非小细胞肺癌一线治疗进展后耐药原因分析

发布时间：2018-06-18 06:10

本文选题：肺癌 + 非小细胞肺癌　；参考：《河北医科大学》2017年硕士论文

【摘要】：目的:目前肺癌已成为世界上最常见的恶性肿瘤之一,而非小细胞肺癌是肺癌中最常见的类型。由于肺癌早期无明显症状,很多患者发现时已丧失手术时机。针对肺癌靶向治疗的研究如火如荼,常见肺癌驱动基因包括:EGFR、ALK、C-MET、ROS-1等,这些位点均已研究出对应药物治疗,并且疗效显著,副反应小,使患者生活质量明显提高,表皮生长因子受体的络氨酸激酶抑制剂(Epidermal growth factor receptor-Tyrosine kinase inhibitor,EGFR-TKI)应用最为广泛,其代表药物有厄洛替尼、吉非替尼、埃克替尼、阿法替尼、奥希替尼等,尤其对亚裔、女性、不吸烟、腺癌患者的疗效尤为显著,其中位无进展生存期多为11-14个月,但随者用药时间的延长,一般患者多在用药9-10个月后出现耐药现象,这使针对肺癌的治疗又进入了另一个瓶颈期。在目前研究结果中,EGFR-TKI最常见的耐药机制为EGFR T790M突变,其占靶向耐药机制的50%左右,其他耐药机制还包括:MET、HER2基因扩增、上皮-间质转化、小细胞癌转变等。而针对上述耐药的药物也应运而生。如目前应用较为广泛的奥希替尼(AZD9291),它针对T790M突变的是第三代EGFR-TKI,其有效率达90%,客观缓解率61%,中位PFS长达9.6个月,疗效显著。针对这些耐药的药物虽已应用,但对耐药的临床特点及耐药后的生存情况尚未完全明确,因此,本研究拟在真实世界中观察肺癌一线治疗耐药后,通过基因检测,发现其耐药原因及耐药分子机制,并进一步探讨耐药机制与临床病理特征的相关性,对其生存情况进行随访,为指导临床工作奠定基础。方法:收集河北医科大学第四医院呼吸科2014年10月至2017年1月期间住院患者,对其进行按入排标准进行筛选,即经组织学或细胞学证实的非小细胞肺癌、TNM分期为IIIB、IV期(包括术后复发)的患者。评价为一线治疗进展及EGFR继发耐药后,收集患者临床信息(性别、年龄、吸烟、一线基因特点及治疗情况、进展部位等),对其进行二次基因检测,根据其基因检测结果推荐合适的治疗,并对其疗效及生存进行随访。结果:自2014年10月至2017年2月,共53例纳入本研究,其中,男性占47.1%(25/53),年龄≥60岁占54.7%(29/53),平均年龄59.3±9.78岁;未吸烟者共37例,占69.8%。一线治疗前,66%的患者行基因检测,而77.4%的患者接受靶向治疗,一线pd后,受累器官大于2个的占20.8%(11/53)。53例受试者中,二次基因检测结果显示,24例发生t790m突变,t790m突变率为45.3%(24/53)。入组患者中,共35例患者一线治疗前接受egfr基因检测;在一线pd后上述患者再次行基因检测,结果显示共7(20%)例患者(19del3例,21l858r4例)原突变位点消失,且t790m突变阴性。入组的53例患者,分别对其性别、年龄、吸烟、一线pd后受累器官数量、一线治疗前egfr突变类型、一线应用靶向药物、一线pd后的检测方法与t790m突变关系进行分析。其中,转移器官数≥2个较2个更易出现t790m突变(81.8%vs.35.7%,p=0.015);经三种检测方法(pcr、arms、ngs),t790m突变率有统计学差异(p=0.012),两两分析后显示应用arms法对t790m检测,其突变率明显高于ngs法(81.8%vs.30%p=0.005)。而性别、年龄、吸烟情况、一线治疗前egfr突变类型、一线应用靶向药物均与t790m无关(p0.05)。53例患者根据检测结果推荐二线治疗方案,随访患者疾病进展后生存时间,绘制生存曲线,截止至2017-2-22,患者中位疾病进展时间为15个月(95%ci:6.1月~23.9月),(成熟度为39.6%)。根据t790m突变与否对53例患者进行分组分析,截止至2017-2-22,t790m阳性及阴性组中位疾病进展时间分别为14.1个月(95%ci:9.5月-18.8月)及7.9个月(95%ci:6.4月~9.4月),突变阳性患者较突变阴性患者生存明显延长,但两者之间无统计学意义(p=0.437)(成熟度为39.6%),而对本研究中的21例死亡患者进行相同分析,其中位疾病进展时间分别为6.0个月(95%ci:1.7-10.3月)及1.0个月(95%ci:0-3.72月),突变阳性患者较突变阴性患者生存有延长趋势,但两者之间无统计学意义(p=0.33)。对53例患者的t790m突变、初次检测egfr的突变情况(exon19、EXON21)、一线治疗(靶向、化疗)、血液标本的检测方法(PCR、NGS、ARMS)、脑膜转移进行了相关因素分析,结果显示:脑膜转移与患者的进展后生存时间相关,而其他因素均与生存时间无关。本研究中,T790M阳性患者均应用“AZD9291”治疗,截止到2017-2-22其疗效评价为CR、PR、SD、PD分别为:0/24(0%),12/24(50.0%),10/24(41.7%),2/24(8.3%),其ORR、DCR分别为:50.0%,91.7%,,仅12例患者达到PFS,11例达到OS。本研究除T790M突变外,还存在小细胞转化1例及TP53突变患者11例,我们对TP53突变阳性患者进行了生存分析,结果显示其与疾病进展后生存时间无关(P0.05)。而其他耐药机制如MET、HER2基因扩增、上皮-间质转化等,本研究中尚未发现。结论:1一线EGFR-TKI耐药约有45%-50%是由于T790M突变所引起的。2转移器官数≥2个的患者较2个的患者更易出现T790M突变。3 PCR、ARMS、NGS三种方法对T790M进行检测,其突变检出率不同,应用ARMS法T790M突变率明显高于NGS法。4 T790M突变阳性的患者对相对于突变阴性的患者,疾病进展后生存时间有延长趋势。5脑膜转移为影响患者疾病进展后生存时间的影响因素。6 TP53突变与否对患者生存无影响。
[Abstract]:Objective: at present, lung cancer has become one of the most common malignant tumors in the world, and non small cell lung cancer is the most common type of lung cancer. Due to no obvious symptoms in the early stage of lung cancer, many patients have lost the time of operation. The study of lung cancer targeting therapy is often seen as a raging fire, often seen as EGFR, ALK, C-MET, ROS-1, and so on. These sites have been studied for corresponding drug treatment, with significant curative effects, small side effects and a significant improvement in the quality of life. The Epidermal growth factor receptor-Tyrosine kinase inhibitor, EGFR-TKI, the epidermal growth factor receptor, is the most widely used, which represents the drugs of erlotinib, gefitinib, and