非小细胞肺癌EGFR基因不同突变位点对TKI治疗反应的meta分析
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摘要
目的比较表皮生长因子受体(EGFR)中外显子19缺失和外显子21 L858R替换两个突变位点对酪氨酸激酶抑制剂(TKI)的反应。方法以"NSCLC""non-small cell lung cancer""mutation""exon""TKI""tyrosine kinase inhibitors""EGFR""epidermal growth factor receptor"为关键词检索公开发表在Pubmed、Embase和Cochran Library上的关于不同基因位点对TKI治疗疗效的临床试验,检索期限为数据库建库至2018年2月1日,采用Revman 5.3软件进行数据分析。结果 27篇文献纳入分析,结果提示:外显子19缺失的非小细胞肺癌(NSCLC)患者在进行TKI治疗时可获得更长的无进展生存期(PFS)(HR=0.66,P<0.001)和总体生存期(OS)(HR=0.75,P<0.001),也可获得更好的客观缓解率(ORR)(OR=0.11,P<0.001)和疾病控制率(DCR)(OR=2.01,P=0.03)。结论 EGFR外显子19缺失突变是预测NSCLC患者对TKI治疗反应的较为敏感的指标,并且较外显子21 L858R替换的患者可以获得更好的疗效。
Objective To compared the response of exon 19 del and exon 21 L858 R substitute in EGFR to tyrosinekinase inhibitors( TKIs). Methods Relevant studies were retrieved from databases including PubMed,Embase,Cochrane Library,and the keywords including "NSCLC""non-small cell lung cancer""mutation""exon""TKI""tyrosine kinase inhibitors""EGFR""epidermal growth factor receptor",dated from construction until February1,2018. Meta-analysis was carried out using Revman 5. 3 software. Results A total of 27 articles were included in the analysis. The results suggested that non-small cell lung cancer( NSCLC) patients with exon 19 deletion can achieve longer progression-free survival( PFS)( HR = 0. 66,P < 0. 001) and overall survival( OS) when treated with TKI,( HR = 0. 75,P < 0. 001),also achieved better objective response rate( ORR)( OR = 0. 11,P <0. 001) and disease control rate( DCR)( OR = 2. 01,P = 0. 03). Conclusion EGFR exon 19 del mutation is more sensitive for predicting TKI response in patients with non-small cell lung cancer,and it can achieve better efficacy than the substitute of exon 21 L858 R.
Objective To compared the response of exon 19 del and exon 21 L858 R substitute in EGFR to tyrosinekinase inhibitors( TKIs). Methods Relevant studies were retrieved from databases including PubMed,Embase,Cochrane Library,and the keywords including "NSCLC""non-small cell lung cancer""mutation""exon""TKI""tyrosine kinase inhibitors""EGFR""epidermal growth factor receptor",dated from construction until February1,2018. Meta-analysis was carried out using Revman 5. 3 software. Results A total of 27 articles were included in the analysis. The results suggested that non-small cell lung cancer( NSCLC) patients with exon 19 deletion can achieve longer progression-free survival( PFS)( HR = 0. 66,P < 0. 001) and overall survival( OS) when treated with TKI,( HR = 0. 75,P < 0. 001),also achieved better objective response rate( ORR)( OR = 0. 11,P <0. 001) and disease control rate( DCR)( OR = 2. 01,P = 0. 03). Conclusion EGFR exon 19 del mutation is more sensitive for predicting TKI response in patients with non-small cell lung cancer,and it can achieve better efficacy than the substitute of exon 21 L858 R.
引文
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[16] Choi C M,Kim M Y,Lee J C.Advanced lung adenocarcinoma harboring a mutation of the epidermal growth factor receptor:CT findings after tyrosine kinase inhibitor therapy[J].Radiology,2014,270(2):574-82.
[17] Lu R L,Hu C P,Yang H P,et al.Biological characteristics and epidermal growth factor receptor tyrosine kinase inhibitors efficacy of EGFR mutation and its subtypes in lung adenocarcinoma[J].Pathol Oncol Res,2014,20(2):445-51.
[18] Fukuoka M,Wu Y L,Thongprasert S,et al.Biomarker analyses and final overall survival results from a phase Ⅲ,randomized,open-label,first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS)[J].J Clin Oncol,2011,29(21):2866-74.
[19] Won Y W,Han J Y,Lee G K,et al.Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations[J].J Clin Pathol,2011,64(11):947-52.
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[21] Sequist L V,Martins R G,Spigel D,et al.First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations[J].Clin Oncol,2008,26(15):2442-9.
[22] Joshi A,Patil V,Noronha V,et al.Efficacy of gefitinib in epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer:Does exon 19 deletion differ from exon 21 mutation?[J].Lung India,2018,35(1):27-30.
