EGFR-TKI治疗非小细胞肺癌后出现获得性耐药的机制研究

发布时间：2018-02-13 13:32

本文关键词： EGFR-TKI 获得性耐药　出处：《北京协和医学院》2017年博士论文　论文类型：学位论文

【摘要】：背景:表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI)治疗具有对TKI敏感的EGFR突变型的非小细胞肺癌(NSCLC)疗效和安全性均较好。但多数患者在治疗开始后的一年内仍会出现病情进展,提示出现了继发的耐药性。研究导致这种获得性耐药的机制,能够为耐药后的进一步治疗方法提供重要的理论依据。方法:本研究通过下一代测序技术(NGS),对25例2010年到2017年在北京协和医院呼吸内科就诊,并经第一代EGFR-TKI治疗后出现获得性耐药的患者留取的耐药后肿瘤标本进行共416个基因的靶向测序,对与肿瘤对EGFR-TKI的耐药性相关的检测结果进行统计汇总和分析,并结合测序结果与患者的临床资料探究耐药机制与临床特点间的联系。结果:25例患者中,48.0%(12/25)检出EGFRT790M的突变;12.0%(3/25)的患者检出PIK3CA的突变,并且其中2人同时存在T790M突变;8.0%(2/25)的患者检出MET基因扩增,均与T790M突变共存。在耐药机制未知的患者中,发现多种可能通过旁路或直接激活EGFR下游通路的基因变异,可能为这些患者产生耐药性的原因。结合临床资料分析发现,T790M突变的发生率可能与年龄相关,在60岁以上的患者中,T790M的出现率远高于60岁以下的患者(83.3%vs15.4%),具有显著性差异(p=0.001)。其余因素包括性别、吸烟史、肿瘤病理分型、使用的EGFR-TKI的种类、是否一线应用TKI治疗以及EGFR初始的敏感突变类型在T790M突变的发生率中未发现统计学差异。而T790M突变阳性的患者总体的总生存期以及进展后生存期比T790M阴性的患者较长,但没有发现显著性差异。结论:EGFR T790M突变为最常见的NSCLC对EGFR-TK1的获得性耐药机制,且年龄超过60岁的患者出现T790M突变的可能性远高于年龄小于60岁的患者。此外,EGFR L833F突变、EGFR exon19缺失突变的丢失、FGFR1基因扩增、AKT2基因扩增、PTEN基因缺失突变、HRAS基因突变等变异也可能是获得性耐药产生的机制。
[Abstract]:Background: EGFR-TKI, an inhibitor of epidermal growth factor receptor tyrosine kinase (EGFR-TKI), is effective and safe in the treatment of non-small cell lung cancer with EGFR mutation sensitive to TKI. This suggests secondary drug resistance. The mechanisms that lead to this acquired drug resistance are studied. Methods: the next generation sequencing technique was used to treat 25 patients from 2010 to 2017 in Department of Respiratory, Beijing Union Hospital. A total of 416 genes were sequenced from the patients with acquired drug resistance after the first generation of EGFR-TKI treatment, and the results related to the drug resistance of the tumor to EGFR-TKI were collected and analyzed. Combining the sequencing results with the clinical data of the patients to explore the relationship between the mechanism of drug resistance and the clinical characteristics. Results the mutation of EGFRT790M was detected in 48.0% of 25 patients (12.0%) and the mutation of PIK3CA was detected in 3 / 25% of the 25 cases. Two of the patients with T790M mutation at the same time detected the amplification of MET gene and coexisted with the T790M mutation. Among the patients with unknown drug resistance mechanism, a variety of gene mutations that could activate the downstream pathway of EGFR by bypass or directly were found. Combined with clinical data analysis, we found that the incidence of T790M mutation may be related to age. The incidence of T790M in patients over 60 years of age was much higher than that in patients under 60 years of age (83.3 vs 15.4g), with a significant difference (P < 0.001). The other factors included sex, smoking history, tumor pathological classification, and the type of EGFR-TKI used. There was no significant difference in the incidence of T790M mutation between first-line TKI therapy and the initial sensitive mutation type of EGFR. The overall overall survival time and progression survival of T790M mutation positive patients was longer than that of T790M negative patients. Conclusion the mutation of T790M is the most common mechanism of acquired drug resistance of NSCLC to EGFR-TK1. Moreover, the possibility of T790M mutation in patients over 60 years old is much higher than that in patients younger than 60 years old. In addition, the loss of EGFR L833F mutation and the loss of FGFR1 gene amplification of AK T 2 gene amplification of PTEN gene deletion mutation and HRAS gene mutation, etc. Mutation may also be the mechanism of acquired drug resistance.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2017
【分类号】：R734.2

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