Egypt. Katinib, afitinib, Ohiti Ni and so on, especially for Asian, female, non smoking, adenocarcinoma, is particularly effective, and the progression free survival time is 11-14 months, but with the prolongation of the time of drug use, the general patients appear to be drug-resistant after 9-10 months of medication, which makes another bottleneck period for the treatment of lung cancer. In the present study, the most common drug resistance mechanism of EGFR-TKI is EGFR T790M mutation, which accounts for about 50% of the targeted drug resistance mechanism, and other mechanisms include MET, HER2 gene amplification, epithelial mesenchymal transformation, small cell carcinoma transformation, etc. and the drug resistant to these drugs should also be shipped. For example, the widely used OHI (AZD9291) is currently used. Its T790M mutation is third generation of EGFR-TKI, with an effective rate of 90%, an objective remission rate of 61%, a median PFS of 9.6 months, and a significant effect. Although the drug resistance has been applied, the clinical characteristics and the survival of the drug resistance are not completely clear. Therefore, this study is to observe the first-line treatment of lung cancer in the real world. After the drug, the causes of drug resistance and the molecular mechanism of drug resistance were found, and the correlation between the drug resistance mechanism and the clinicopathological features was further investigated. The survival situation was followed up to guide the clinical work. Methods: the patients were collected from the Department of respiration of the fourth hospital of Hebei Medical University from October 2014 to January 2017. It was selected according to the standard of entry and exclusion, that is, non small cell lung cancer confirmed by histology or cytology, TNM staging IIIB, IV stage (including postoperative recurrence). The evaluation of the patients' clinical information (sex, age, smoking, front-line gene characteristics and treatment, progression site, etc.) was evaluated for the progression of the first line treatment and the secondary drug resistance of EGFR. Two gene tests were carried out to recommend appropriate treatment according to the results of its gene detection and follow up its efficacy and survival. Results: from October 2014 to February 2017, a total of 53 cases were included in this study, of which men accounted for 47.1% (25/53), age 60 years old and 54.7% (29/53), the average age was 59.3 + 9.78 years, and 37 cases of non smokers, accounting for 69.8%. first-line treatment. Before, 66% of the patients were detected by gene detection, while 77.4% of the patients received targeted therapy. After PD, 20.8% (11/53).53 cases involved more than 2 involved organs, two gene detection results showed that 24 cases had T790M mutation and T790M mutation rate was 45.3% (24/53). Among the patients, a total of 35 patients received EGFR gene detection before first line treatment; at the same time, they were detected by EGFR gene detection. After line PD, the above patients were detected again. The results showed that 7 (20%) patients (19del3 cases, 21l858r4 cases) disappeared, and the T790M mutation was negative. The 53 patients enrolled in the group showed their sex, age, smoking, the number of involved organs after the first line PD, the EGFR mutation before the first-line treatment, the first line application of target drugs, and the detection of PD after the first line. The relationship between the method and the T790M mutation was analyzed. Among them, the number of metastatic organs more than 2 more than 2 more easily appeared T790M mutation (81.8%vs.35.7%, p=0.015). After three detection methods (PCR, arms, NGS), the mutation rate of T790M was statistically different (p=0.012). 