继发性T790M突变对晚期非小细胞肺癌患者的影响及预后因素分析

发布时间：2018-08-06 20:44

【摘要】：目的:表皮生长因子受体酪氨酸激酶抑制剂(Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors,EGFR-TKIs)对有EGFR突变的晚期非小细胞肺癌(Non-small cell lung cancer,NSCLC)患者具有良好的治疗效果。然而,几乎所有患者在应用EGFR-TKIs治疗的过程中均会面临耐药的问题,其中最常见的耐药机制是T790M突变。本研究主要探讨晚期肺腺癌患者T790M基因突变与EGFR-TKIs继发耐药及患者预后的关系,从而为后续治疗方案的选择提供理论依据。方法:1筛选符合试验标准的病例,共纳入19例经病理组织学和/或细胞学确诊的晚期肺腺癌患者的临床病例资料。所有患者均有EGFR基因(18、19或21)突变并接受吉非替尼、厄洛替尼或埃克替尼治疗,在病情进展后,对患者进行外周血EGFR基因突变的检测,根据检测结果将患者分为两组:T790M突变组和无T790M突变组。T790M突变组后续给予奥希替尼靶向治疗,无T790M突变组后续给予化疗或除奥希替尼外的靶向药物。每种方案应用1个月后,根据RECIST1.1实体瘤疗效评价标准对两组进行疗效评价,比较两组之间的客观有效率(Objective Response Rate,ORR)、疾病控制率(Disease Control Rate,DCR)、无进展生存期(Progression Free Survival,PFS)、总生存期(Overall Survival,OS)。同时根据年龄、性别、身体状况(Performance Status,PS)评分、治疗史(原发病手术史、化疗史)、有无慢性病(高血压病、冠心病、血栓状态)、转移器官等几方面进行单因素及多因素分析,从而寻找影响疗效的因素。2通过电话随访、收集住院或门诊复查病例进行随访。随访时间从患者入组后第1天开始计算,截止日期为2017年1月31日。截至随访结束日期,19例患者中9人死亡,0人失访,随访率:100%。患者治疗开始为研究起点,终点为最近一次随访时间、失访、患者死亡时间。3应用SPSS 21.0统计软件进行统计分析,计数资料采用χ2检验;用Kaplan-Meier法绘制生存曲线,OS的影响因素采用Cox回归分析,所得数据P0.05有统计学意义。结果:1 T790M在获得性EGFR-TKIs耐药的NSCLC患者中的状态19例患者二次检测后的EGFR突变状态:4例患者为EGFR 19合并T790M突变,5例患者为EGFR 21合并T790M突变,3例患者为T790M突变,7例患者无T790M突变(同时无其他EGFR基因突变)。其中,共有12例患者的外周血中检测到T790M突变,占总研究对象的63.15%。2获得性EGFR-TKIs耐药的NSCLC患者后续治疗的选择情况在19例入组患者中,T790M突变组患者12例,后续均给予奥希替尼治疗;无T790M突变组患者7例,其中5例患者给予除奥希替尼以外的其它靶向药物(吉非替尼、厄洛替尼或埃克替尼),2例患者给予含多西他赛化疗方案治疗。3获得性EGFR-TKIs耐药的NSCLC患者经不同治疗后其DCR及ORR的情况T790M突变组患者的DCR为50.0%(6/12),无T790M突变组患者的DCR为57.1%(4/7),两组患者的疾病控制率没有显著性差异(P=0.764)。两组患者的ORR均为0。4获得性EGFR-TKIs耐药的NSCLC患者经不同治疗后其PFS及OS的情况在19例入组患者中,共12例患者获得PFS的数据,其中T790M突变组患者8例,无T790M突变组患者4例。T790M突变组中位PFS为4个月,95%可信区间为[3.105,4.895],无T790M突变组中位PFS为3个月,95%可信区间为[1.503,4.497],P=0.486,无统计学差异。所有患者均纳入到OS统计中,T790M突变组患者中位OS为31个月,95%可信区间为[22.423,39.577],无T790M突变组中位OS为26个月,95%可信区间为[10.728,41.272],P=0.044,存在统计学差异。5影响获得性EGFR-TKIs耐药的NSCLC患者预后的因素所有患者均入组预后分析,结果针对患者预后因素,包括:年龄、性别、PS评分、有无原发灶手术、有无联合血管靶向药、血清CEA水平、有无化疗史、有无骨转移、有无脑转移、有无恶性胸水、有无肺转移、有无淋巴结转移、凝血功能情况、有无高血压、有无心脏病、是否存在血栓进行单因素分析,发现患者有无心脏病、是否存在血栓与OS相关(P0.05)。将单因素分析筛选出的P0.05的变量进行多因素分析结果显示:有无心脏病、是否存在血栓为EGFR-TKIs耐药后NSCLC患者OS的独立影响因素(P0.05)。结论:1 T790M突变是晚期非小细胞肺癌患者经过EGFR-TKIs治疗后最常出现的耐药突变。2通过外周血可以动态监测晚期非小细胞肺癌患者EGFR基因突变状态,及时发现有无T790M基因的突变,从而为后续治疗提供理论依据。3在获得性EGFR-TKIs耐药的晚期非小细胞肺癌患者中,T790M突变患者经奥希替尼治疗后其OS较经化疗或非奥希替尼靶向治疗的非T790M突变患者显著延长。4对于EGFR-TKIs耐药后的晚期非小细胞肺癌患者,有无心脏病、是否存在血栓是OS的独立影响因素。
[Abstract]:Objective: the epidermal growth factor receptor tyrosine kinase inhibitor (Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors, EGFR-TKIs) has a good therapeutic effect on patients with advanced non-small cell lung cancer (Non-small cell lung cancer) with EGFR mutation. The most common drug resistance mechanism is T790M mutation. This study mainly discusses the relationship between T790M gene mutation and EGFR-TKIs secondary resistance and the prognosis of patients with advanced lung adenocarcinoma, so as to provide a theoretical basis for the selection of follow-up treatment scheme. Method: 1 cases were selected to meet the test standard, and 19 cases were included in the disease. Clinical case data of patients with advanced lung adenocarcinoma diagnosed by histology and / or cytology. All patients had EGFR gene (18,19 or 21) mutation and received gefitinib, erlotinib or ectinib. After the progression of the disease, the EGFR gene mutation in peripheral blood was detected in the patients, and the patients were divided into two groups according to the results: T790M process. The.T790M mutation group in the variable group and the non T790M mutation group was followed by the target therapy of oheminib, no T790M mutation group followed by chemotherapy or target drugs except oheminib. After 1 months of each scheme, the two groups were evaluated according to the evaluation criteria of RECIST1.1 solid tumor effect, and the objective efficiency was compared between the two groups (Objective Res Ponse Rate, ORR), the disease control rate (Disease Control Rate, DCR), the progression free survival period (Progression Free Survival, PFS), the total survival period (Overall), and the history of treatment (history of primary surgery, chemotherapy), and the history of treatment (the history of primary surgery, chemotherapy), and whether there is chronic disease (hypertension, coronary heart disease, thrombus) Single factor and multi factor analysis were carried out in several aspects, such as transfer organs, so as to find the factors affecting the effect,.2 through telephone follow-up, collect hospitalization or outpatient reexamination cases