發(fā)布時間：2018-06-18 06:10

  本文選題：肺癌 + 非小細(xì)胞肺癌��； 參考：《河北醫(yī)科大學(xué)》2017年碩士論文

【摘要】：目的:目前肺癌已成為世界上最常見的惡性腫瘤之一,而非小細(xì)胞肺癌是肺癌中最常見的類型。由于肺癌早期無明顯癥狀,很多患者發(fā)現(xiàn)時已喪失手術(shù)時機。針對肺癌靶向治療的研究如火如荼,常見肺癌驅(qū)動基因包括:EGFR、ALK、C-MET、ROS-1等,這些位點均已研究出對應(yīng)藥物治療,并且療效顯著,副反應(yīng)小,使患者生活質(zhì)量明顯提高,表皮生長因子受體的絡(luò)氨酸激酶抑制劑(Epidermal growth factor receptor-Tyrosine kinase inhibitor,EGFR-TKI)應(yīng)用最為廣泛,其代表藥物有厄洛替尼、吉非替尼、�？颂婺�、阿法替尼、奧希替尼等,尤其對亞裔、女性、不吸煙、腺癌患者的療效尤為顯著,其中位無進展生存期多為11-14個月,但隨者用藥時間的延長,一般患者多在用藥9-10個月后出現(xiàn)耐藥現(xiàn)象,這使針對肺癌的治療又進入了另一個瓶頸期。在目前研究結(jié)果中,EGFR-TKI最常見的耐藥機制為EGFR T790M突變,其占靶向耐藥機制的50%左右,其他耐藥機制還包括:MET、HER2基因擴增、上皮-間質(zhì)轉(zhuǎn)化、小細(xì)胞癌轉(zhuǎn)變等。而針對上述耐藥的藥物也應(yīng)運而生。如目前應(yīng)用較為廣泛的奧希替尼(AZD9291),它針對T790M突變的是第三代EGFR-TKI,其有效率達90%,客觀緩解率61%,中位PFS長達9.6個月,療效顯著。針對這些耐藥的藥物雖已應(yīng)用,但對耐藥的臨床特點及耐藥后的生存情況尚未完全明確,因此,本研究擬在真實世界中觀察肺癌一線治療耐藥后,通過基因檢測,發(fā)現(xiàn)其耐藥原因及耐藥分子機制,并進一步探討耐藥機制與臨床病理特征的相關(guān)性,對其生存情況進行隨訪,為指導(dǎo)臨床工作奠定基礎(chǔ)。方法:收集河北醫(yī)科大學(xué)第四醫(yī)院呼吸科2014年10月至2017年1月期間住院患者,對其進行按入排標(biāo)準(zhǔn)進行篩選,即經(jīng)組織學(xué)或細(xì)胞學(xué)證實的非小細(xì)胞肺癌、TNM分期為IIIB、IV期(包括術(shù)后復(fù)發(fā))的患者。評價為一線治療進展及EGFR繼發(fā)耐藥后,收集患者臨床信息(性別、年齡、吸煙、一線基因特點及治療情況、進展部位等),對其進行二次基因檢測,根據(jù)其基因檢測結(jié)果推薦合適的治療,并對其療效及生存進行隨訪。結(jié)果:自2014年10月至2017年2月,共53例納入本研究,其中,男性占47.1%(25/53),年齡≥60歲占54.7%(29/53),平均年齡59.3±9.78歲;未吸煙者共37例,占69.8%。一線治療前,66%的患者行基因檢測,而77.4%的患者接受靶向治療,一線pd后,受累器官大于2個的占20.8%(11/53)。53例受試者中,二次基因檢測結(jié)果顯示,24例發(fā)生t790m突變,t790m突變率為45.3%(24/53)。入組患者中,共35例患者一線治療前接受egfr基因檢測;在一線pd后上述患者再次行基因檢測,結(jié)果顯示共7(20%)例患者(19del3例,21l858r4例)原突變位點消失,且t790m突變陰性。入組的53例患者,分別對其性別、年齡、吸煙、一線pd后受累器官數(shù)量、一線治療前egfr突變類型、一線應(yīng)用靶向藥物、一線pd后的檢測方法與t790m突變關(guān)系進行分析。其中,轉(zhuǎn)移器官數(shù)≥2個較2個更易出現(xiàn)t790m突變(81.8%vs.35.7%,p=0.015);經(jīng)三種檢測方法(pcr、arms、ngs),t790m突變率有統(tǒng)計學(xué)差異(p=0.012),兩兩分析后顯示應(yīng)用arms法對t790m檢測,其突變率明顯高于ngs法(81.8%vs.30%p=0.005)。而性別、年齡、吸煙情況、一線治療前egfr突變類型、一線應(yīng)用靶向藥物均與t790m無關(guān)(p0.05)。53例患者根據(jù)檢測結(jié)果推薦二線治療方案,隨訪患者疾病進展后生存時間,繪制生存曲線,截止至2017-2-22,患者中位疾病進展時間為15個月(95%ci:6.1月~23.9月),(成熟度為39.6%)。根據(jù)t790m突變與否對53例患者進行分組分析,截止至2017-2-22,t790m陽性及陰性組中位疾病進展時間分別為14.1個月(95%ci:9.5月-18.8月)及7.9個月(95%ci:6.4月~9.4月),突變陽性患者較突變陰性患者生存明顯延長,但兩者之間無統(tǒng)計學(xué)意義(p=0.437)(成熟度為39.6%),而對本研究中的21例死亡患者進行相同分析,其中位疾病進展時間分別為6.0個月(95%ci:1.7-10.3月)及1.0個月(95%ci:0-3.72月),突變陽性患者較突變陰性患者生存有延長趨勢,但兩者之間無統(tǒng)計學(xué)意義(p=0.33)。對53例患者的t790m突變、初次檢測egfr的突變情況(exon19、EXON21)、一線治療(靶向、化療)、血液標(biāo)本的檢測方法(PCR、NGS、ARMS)、腦膜轉(zhuǎn)移進行了相關(guān)因素分析,結(jié)果顯示:腦膜轉(zhuǎn)移與患者的進展后生存時間相關(guān),而其他因素均與生存時間無關(guān)。本研究中,T790M陽性患者均應(yīng)用“AZD9291”治療,截止到2017-2-22其療效評價為CR、PR、SD、PD分別為:0/24(0%),12/24(50.0%),10/24(41.7%),2/24(8.3%),其ORR、DCR分別為:50.0%,91.7%,,僅12例患者達到PFS,11例達到OS。本研究除T790M突變外,還存在小細(xì)胞轉(zhuǎn)化1例及TP53突變患者11例,我們對TP53突變陽性患者進行了生存分析,結(jié)果顯示其與疾病進展后生存時間無關(guān)(P0.05)。而其他耐藥機制如MET、HER2基因擴增、上皮-間質(zhì)轉(zhuǎn)化等,本研究中尚未發(fā)現(xiàn)。結(jié)論:1一線EGFR-TKI耐藥約有45%-50%是由于T790M突變所引起的。2轉(zhuǎn)移器官數(shù)≥2個的患者較2個的患者更易出現(xiàn)T790M突變。3 PCR、ARMS、NGS三種方法對T790M進行檢測,其突變檢出率不同,應(yīng)用ARMS法T790M突變率明顯高于NGS法。4 T790M突變陽性的患者對相對于突變陰性的患者,疾病進展后生存時間有延長趨勢。5腦膜轉(zhuǎn)移為影響患者疾病進展后生存時間的影響因素。6 TP53突變與否對患者生存無影響。
[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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R734.2

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本文編號：2034462