[23] Mitsudomi T,Morita S,Yatabe Y,et al.Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405):an open label,randomized phase 3 trial[J].Lancet Oncol,2010,11(2):121-8.
[24] Satouchi M,Negoro S,Funada Y,et al.Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib[J].Brit J Cancer,2007,96(8):1191-6.
[25] Inoue A,Suzuki T,Fukuhara T,et al.Prospective phase Ⅱ study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations[J].J Clin Oncol,2006,24(21):3340-6.
[26] Sugio K,Uramoto H,Onitsuka T,et al.Prospective phase Ⅱ study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations[J].Lung Cancer,2009,64(3):314-8.
[27] Yoshida K,Yatabe Y,Park J Y,et al.Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer[J].J Thorac Oncol,2007,2(1):22-8.
[28] Zheng Z,Jin X,Lin B,et al.Efficacy of second-line tyrosine kinase inhibitors in the treatment of metastatic advanced non-small-cell lung cancer harboring exon 19 and 21 EGFR mutations[J].J Cancer,2017,8(4):597-605.
[29] Sheng M,Wang F,Zhao Y,et al.Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 OR exon 21 mutations after tyrosine kinase inhibitors treatment:a meta-analysis[J].Eur J Clin Pharmacol,2016,72(1):1-11.
[30] Park K,Tan E H,O′Byrne K,et al.Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7):a phase 2B,open-label,randomized controlled trial[J].Lancet Oncol,2016,17(5):577-89.
[31] Wu Y L,Cheng Y,Zhou X,et al.Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050):a randomized,open-label,phase 3 trial[J].Lancet Oncol,2017,18(11):1454-66.
[2] Sun J M,Won Y W,Kim S T,et al.The different efficacy of gefitinib or erlotinib according to epidermal growth factor receptor exon 19 and exon 21 mutations in Korean non-small cell lung cancer patients[J].J Cancer Res Clin,2011,137(4):687-94.
[3] Carey K D,Garton A J,Romero M S,et al.Kinetic analysis of epidermal growth factor receptor somatic mutant proteins shows increased sensitivity to the epidermal growth factor receptor tyrosine kinase inhibitor,erlotinib[J].Cancer Res,2006,66(16):8163-71.
[4] Riely G J,Pao W,Pham D,et al.Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib OR erlotinib[J].Clin Cancer Res,2006,12(3 Pt 1):839-44.
[5] Maemondo M,Inoue A,Kobayashi K,et al.Gefitinib OR chemotherapy for non-small-cell lung cancer with mutated EGFR[J].N Engl J Med,2010,362(25):2380-8.
[6] Liu H L,Han G,Peng M,et al.Efficacy of EGFR tyrosine kinase inhibitors in non-small cell lung cancer patients harboring different types of EGFR mutations:A retrospective analysis[J].J HuaZhong Univ Sci Technolog Med Sci,2017,37(6):864-72.
[7] Zhuo M,Zheng Q,Zhao J,et al.Survival difference between Del19 and L858R mutant advanced non-small cell lung cancer patients receiving gefitinib:a propensity score matching analysis[J].Chin J Cancer Res,2017,29(6):553-60.
[8] Liu J J,Zhang S,Wu C J,et al.Comparison of clinical outcomes of patients with non-small cell lung cancer harboring different types of epidermal growth factor receptor sensitive mutations after first-line EGFR-TKI treatment[J].Zhonghua ZhongLiu Za Zhi,2016,38(3):211-7.
[9] Patel N,Wu P,Zhang H.Comparison of gefitinib as first- and second-line therapy for advanced lung adenocarcinoma patients with positive exon 21 OR 19 del epidermal growth factor receptor mutation[J].Cancer Manag Res,2017,9:243-8.
[10] Xue Z X,Wen W X,Zhuang Y,et al.Comparison of the efficacy of icotinib in patients with non-small-cell lung cancer according to the type of epidermal growth factor receptor mutation[J].Mol Clin Oncol,2016,5(3):265-8.
[11] Koyama N,Watanabe Y,Iwai Y,et al.Distinct benefit of overall survival between patients with non-small-cell lung cancer harboring EGFR exon 19 deletion and exon 21 L858R substitution[J].Chemotherapy,2017,62(3):151-8.
[12] Sutiman N,Tan S W,Tan E H,et al.EGFR Mutation subtypes influence survival outcomes following first-line gefitinib therapy in advanced Asian NSCLC patients[J].J Thorac Oncol,2017,12(3):529-38.
