繼發(fā)性T790M突變對(duì)晚期非小細(xì)胞肺癌患者的影響及預(yù)后因素分析
發(fā)布時(shí)間：2018-08-06 20:44
【摘要】：目的:表皮生長(zhǎng)因子受體酪氨酸激酶抑制劑(Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors,EGFR-TKIs)對(duì)有EGFR突變的晚期非小細(xì)胞肺癌(Non-small cell lung cancer,NSCLC)患者具有良好的治療效果。然而,幾乎所有患者在應(yīng)用EGFR-TKIs治療的過(guò)程中均會(huì)面臨耐藥的問(wèn)題,其中最常見(jiàn)的耐藥機(jī)制是T790M突變。本研究主要探討晚期肺腺癌患者T790M基因突變與EGFR-TKIs繼發(fā)耐藥及患者預(yù)后的關(guān)系,從而為后續(xù)治療方案的選擇提供理論依據(jù)。方法:1篩選符合試驗(yàn)標(biāo)準(zhǔn)的病例,共納入19例經(jīng)病理組織學(xué)和/或細(xì)胞學(xué)確診的晚期肺腺癌患者的臨床病例資料。所有患者均有EGFR基因(18、19或21)突變并接受吉非替尼、厄洛替尼或�？颂婺嶂委�,在病情進(jìn)展后,對(duì)患者進(jìn)行外周血EGFR基因突變的檢測(cè),根據(jù)檢測(cè)結(jié)果將患者分為兩組:T790M突變組和無(wú)T790M突變組。T790M突變組后續(xù)給予奧希替尼靶向治療,無(wú)T790M突變組后續(xù)給予化療或除奧希替尼外的靶向藥物。每種方案應(yīng)用1個(gè)月后,根據(jù)RECIST1.1實(shí)體瘤療效評(píng)價(jià)標(biāo)準(zhǔn)對(duì)兩組進(jìn)行療效評(píng)價(jià),比較兩組之間的客觀有效率(Objective Response Rate,ORR)、疾病控制率(Disease Control Rate,DCR)、無(wú)進(jìn)展生存期(Progression Free Survival,PFS)、總生存期(Overall Survival,OS)。同時(shí)根據(jù)年齡、性別、身體狀況(Performance Status,PS)評(píng)分、治療史(原發(fā)病手術(shù)史、化療史)、有無(wú)慢性病(高血壓病、冠心病、血栓狀態(tài))、轉(zhuǎn)移器官等幾方面進(jìn)行單因素及多因素分析,從而尋找影響療效的因素。2通過(guò)電話隨訪、收集住院或門診復(fù)查病例進(jìn)行隨訪。隨訪時(shí)間從患者入組后第1天開(kāi)始計(jì)算,截止日期為2017年1月31日。截至隨訪結(jié)束日期,19例患者中9人死亡,0人失訪,隨訪率:100%。患者治療開(kāi)始為研究起點(diǎn),終點(diǎn)為最近一次隨訪時(shí)間、失訪、患者死亡時(shí)間。3應(yīng)用SPSS 21.0統(tǒng)計(jì)軟件進(jìn)行統(tǒng)計(jì)分析,計(jì)數(shù)資料采用χ2檢驗(yàn);用Kaplan-Meier法繪制生存曲線,OS的影響因素采用Cox回歸分析,所得數(shù)據(jù)P0.05有統(tǒng)計(jì)學(xué)意義。結(jié)果:1 T790M在獲得性EGFR-TKIs耐藥的NSCLC患者中的狀態(tài)19例患者二次檢測(cè)后的EGFR突變狀態(tài):4例患者為EGFR 19合并T790M突變,5例患者為EGFR 21合并T790M突變,3例患者為T790M突變,7例患者無(wú)T790M突變(同時(shí)無(wú)其他EGFR基因突變)。其中,共有12例患者的外周血中檢測(cè)到T790M突變,占總研究對(duì)象的63.15%。2獲得性EGFR-TKIs耐藥的NSCLC患者后續(xù)治療的選擇情況在19例入組患者中,T790M突變組患者12例,后續(xù)均給予奧希替尼治療;無(wú)T790M突變組患者7例,其中5例患者給予除奧希替尼以外的其它靶向藥物(吉非替尼、厄洛替尼或�？