非小细胞肺癌表皮生长因子受体突变的检测与分子靶向治疗

目的探讨非小细胞肺癌患者表皮生长因子受体(EGFR)基因突变率和突变类型,分析其临床特征,并观察EGFR突变与表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)治疗疗效的相关性。方法收集203例非小细胞肺癌患者外科手术、淋巴结活检、经皮肺穿刺活检、气管镜活检和胸腔积液沉渣石蜡标本,应用ADx-ARMS法进行EGFR基因突变检测,分析基因的突变率及其与临床特征的关系;观察非小细胞肺癌(NSCLC)接受EGFR-TKIs治疗的非小细胞肺癌患者的疗效。应用SPSS23.0软件进行统计学分析,计数资料比较采用χ2检验,采用Kaplan-Meier法计算患者的PFS,采用Log-Rank检验分析各种因素对生存期的影响。结果 203例NSCLC患者,男性116例,女性87例,年龄为25~82岁。吸烟指数≥400支/者61例,小于400支/年和不吸烟者142例,腺癌152例,鳞癌21例,腺鳞癌14例,其他NSCLC16例。203例NSCLC患者EGFR总突变率为51.2%(104/203),包括19外显子缺失突变51例(49.0%),21外显子L858R突变44例(42.3%),19del及L858R总突变率占所有突变的96.1%,18外显子G719X点突变3例(2.9%),19del+L858R双突变3例(2.9%),1例20ins,2例T790M突变分别为1例19del+T790M和1例L858R+T790M。EGFR基因阳性突变率女性组高于男性组(66.7%vs.36.2%);非吸烟组高于吸烟组(63.4%vs.16.4%);腺癌组高于鳞癌组(53.3%vs.33.3%),P0.05。而EGFR基因突变状况与标本类型如手术、淋巴结活检、肺穿刺活检、气管镜活检和胸腔积液沉渣标本间无统计学差异,P=0.418。101例接受TKI治疗的NSCLC患者客观缓解率(ORR)为61.4%,疾病控制率(DCR)为71.3%,中位疾病无进展生存期(PFS)为10个月。其中EGFR突变阳性患者接受EGFR-TKIs治疗的ORR及DCR均要显著高于EGFR突变阴性及EGFR突变状态未明确人群(88.6%vs.16.7%vs.43.1%,P=0.000;95.5%vs.16.7%vs.56.9%,P=0.000)。EGFR突变阳性患者接受EGFR-TKIs治疗的中位PFS较EGFR突变阴性及EGFR突变状态未明确患者延长,有统计学差异(P=0.001)。进一步分析EGFR突变阳性19del组NSCLC患者ORR、DCR均高于L858R组(91.2%vs.85%,P=0.646;100%vs.90%,P=0.201);19del组NSCLC患者TKI治疗后中位PFS 14.5个月较L858R组10个月长,有统计学差异(P=0.010)。结论非小细胞肺癌患者EGFR突变高,以女性、不吸烟、腺癌为优势人群,EGFR敏感突变阳性者对EGFR-TKI疗效好,EGFR突变中19del者较L858R疗效更佳,基因检测结果可以较好地预测分子靶向药物的疗效,降低肿瘤进展的风险。

Detection of EGFR mutations in non small cell lung cancer and molecular targeted therapy

Objective To detect epidermal growth factor receptor ( EGFR) mutations in non-small cell lung cancer ( NSCLC) patients, and to study the relationship between EGFR mutation and clinical features, pathological features, the therapy efficacy. Methods Collect 203 NSCLC patients, specimens, including surgical specimen, lymph node tissues, transthoracic needle biopsyspecimen, bronchoscopy biopsy specimen and pleural effusion cells specimen. EGFR mutations in 203 NSCLC were analyzed by ADx-AMRS assay. The relationship between the muta-tions and the clinicopathologic features was further evaluated. And observed the clinical efficacy of EGFR-TKIs. SPSS23. 0 software was used for statistical analysis, the data were compared with chi square test, PFS was calculated by Kaplan-Meier method, and the influence of various factors on survival was analyzed by Log-rank test. Results The age of 203 NSCLC patients, inluding 116 male and 87 female, was range 25 years to 82 years. Smoking index was greater than or equal to 400 in 61 cases, less than 400 in 142 cases. The pathological characteristics of 203 cases were different, ininluding 152 cases of adenocarcinoma, 21 cases of squamous cell carcinoma, 14 cases of adenocarcinoma-squamous carcinoma, and other NSCLC 16 cases. The EGFR mutation rate of 203 cases in patients with NSCLC was 51.2％ (104/203), including 51 deletions in exon 19 ( 49. 0％) , 44 cases of exon 21 mutation, 3 cases of exon 18 mutation (2.9％), 1 case of exon 20 mutation, 3 exon 19/21 double mutation(2.9％), 1 case of 19del/T790M and 1 case of L858R/T790M. The mutation rate of 19del and L858R were higher 96.1％ in 104 cases. The mutation rates of EGFR were higher in females than those in males ( 66. 7％ vs. 36. 2％); Non smoking group EGFR mutation rate was higher than that in the smoking group(63.4％ vs. 16.4％); EGFR mutation rate of patients, with lung adenocarcinoma was higher than that of squamous cell carcinoma ( 53. 3％ vs. 33. 3％) , P<0. 05. Conversely, between EGFR gene mutation status and specimen type, including surgicai specimen, lymph node biopsy, lung biopsy, bronchoscopy, and pleural effusions, was no significant statistical difference ( P=0. 418 ). The objective response rate (ORR) to first-line TKI treatment of 101 patients was 61.4％. The disease control rate ( DCR) was 71.3％, and the median progression-free survival ( PFS) was 10 months. The ORR and DCR to EGFR-TKIs therapy of patients with EGFR mutation were significantly higher than those of patients with EGFR mutation/ undefined EGFR mutation (88.6％ vs. 16.7％ vs. 43.1％, P=0.000; 95.5％ vs. 16.7％ vs. 56.9％, P=0.000); the median PFS was also significantly longer (P=0.001). Furthermore, the ORR and DCR in 19-del group were higher than that of group L858R (91.2％ vs. 85％, P=0.646100％;vs. 90％, P=0.201); Patients with NSCLC in after TKI treatment, the median PFS was 14. 5 months compared with 10 months in the L858R group, there were significant differences ( P=0.010) . Conclusion EGFR mutation rate was higher in NSCLC with the advantages of female, non smoking and adenocarcinoma. EGFR mutation detection can better predict the efficacy of molecular targeted drugs and reduce the risk of tumor progression, especialli in 19-del or L858R mutation.