[13] Kim D W,Lee S H,Lee J S,et al.A multicenter phase II study to evaluate the efficacy and safety of gefitinib as first-line treatment for Korean patients with advanced pulmonary adenocarcinoma harboring EGFR mutations[J].Lung Cancer,2011,71(1):65-9.
[14] Asahina H,Yamazaki K,Kinoshita I,et al.A phase II trial of gefitinib as first-line therapy for advanced non-small cell lung cancer with epidermal growth factor receptor mutations[J].Brit J Cancer,2006,95(8):998-1004.
[15] Goto K,Nishio M,Yamamoto N,et al.A prospective,phase II,open-label study (JO22903) of first-line erlotinib in Japanese patients with epidermal growth factor receptor (EGFR) mutation-positive advanced non-small-cell lung cancer (NSCLC)[J].Lung Cancer,2013,82(1):109-14.
[16] Choi C M,Kim M Y,Lee J C.Advanced lung adenocarcinoma harboring a mutation of the epidermal growth factor receptor:CT findings after tyrosine kinase inhibitor therapy[J].Radiology,2014,270(2):574-82.
[17] Lu R L,Hu C P,Yang H P,et al.Biological characteristics and epidermal growth factor receptor tyrosine kinase inhibitors efficacy of EGFR mutation and its subtypes in lung adenocarcinoma[J].Pathol Oncol Res,2014,20(2):445-51.
[18] Fukuoka M,Wu Y L,Thongprasert S,et al.Biomarker analyses and final overall survival results from a phase Ⅲ,randomized,open-label,first-line study of gefitinib versus carboplatin/paclitaxel in clinically selected patients with advanced non-small-cell lung cancer in Asia (IPASS)[J].J Clin Oncol,2011,29(21):2866-74.
[19] Won Y W,Han J Y,Lee G K,et al.Comparison of clinical outcome of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 or exon 21 mutations[J].J Clin Pathol,2011,64(11):947-52.
[20] Jackman D M,Yeap B Y,Sequist L V,et al.Exon 19 deletion mutations of epidermal growth factor receptor are associated with Prolonged survival in non-small cell lung cancer patients treated with gefitinib or erlotinib[J].Clin Cancer Res,2006,12(13):3908-14.
[21] Sequist L V,Martins R G,Spigel D,et al.First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations[J].Clin Oncol,2008,26(15):2442-9.
[22] Joshi A,Patil V,Noronha V,et al.Efficacy of gefitinib in epidermal growth factor receptor-activating mutation-positive non-small cell lung cancer:Does exon 19 deletion differ from exon 21 mutation?[J].Lung India,2018,35(1):27-30.
[23] Mitsudomi T,Morita S,Yatabe Y,et al.Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405):an open label,randomized phase 3 trial[J].Lancet Oncol,2010,11(2):121-8.
[24] Satouchi M,Negoro S,Funada Y,et al.Predictive factors associated with prolonged survival in patients with advanced non-small-cell lung cancer (NSCLC) treated with gefitinib[J].Brit J Cancer,2007,96(8):1191-6.
[25] Inoue A,Suzuki T,Fukuhara T,et al.Prospective phase Ⅱ study of gefitinib for chemotherapy-naive patients with advanced non-small-cell lung cancer with epidermal growth factor receptor gene mutations[J].J Clin Oncol,2006,24(21):3340-6.
[26] Sugio K,Uramoto H,Onitsuka T,et al.Prospective phase Ⅱ study of gefitinib in non-small cell lung cancer with epidermal growth factor receptor gene mutations[J].Lung Cancer,2009,64(3):314-8.
[27] Yoshida K,Yatabe Y,Park J Y,et al.Prospective validation for prediction of gefitinib sensitivity by epidermal growth factor receptor gene mutation in patients with non-small cell lung cancer[J].J Thorac Oncol,2007,2(1):22-8.
[28] Zheng Z,Jin X,Lin B,et al.Efficacy of second-line tyrosine kinase inhibitors in the treatment of metastatic advanced non-small-cell lung cancer harboring exon 19 and 21 EGFR mutations[J].J Cancer,2017,8(4):597-605.
[29] Sheng M,Wang F,Zhao Y,et al.Comparison of clinical outcomes of patients with non-small-cell lung cancer harbouring epidermal growth factor receptor exon 19 OR exon 21 mutations after tyrosine kinase inhibitors treatment:a meta-analysis[J].Eur J Clin Pharmacol,2016,72(1):1-11.
[30] Park K,Tan E H,O′Byrne K,et al.Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7):a phase 2B,open-label,randomized controlled trial[J].Lancet Oncol,2016,17(5):577-89.
[31] Wu Y L,Cheng Y,Zhou X,et al.Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050):a randomized,open-label,phase 3 trial[J].Lancet Oncol,2017,18(11):1454-66.