颂婺�),2例患者給予含多西他賽化療方案治療。3獲得性EGFR-TKIs耐藥的NSCLC患者經(jīng)不同治療后其DCR及ORR的情況T790M突變組患者的DCR為50.0%(6/12),無(wú)T790M突變組患者的DCR為57.1%(4/7),兩組患者的疾病控制率沒(méi)有顯著性差異(P=0.764)。兩組患者的ORR均為0。4獲得性EGFR-TKIs耐藥的NSCLC患者經(jīng)不同治療后其PFS及OS的情況在19例入組患者中,共12例患者獲得PFS的數(shù)據(jù),其中T790M突變組患者8例,無(wú)T790M突變組患者4例。T790M突變組中位PFS為4個(gè)月,95%可信區(qū)間為[3.105,4.895],無(wú)T790M突變組中位PFS為3個(gè)月,95%可信區(qū)間為[1.503,4.497],P=0.486,無(wú)統(tǒng)計(jì)學(xué)差異。所有患者均納入到OS統(tǒng)計(jì)中,T790M突變組患者中位OS為31個(gè)月,95%可信區(qū)間為[22.423,39.577],無(wú)T790M突變組中位OS為26個(gè)月,95%可信區(qū)間為[10.728,41.272],P=0.044,存在統(tǒng)計(jì)學(xué)差異。5影響獲得性EGFR-TKIs耐藥的NSCLC患者預(yù)后的因素所有患者均入組預(yù)后分析,結(jié)果針對(duì)患者預(yù)后因素,包括:年齡、性別、PS評(píng)分、有無(wú)原發(fā)灶手術(shù)、有無(wú)聯(lián)合血管靶向藥、血清CEA水平、有無(wú)化療史、有無(wú)骨轉(zhuǎn)移、有無(wú)腦轉(zhuǎn)移、有無(wú)惡性胸水、有無(wú)肺轉(zhuǎn)移、有無(wú)淋巴結(jié)轉(zhuǎn)移、凝血功能情況、有無(wú)高血壓、有無(wú)心臟病、是否存在血栓進(jìn)行單因素分析,發(fā)現(xiàn)患者有無(wú)心臟病、是否存在血栓與OS相關(guān)(P0.05)。將單因素分析篩選出的P0.05的變量進(jìn)行多因素分析結(jié)果顯示:有無(wú)心臟病、是否存在血栓為EGFR-TKIs耐藥后NSCLC患者OS的獨(dú)立影響因素(P0.05)。結(jié)論:1 T790M突變是晚期非小細(xì)胞肺癌患者經(jīng)過(guò)EGFR-TKIs治療后最常出現(xiàn)的耐藥突變。2通過(guò)外周血可以動(dòng)態(tài)監(jiān)測(cè)晚期非小細(xì)胞肺癌患者EGFR基因突變狀態(tài),及時(shí)發(fā)現(xiàn)有無(wú)T790M基因的突變,從而為后續(xù)治療提供理論依據(jù)。3在獲得性EGFR-TKIs耐藥的晚期非小細(xì)胞肺癌患者中,T790M突變患者經(jīng)奧希替尼治療后其OS較經(jīng)化療或非奧希替尼靶向治療的非T790M突變患者顯著延長(zhǎng)。4對(duì)于EGFR-TKIs耐藥后的晚期非小細(xì)胞肺癌患者,有無(wú)心臟病、是否存在血栓是OS的獨(dú)立影響因素。
[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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R734.2
本文編號(hào)：2168936
[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.
【學(xué)位授予單位】：河北醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類號(hào)】：R734.2
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