【作者】 丁丁；

【导师】 陆舜；

【作者基本信息】 上海交通大学 ， 肿瘤学， 2014， 博士

【摘要】 背景和目的T790M突变是表皮生长因子受体（epidermal growth factor receptor，EGFR）敏感突变非小细胞肺癌（non-small cell lung cancer，NSCLC）患者使用酪氨酸激酶抑制剂（tyrosine kinase inhibitor，TKI）治疗耐药的主要原因。虽然作为耐药基因被发现，但越来越多的研究中证实T790M突变在EGFR敏感突变但未使用过TKI的患者中已有存在，即在EGFR-TKI治疗前即同时存在EGFR敏感突变和T790M突变。并且随着检测方法准确性和敏感性的提高，检测出的治疗前T790M突变阳性率亦较高。鉴于目前指南推荐对EGFR敏感突变患者一线或二线使用TKI，而同时存在T790M突变对于TKI治疗的疗效及预后的影响仍不明确，本研究的目的即在于分析治疗前T790M突变对EGFR敏感突变的NSCLC患者接受EGFR-TKI治疗疗效的影响。材料和方法本研究采用Meta分析的方法对TKI治疗前T790M突变对EGFR敏感突变患者接受TKI治疗效果影响的研究进行汇总分析。分别提取各研究中T790M突变对TKI治疗PFS的风险度系数（hazard ratio，HR）和其95%置信区间（confidenceintervals，CIs），分别使用随机效应模型和固定效应模型进行汇总分析。结果本研究从372篇文献中最终挑选出5篇文献，共纳入299位患者。纳入的患者均为EGFR敏感突变阳性，其中EGFR-TKI治疗前就有T790M突变的比例为47.5%（142/299），范围从34.9%~80%。对上述299个样本的分析提示T790M对TKI治疗的PFS的HR为2.366（95%CI[1.011-6.695]）,异质性分析提示入选研究间存在明显异质性。而在剔除了罕见EGFR敏感突变和非一线接受TKI的样本后，227个样本的分析提示T790M对TKI治疗的PFS的HR为1.888（95%CI[1.574-2.265]），入选研究间异质性不显著，同时无显著的发表偏倚。结论本Meta分析研究发现TKI治疗前即同时存在T790M和EGFR敏感双突变患者使用TKI治疗的PFS较只有EGFR敏感突变的患者短，且差别具有统计学意义。更多还原

【Abstract】 Background and PurposeT790M mutation is the main reason for resistance in non-small-cell lung cancer(NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation undertyrosine kinase inhibitor (TKI) treatment. Although initially found as a resistance gene,recently more and more studies have confirmed T790M mutation in TKI naive NSCLCpatients with EGFR sensitive mutation, which means these patients have both sensitiveand T790M mutation before EGFR-TKI treatment. Coming along with the improvementof detection method, both in sensitivity and accuracy, the detected positive ratio of T790Mmutation comes out much higher. Although current guidelines all recommend TKI asfirst-line therapy in advanced NSCLC patients with sensitive EGFR mutation, the role ofpretreatment T790M mutation on these patients with EGFR-TKI therapy is not clearly yet.The purpose of the current study is to analyze the role of pretreatment T790M on NSCLCpatients with EGFR sensitive mutation having TKI treatment.Material and MethodThe study uses meta-analysis as the main method to pool the studies focusing on therole of pretreatment T790M in patients with EGFR sensitive mutation accepting TKItreatment. By extracting the hazard ration (HR) and its95%confidence intervals (CI) ofpretreatment on the PFS of TKI therapy in individual studies, the study uses random effect model and fixed effect model to combine，calculate and analyze.ResultsThis study picks5articles from a total of372articles, with a total of299patients. Allthe patients involved have EGFR sensitive mutation, and the pretreatment T790Mmutation rate is47.5%(142/299), ranging from34.9%to80%. Analysis on the299casesshows T790M mutation has negative predictive effect on TKI treated PFS, with a HR of2.366(95%CI[1.011-6.695]), and heterogeneity is significant among the selected studies.While after deleting rare EGFR sensitive mutation and non-first-line TKI cases, analysison277cases left shows the HR of T790M mutation on TKI treated PFS is1.888(95%CI[1.574-2.265]), and there is no significant heterogeneity among the selected studies.There is no significant publication bias as well.ConclusionThis meta-analysis found out TKI naive patients with both EGFR sensitive mutationand T790M mutation have shorter PFS than those with only EGFR sensitive mutationwhen treated with TKI, and the difference is significant.更多还原