非小细胞肺癌患者EGFR突变率及与临床病理关系和TKI靶向治疗效果
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摘要
目的探讨非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)突变率及与临床病理关系和酪氨酸酶抑制剂(TKI)靶向治疗效果。方法选取2014年5月至2016年8月我院收治的NSCLC患者100例为研究对象,采用聚合酶链反应-直接测序法检测患者肿瘤组织EGFR基因18-21号外显子突变情况,分析EGFR突变与临床病理的关系及其突变特点,比较EGFR突变型与野生型采用TKI靶向治疗的疗效及1年生存率、2年生存率。结果本次纳入的100例NSCLC患者中共44例发生EGFR突变,EGFR突变率为44.00%; NSCLC患者EGFR突变率特点:女性高于男性,吸烟患者高于不吸烟患者,腺癌高于非腺癌,差异对比均有统计学意义(P<0.05); Logistic回归分析显示性别为女性、病理类型为腺癌是导致NSCLC患者发生EGFR突变的独立危险因素(P<0.05); EGFR突变类型包括18号外显子点突变4.54%(2/44)、19号外显子缺失突变43.19%(19/44)、20号外显子插入突变及点突变11.36%(5/44)、21号外显子点突变40.91%(18/44); EGFR突变型患者TKI治疗有效率68.18%明显高于EGFR野生型10.71%(P<0.05); EGFR突变型与野生型患者1年、2年生存率对比差异无统计学意义(P>0.05)。结论性别、病理类型是导致NSCLC患者发生EGFR基因突变的独立危险因素,对于EGFR突变型患者采用TKI靶向治疗可获得较好疗效,但2年生存率与EGFR野生型患者尚无明显差异。
Objective To observe the mutation rate of epidermal growth factor receptor (EGFR) in the patients with non-small cell lung cancer (NSCLC) and its relationship with the clinical pathology and tyrosinase inhibitor (TKI)-targeted therapy effect. Methods A total of 100 NSCLC patients treated in our hospital from May 2014 to August 2016 were selected for this study. The mutations of EGFR gene 18-21 exons were detected by polymerase chain reaction (PCR)-direct sequencing. The mutation features and the relationship between EGFR mutations and the clinical pathology were analyzed. The efficacies of the mutant type and the wild type of EGFI treated with TKI-targeted therapy and their 1-year survival rate and 2-year survival rate were compared. Results EGFR mutations occurred in 44 cases,with the EGFR mutation rate of 44%among the 100 NSCLC patients. The features of the EGFR mutation rate in NSCLC patients were that females had a higher risk than males, smokers had a higher risk than non-smokers, and the patients with adenocarcinoma had a higher risk than those without adenocarcinoma (P < 0. 05). Logistic regression analysis showed that the gender of female and the pathological type of adenocarcinoma were independent risk factors for EGFR mutation in the NSCLC patients (P<0.05). EGFR mutation types included point mutation of exon 18 in2 cases (4.54%),deletion mutation of exon 19 in 19 cases (43.19%),insertion mutation and point mutation of exon 20 in 5 cases (11.36%),and point mutation of exon 21 in 18 cases (40.91%). The effective rate of TKI treatment in the EGFR mutant patients was significantly higher than that in the EGFR wild type patients (68.18% vs 10.71%,P<0.05). There was no significant difference in the EGFR mutant type and wild type about 1-year and 2-year survival rates (P>0.05). Conclusion Gender and pathological type are independent risk factors for EGFR mutations in the NSCLC patients. TKI-targeted therapy has better effect in the EGFR mutant patients,but there is no significant difference in the 2-year survival rate compared with EGFR wild type patients.
Objective To observe the mutation rate of epidermal growth factor receptor (EGFR) in the patients with non-small cell lung cancer (NSCLC) and its relationship with the clinical pathology and tyrosinase inhibitor (TKI)-targeted therapy effect. Methods A total of 100 NSCLC patients treated in our hospital from May 2014 to August 2016 were selected for this study. The mutations of EGFR gene 18-21 exons were detected by polymerase chain reaction (PCR)-direct sequencing. The mutation features and the relationship between EGFR mutations and the clinical pathology were analyzed. The efficacies of the mutant type and the wild type of EGFI treated with TKI-targeted therapy and their 1-year survival rate and 2-year survival rate were compared. Results EGFR mutations occurred in 44 cases,with the EGFR mutation rate of 44%among the 100 NSCLC patients. The features of the EGFR mutation rate in NSCLC patients were that females had a higher risk than males, smokers had a higher risk than non-smokers, and the patients with adenocarcinoma had a higher risk than those without adenocarcinoma (P < 0. 05). Logistic regression analysis showed that the gender of female and the pathological type of adenocarcinoma were independent risk factors for EGFR mutation in the NSCLC patients (P<0.05). EGFR mutation types included point mutation of exon 18 in2 cases (4.54%),deletion mutation of exon 19 in 19 cases (43.19%),insertion mutation and point mutation of exon 20 in 5 cases (11.36%),and point mutation of exon 21 in 18 cases (40.91%). The effective rate of TKI treatment in the EGFR mutant patients was significantly higher than that in the EGFR wild type patients (68.18% vs 10.71%,P<0.05). There was no significant difference in the EGFR mutant type and wild type about 1-year and 2-year survival rates (P>0.05). Conclusion Gender and pathological type are independent risk factors for EGFR mutations in the NSCLC patients. TKI-targeted therapy has better effect in the EGFR mutant patients,but there is no significant difference in the 2-year survival rate compared with EGFR wild type patients.