for follow-up. The follow-up time was calculated from first days after the patients entered the group, the deadline was January 31, 2017. As of the end of the follow-up, 9 people died and 0 were 0. Loss of visits, follow-up rate: 100%. patients started as the starting point of the study, the end of the last follow-up time, the loss of visit, the patient's time of death.3 using SPSS 21 statistical software for statistical analysis, count data using the chi 2 test, Kaplan-Meier method to draw the survival curve, the factors of OS using Cox regression analysis, the data P0.05 has statistical meaning. Results: 1 T790M in 19 patients with acquired EGFR-TKIs resistant NSCLC patients, the EGFR mutation status after two tests: 4 patients were EGFR 19 with T790M mutation, 5 patients were EGFR 21 with T790M mutation, 3 patients were T790M mutations, 7 patients had no T790M mutations (and no other EGFR gene mutation). Among them, 12 patients suffered from 12 patients. The T790M mutation was detected in the peripheral blood of the patients, and the selection of the follow-up treatment for the 63.15%.2 acquired EGFR-TKIs resistant NSCLC patients in the total study was in 19 patients, 12 in the T790M mutation group, and the following were all given the treatment of O, and 7 in the non T790M mutation group, of which 5 patients were given other than Ohiti Ni. Targeted drugs (gefitinib, erlotinib, or ekinib), 2 patients were treated with docetaxel chemotherapy for.3 acquired EGFR-TKIs resistant NSCLC patients after different treatments of DCR and ORR in the T790M mutation group, the DCR was 50% (6/12), the DCR in the non T790M mutation group was 57.1% (4/7), and the rate of disease control in the two groups of patients. There was no significant difference (P=0.764). The ORR of two groups of patients was 0.4 acquired EGFR-TKIs resistant NSCLC patients with PFS and OS in 19 patients after different treatment. A total of 12 patients received PFS data, of which 8 cases in T790M mutation group and 4.T790M mutation group without T790M mutation group were 4 months, 95% confidence interval. For [3.105,4.895], the median PFS in the non T790M mutation group was 3 months, the 95% confidence interval was [1.503,4.497], and there was no statistical difference. All the patients were included in the OS statistics. The median OS in the T790M mutation group was 31 months, the 95% confidence interval was [22.423,39.577], the middle OS of the T790M mutation group was 26 months, and the 95% confidence interval was [10.728,41.272]. 44, there were statistical differences in the prognostic factors of.5 patients with acquired EGFR-TKIs resistance in all patients, all patients were included in the prognostic analysis. The results were based on the prognosis factors of patients, including age, sex, PS score, or not primary surgery, combined blood vessel targeting drug, serum CEA level, chemotherapy history, bone metastases, or brain metastases. No malignant pleural effusion, pulmonary metastasis, lymph node metastasis, coagulation function, hypertension, heart disease, and whether there was a single factor analysis of thrombus, whether there was heart disease, or whether there was thrombus and OS correlation (P0.05). The multivariate analysis of the variables selected by single factor analysis showed that there was no heart. Whether there is an independent influence factor (P0.05) of OS in patients with NSCLC after EGFR-TKIs resistance. Conclusion: 1 T790M mutation is the most frequently occurring mutation of.2 in patients with advanced non-small cell lung cancer after EGFR-TKIs treatment. The mutation of EGFR gene in patients with advanced non-small cell lung cancer can be dynamically monitored by peripheral blood, and there is a timely discovery of T in patients with advanced non-small cell lung cancer. The mutation of the 790M gene provides a theoretical basis for subsequent treatment of.3 in patients with acquired EGFR-TKIs resistant advanced non-small cell lung cancer, and the T790M mutant patients whose OS has significantly extended the.4 to non small cell lung after EGFR-TKIs resistance after the treatment of the non T790M mutations in the chemotherapy or non - O - target treatment of the non - T790M mutants. Whether cancer patients have heart disease and whether there is thrombosis is an independent influence factor of OS.
【学位授予单位】：河北医科大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R734.2

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