22 analysis showed that the arms method was used for T790M detection, and the mutation rate was significantly higher than that of NGS method. And sex, age, smoking, EGFR mutation before first line treatment, T790M for first line use of targeted drugs (P0.05),.53 patients recommended a second line therapy based on the results of the test, followed up the patient's survival time after disease progression, and drew a survival curve to 2017-2-22, and the patient's median disease was progressed for 15 months (95%ci:6.1 months). 23.9 months) (maturity was 39.6%). According to the T790M mutation or not, 53 patients were divided into two groups. The progression time of the T790M positive and negative group was 14.1 months (95%ci:9.5 month -18.8 month) and 7.9 months (95%ci:6.4 month ~9.4 month), respectively. The mutation positive patients were significantly longer than the mutant negative patients, but the difference between the two groups was significantly longer than that of the mutant negative patients. No statistical significance (p=0.437) (maturity is 39.6%), and 21 cases of death in this study were the same analysis, the progression of the disease was 6 months (95%ci:1.7-10.3 month) and 1 months (95%ci:0-3.72 month), and the mutation positive patients had a longer survival trend than the mutant negative patients, but there was no statistical significance between the two cases (p=0.33 T790M mutations in 53 patients, first detection of EGFR mutation (Exon19, EXON21), first line therapy (targeting, chemotherapy), blood specimen detection (PCR, NGS, ARMS), and meningeal metastasis were analyzed. The results showed that meningeal metastasis was related to the survival time of the patients, and other factors were not related to the survival time. In the study, T790M positive patients were treated with "AZD9291", and the curative effect of 2017-2-22 was CR, PR, SD, PD were 0/24 (0%), 12/24 (50%), 10/24 (41.7%), 2/24 (8.3%), respectively, 50%, 91.7%, respectively, and 11 cases reached the mutation, there were also 1 cases of small cell transformation. In 11 cases, we analyzed the survival of TP53 mutation positive patients. The results showed that the survival time was not related to the survival time of the disease (P0.05). Other mechanisms such as MET, HER2 gene amplification, epithelial mesenchymal transition, etc. have not been found in this study. Conclusion: the 1 line EGFR-TKI tolerance of about 45%-50% is the.2 transfer device caused by the T790M mutation. The patients with more than 2 officers were more likely to have T790M mutation.3 PCR, ARMS, NGS and three methods to detect T790M, and the mutation detection rate was different. The T790M mutation rate of ARMS method was significantly higher than that of NGS method.4 T790M mutation. .6 TP53 mutation had no effect on the survival of patients.
【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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