引文
1何江,金星,李钟.胸腔镜辅助小切口术在非小细胞肺癌治疗中的应用价值及对患者C反应蛋白的影响[J].湖南师范大学学报(医学版),2016,13(6):38-40.
2李曦,秦娜,王敬慧,等.盐酸埃克替尼治疗EGFR突变状态明确的晚期非小细胞肺癌的临床观察[J].中国肺癌杂志,2015,18(12):734-739.
3杨宁,郭妹,宋玉兰,等.430例中国非小细胞肺癌患者EGFR、KRAS、BRAF和PIK3CA基因突变状态及其临床意义[J].中国肿瘤生物治疗杂志,2015,22(6):734-739.
4刘田田,毕经旺,王俊,等.非小细胞肺癌EGFR突变与脑转移的关系[J].肿瘤防治研究,2017,44(3):189-192.
5 Ke EE,Wu YL.EGFR as a Pharmacological target in EGFR-mutant non-small-cell lung cancer:Where do we stand now?[J].Trends Pharmacol Sci,2016,37(11):887-903.
6梁颖,林勇平,徐韫健,等.非小细胞肺癌EGFR基因突变的异质性[J].热带医学杂志,2015,15(12):1590-1594.
7张世强,张旭东,王保庆,等.晚期非小细胞肺癌患者外周血游离DNA中EGFR突变与靶向药物一线治疗疗效的相关性[J].山西医科大学学报,2015,46(7):645-648.
8赵皓,黄纯,居建平,等.非小细胞肺癌EGFR-TKI耐药后化疗序贯TKI治疗的效果[J].江苏医药,2015,41(2):165-167.
9 Corallo S,D'Argento E,Strippoli A,et al.Treatment options for EGFR T790M-negative EGFR tyrosine kinase inhibitor-resistant nonsmall cell lung cancer[J].Target Oncol,2017,12(2):153-161.
10中国医师协会肿瘤医师分会,中国抗癌协会肿瘤临床化疗专业委员会.中国表皮生长因子受体基因突变和间变淋巴瘤激酶融合基因阳性非小细胞肺癌诊断治疗指南(2013版)[J].中华肿瘤杂志,2013,35(6):478-480.
11李伟,段超,马传胜,等.基因突变检测技术在非小细胞肺癌EGFR与临床病理特征的关系研究中的作用[J].中国微生态学杂志,2015,27(1):66-68.
12纪春东,于秀芹,赖永新.盐酸埃克替尼治疗EGFR突变状态明确的晚期非小细胞肺癌的临床观察[J].河北医学,2017,23(1):100-102.
13涂长玲,朱颖,董坚,等.晚期非小细胞肺癌循环肿瘤细胞EGFR表达与细胞免疫的相关性研究[J].西部医学,2016,28(9):1221-1226.
14陈建华,喻珣.晚期非小细胞肺癌组织与血浆EGFR基因表达差异及临床意义[J].医学临床研究,2016,33(8):1463-1465,1469.
15 Lee CK,Kim S,Lee JS,et al.Next-generation sequencing reveals novel resistance mechanisms and molecular heterogeneity in EGFR-mutant non-small cell lung cancer with acquired resistance to EGFR-TKIs[J].Lung Cancer,2017,113(1):106-114.
16张怡湜,何雅億,李雪飞,等.非小细胞肺癌患者EGFR基因突变状态影响因素的临床分析[J].肿瘤,2014,34(2):147-152.
17何诚,黄榕芳,徐建平,等.非小细胞肺癌患者外周血与组织中EGFR基因突变的研究[J].贵州医药,2017,41(2):127-128.
18邱田,凌云,山灵,等.非小细胞肺癌患者表皮生长因子受体Kras基因突变检测及与临床病理特征的相关性[J].中国肿瘤临床与康复,2015,22(6):678-680.
