with UGT1A1*28 TA7/7 genotype occurred grade 4 diarrhea.No neutropenia was observed in the patient with UGT1A1*6 AA genotype,however,both of the two patients with UGT1A1*28 TA7/7 genotype occurred grade 3-4 neutropenia.Patients with UGT1A1*28 genetic polymorphism(TA 6/7 or TA7/7)had a higher response rate compared with wild-type TA6/6 carriers.(55.6%versus 26.5%).Conclusions The homozygous genotype of UGT1A1*6 AA and UGT1A1*28 TA7/7 are rare(<5%)in Chinese ESCC population.Not all homozygous AA and TA7/7 carriers occur severe dose limited toxicities(DLT)when treated with irinotecan(160 mg/m2)plus S-1 regimen for 2 weeks.However,it′s still necessary torigorously observe the occurrence of severe diarrhea and neutropenia in patients with UGT1A1*6 AA and UGT1A1*28 TA7/7 and adjust the dose timely.

关 键 词：食管鳞癌 伊立替康 不良反应 尿苷二磷酸葡萄糖醛酸转移酶1A1 基因多态性 腹泻 中性粒细胞减少 

分 类 号：R735.1[医药卫生—肿瘤]