19马玲,张琰,单莉,等.维吾尔族晚期非小细胞肺癌患者EGFR、KRAS基因突变状态及其与TKI靶向治疗效果的关系[J].山东医药,2016,56(31):66-68.
20王群慧,郑华,胡范彬,等.伴有EGFR突变的非小细胞肺癌血清CYFRA21-1和CEA水平与EGFR-TKIs的疗效关系[J].中国肺癌杂志,2016,19(8):550-558.
21 Chen Z,Liu X,Zhao J,et al.Correlation of EGFR mutation and histological subtype according to the IASLC/ATS/ERS classification of lung adenocarcinoma[J].Int J Clin Exp Pathol,2014,7(11):8039-8045.
22 Jie L,Li XY,Zhao YQ,et al.Genotype-phenotype correlation in Chinese patients with pulmonary mixed type adenocarcinoma:relationship betwen histologic subtypes,TITF-1/SP-A expressions and EGFR mutations[J].Pathol Res Pract,2014,210(3):176-181.
23 Castellanos E,Feld E,Horn L.Driven by Mutations:The Predictive value of mutation subtype in EGFR-mutated non-small cell lung cancer[J].J Thorac Oncol,2017,12(4):612-623.
24王珊,董丽儒,刘爱东,等.EGFR及KRAS基因突变与非小细胞肺癌临床病理特征的关系[J].临床与实验病理学杂志,2017,33(4):379-383.
25尹迎春,王新美,李良,等.非小细胞肺癌胸腔积液细胞蜡块检测EGFR与K-rasras基因突变和EML4-ALK融合基因及其临床病理特征[J].中国胸心血管外科临床杂志,2015,22(9):870-874.
26姚晓燕,申淑景,王晔,等.EGFR突变与非小细胞肺癌临床病理和TKI治疗疗效预测相关性分析[J].中华肿瘤防治杂志,2016,23(6):369-372.
27陈敏.非小细胞肺癌患者EGFR突变状态与临床分期的关系及EGFR-TKIs疗效预测因素探索的多中心临床回顾性研究[D].南方医科大学,2016:35-56.
28韩义明,郑杰,姜云惠,等.非小细胞肺癌中EGFR基因突变与ERCC1、Ki-67表达及临床病理特征的关系[J].临床与实验病理学杂志,2015,31(7):759-763.
29凌云,邱田,李卓,等.非小细胞肺癌中EGFR和KRAS基因突变的特点及与临床病理特征的关系[J].临床与实验病理学杂志,2015,31(5):536-541.
30冯卫能,张华,陈泽程,等.血浆EGFR基因突变检测在晚期非小细胞肺癌患者EGFR-TKI疗效评估中的价值[J].山东医药,2017,57(13):17-19.
31仇晓军,姚登福,季斌,等.非小细胞肺癌58例表皮生长因子受体突变状态[J].江苏医药,2013,39(7):804-806.
2李曦,秦娜,王敬慧,等.盐酸埃克替尼治疗EGFR突变状态明确的晚期非小细胞肺癌的临床观察[J].中国肺癌杂志,2015,18(12):734-739.
3杨宁,郭妹,宋玉兰,等.430例中国非小细胞肺癌患者EGFR、KRAS、BRAF和PIK3CA基因突变状态及其临床意义[J].中国肿瘤生物治疗杂志,2015,22(6):734-739.
4刘田田,毕经旺,王俊,等.非小细胞肺癌EGFR突变与脑转移的关系[J].肿瘤防治研究,2017,44(3):189-192.
5 Ke EE,Wu YL.EGFR as a Pharmacological target in EGFR-mutant non-small-cell lung cancer:Where do we stand now?[J].Trends Pharmacol Sci,2016,37(11):887-903.
6梁颖,林勇平,徐韫健,等.非小细胞肺癌EGFR基因突变的异质性[J].热带医学杂志,2015,15(12):1590-1594.
7张世强,张旭东,王保庆,等.晚期非小细胞肺癌患者外周血游离DNA中EGFR突变与靶向药物一线治疗疗效的相关性[J].山西医科大学学报,2015,46(7):645-648.
8赵皓,黄纯,居建平,等.非小细胞肺癌EGFR-TKI耐药后化疗序贯TKI治疗的效果[J].江苏医药,2015,41(2):165-167.
9 Corallo S,D'Argento E,Strippoli A,et al.Treatment options for EGFR T790M-negative EGFR tyrosine kinase inhibitor-resistant nonsmall cell lung cancer[J].Target Oncol,2017,12(2):153-161.
10中国医师协会肿瘤医师分会,中国抗癌协会肿瘤临床化疗专业委员会.中国表皮生长因子受体基因突变和间变淋巴瘤激酶融合基因阳性非小细胞肺癌诊断治疗指南(2013版)[J].中华肿瘤杂志,2013,35(6):478-480.
11李伟,段超,马传胜,等.基因突变检测技术在非小细胞肺癌EGFR与临床病理特征的关系研究中的作用[J].中国微生态学杂志,2015,27(1):66-68.
12纪春东,于秀芹,赖永新.盐酸埃克替尼治疗EGFR突变状态明确的晚期非小细胞肺癌的临床观察[J].河北医学,2017,23(1):100-102.
13涂长玲,朱颖,董坚,等.晚期非小细胞肺癌循环肿瘤细胞EGFR表达与细胞免疫的相关性研究[J].西部医学,2016,28(9):1221-1226.
14陈建华,喻珣.晚期非小细胞肺癌组织与血浆EGFR基因表达差异及临床意义[J].医学临床研究,2016,33(8):1463-1465,1469.
15 Lee CK,Kim S,Lee JS,et al.Next-generation sequencing reveals novel resistance mechanisms and molecular heterogeneity in EGFR-mutant non-small cell lung cancer with acquired resistance to EGFR-TKIs[J].Lung Cancer,2017,113(1):106-114.
16张怡湜,何雅億,李雪飞,等.非小细胞肺癌患者EGFR基因突变状态影响因素的临床分析[J].肿瘤,2014,34(2):147-152.
17何诚,黄榕芳,徐建平,等.非小细胞肺癌患者外周血与组织中EGFR基因突变的研究[J].贵州医药,2017,41(2):127-128.
18邱田,凌云,山灵,等.非小细胞肺癌患者表皮生长因子受体Kras基因突变检测及与临床病理特征的相关性[J].中国肿瘤临床与康复,2015,22(6):678-680.
19马玲,张琰,单莉,等.维吾尔族晚期非小细胞肺癌患者EGFR、KRAS基因突变状态及其与TKI靶向治疗效果的关系[J].山东医药,2016,56(31):66-68.
20王群慧,郑华,胡范彬,等.伴有EGFR突变的非小细胞肺癌血清CYFRA21-1和CEA水平与EGFR-TKIs的疗效关系[J].中国肺癌杂志,2016,19(8):550-558.
21 Chen Z,Liu X,Zhao J,et al.Correlation of EGFR mutation and histological subtype according to the IASLC/ATS/ERS classification of lung adenocarcinoma[J].Int J Clin Exp Pathol,2014,7(11):8039-8045.
22 Jie L,Li XY,Zhao YQ,et al.Genotype-phenotype correlation in Chinese patients with pulmonary mixed type adenocarcinoma:relationship betwen histologic subtypes,TITF-1/SP-A expressions and EGFR mutations[J].Pathol Res Pract,2014,210(3):176-181.
23 Castellanos E,Feld E,Horn L.Driven by Mutations:The Predictive value of mutation subtype in EGFR-mutated non-small cell lung cancer[J].J Thorac Oncol,2017,12(4):612-623.
24王珊,董丽儒,刘爱东,等.EGFR及KRAS基因突变与非小细胞肺癌临床病理特征的关系[J].临床与实验病理学杂志,2017,33(4):379-383.
25尹迎春,王新美,李良,等.非小细胞肺癌胸腔积液细胞蜡块检测EGFR与K-rasras基因突变和EML4-ALK融合基因及其临床病理特征[J].中国胸心血管外科临床杂志,2015,22(9):870-874.
26姚晓燕,申淑景,王晔,等.EGFR突变与非小细胞肺癌临床病理和TKI治疗疗效预测相关性分析[J].中华肿瘤防治杂志,2016,23(6):369-372.
27陈敏.非小细胞肺癌患者EGFR突变状态与临床分期的关系及EGFR-TKIs疗效预测因素探索的多中心临床回顾性研究[D].南方医科大学,2016:35-56.
28韩义明,郑杰,姜云惠,等.非小细胞肺癌中EGFR基因突变与ERCC1、Ki-67表达及临床病理特征的关系[J].临床与实验病理学杂志,2015,31(7):759-763.
29凌云,邱田,李卓,等.非小细胞肺癌中EGFR和KRAS基因突变的特点及与临床病理特征的关系[J].临床与实验病理学杂志,2015,31(5):536-541.
30冯卫能,张华,陈泽程,等.血浆EGFR基因突变检测在晚期非小细胞肺癌患者EGFR-TKI疗效评估中的价值[J].山东医药,2017,57(13):17-19.
31仇晓军,姚登福,季斌,等.非小细胞肺癌58例表皮生长因子受体突变状态[J].江苏医药,2013,39(7):804-806.