ctDNA检测晚期NSCLC患者EGFR基因突变的Meta分析
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摘要
目的探讨循环肿瘤DNA(ctDNA)在晚期非小细胞肺癌(NSCLC)患者表皮生长因子受体(EGFR)突变检测中的应用价值。方法检索PubMed、Embase、Medline、万方数据库、中国知网数据库、中国生物医学文献数据库、维普数据库,纳入报道了ctDNA检测晚期NSCLC患者EGFR突变灵敏度与特异度的文献;采用合并灵敏度、特异度、似然比点状图、集成受试者工作特征(SROC)曲线及曲线下面积(AUC)评估ctDNA诊断价值。结果共纳入28篇文献,包括3 644例晚期NSCLC患者,合并后的灵敏度、特异度分别为64.0%(95%CI:0.59～0.70)、98.0%(95%CI:0.95～0.99)。SROC曲线下面积为0.85(95%CI:0.82～0.88),表明ctDNA有较高的诊断价值。结论对于晚期NSCLC患者EGFR突变的检测,ctDNA是一个高特异性及高诊断价值的生物标志物,ctDNA基因检测将是晚期NSCLC患者个体化靶向治疗的重要组成部分。
Objective To investigate the diagnostic value of circulating tumor DNA(ctDNA)for the detection of epidermal growth factor receptor(EGFR)mutation in patients with advanced non-small lung cancer(NSCLC).Methods PubMed,Embase,Medline,CNKI,Wangfang Database,CBMdisc and VIP Database were retrieved to identify eligible studies which reported the sensitivity and specificity of ctDNA for detection of EGFR mutation status in advanced NSCLC.Overall diagnostic performance of the test was evaluated by pooled sensitivity,specificity,likelihood ratio scatter gram,SROC and AUC.Results Twenty eight eligible studies involving 3 644 participants were included.Pooled sensitivity,specificity was 64.0%(95%CI:0.59-0.70),98.0%(95%CI:0.95-0.99).The AUC diagnostic value was 0.85(95%CI:0.82-0.88),indicating the high diagnostic performance of ctDNA.Conclusion CtDNA is a highly specific and effective biomarker for the detection of EGFR mutation in advanced patients with NSCLC,and ctDNA will be a key part of personalized cancer therapy of advanced NSCLC.
Objective To investigate the diagnostic value of circulating tumor DNA(ctDNA)for the detection of epidermal growth factor receptor(EGFR)mutation in patients with advanced non-small lung cancer(NSCLC).Methods PubMed,Embase,Medline,CNKI,Wangfang Database,CBMdisc and VIP Database were retrieved to identify eligible studies which reported the sensitivity and specificity of ctDNA for detection of EGFR mutation status in advanced NSCLC.Overall diagnostic performance of the test was evaluated by pooled sensitivity,specificity,likelihood ratio scatter gram,SROC and AUC.Results Twenty eight eligible studies involving 3 644 participants were included.Pooled sensitivity,specificity was 64.0%(95%CI:0.59-0.70),98.0%(95%CI:0.95-0.99).The AUC diagnostic value was 0.85(95%CI:0.82-0.88),indicating the high diagnostic performance of ctDNA.Conclusion CtDNA is a highly specific and effective biomarker for the detection of EGFR mutation in advanced patients with NSCLC,and ctDNA will be a key part of personalized cancer therapy of advanced NSCLC.
引文
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[14]JIANG B,LIU F,YANG L,et al.Serum detection of epidermal growth factor receptor gene mutations using mutant-enriched sequencing in Chinese patients with advanced non-small cell lung cancer[J].J Int Med Res,2011,39(4):1392-1401.
[15]SHI C,ZHENG Y,LI Y,et al.Association between clinical characteristics and the diagnostic accuracy of circulating single-molecule amplification and resequencing technology on detection epidermal growth factor receptor mutation status in plasma of lung adenocarcinoma[J].J Clin Lab Anal,2018,32(2):1-8.
[16]QUE D,XIAO H,ZHAO B,et al.EGFR mutation status in plasma and tumor tissues in non-small cell lung cancer serves as a predictor of response to EGFR-TKI treatment[J].Cancer Biol Ther,2016,17(3):320-327.
[17]苏飞,郑可,付祎云,等.不同治疗对肺癌患者血液循环游离DNA检测EGFR基因突变的影响及预后分析[J].中国肺癌杂志,2018,21(5):389-396.
[18]XU F,WU J,XUE C,et al.Comparison of different methods for detecting epidermal growth factor receptor mutations in peripheral blood and tumor tissue of nonsmall cell lung cancer as a predictor of response to gefitinib[J].Onco Targets Ther,2012,5:439-447.
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[20]DUAN H,LU J,LU T,et al.Comparison of EGFR mutation status between plasma and tumor tissue in non-small cell lung cancer using the Scorpion ARMS method and the possible prognostic significance of plasma EGFR mutation status[J].Int J Clin Exp Pathol,2015,8(10):13136-13145.
[21]KIMURA H,SUMINOE M,KASAHARA K,et al.Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib(IRESSA)[J].Br J Cancer,2007,97(6):778-784.
[22]ZHANG H,LIU D,LI S,et al.Comparison of EGFR signaling pathway somatic DNA mutations derived from peripheral blood and corresponding tumor tissue of patients with advanced non-small-cell lung cancer using liquidchip technology[J].J Mol Diagn,2013,5(6):819-826.
[23]杜俊,王征,杨丽,等.肺腺癌患者血浆和肿瘤标本中表皮生长因子受体基因T790M位点突变检测一致性研究[J].中华肿瘤杂志,2018,40(1):35-39.
[24]DOUILLARD J Y,OSTOROS G,COBO M,et al.Firstline gefitinib in Caucasian EGFR mutation-positive NSCLC patients:aphase-Ⅳ,open-label,single-arm study[J].Br J Cancer,2014,110(1):55-62.
[25]MA M,SHI C,QIAN J,et al.Comparison of plasma and tissue samples in epidermal growth factor receptor mutation by ARMS in advanced non-small cell lung cancer[J].Gene,2016,591(1):58-64.
[26]VAZQUEZ S,CASAL J,AFONSO A F,et al.EGFR testing and clinical management of advanced NSCLC:a Galician Lung Cancer Group study(GGCP 048-10)[J].Cancer Manag Res,2016,8:11-20.
[27]YUNG T K,CHAN K C,MOK T S,et al.Single-molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non-small cell lung cancer patients[J].Clin Cancer Res,2009,15(6):2076-2084.
[28]LI X,REN R,REN S,et al.Peripheral blood for epidermal growth factor receptor mutati detection in non-small cell lung cancer patients[J].Transl Oncol,2014,7(3):341-348.
[29]LIU X,LU Y,ZHU G,et al.The diagnostic accuracy of pleural effusion and plasma samples versus tumour tissue for detection of EGFR mutation in patients with advanced non-small cell lung cancer:Comparison of methodologies[J].J Clin Pathol,2013,66(12):1065-1069.
[30]ZHANG X,CHANG N,YANG G,et al.A comparison of ARMS-Plus and droplet digital PCR for detecting EGFRactivating mutations in plasma[J].Oncotarget,2017,8(67):112014-112023.
[31]ZHAO X,HAN R B,ZHAO J,et al.Comparison of epidermal growth factor receptor mutation statuses in tissue and plasma in stageⅠ-Ⅳnon-small cell lung cancer patients[J].Respiration,2013,85(2):119-125.
[32]ZHANG Y,XU Y,ZHONG W,et al.Total DNA input is a crucial determinant of the sensitivity of plasma cell-free DNA EGFR mutation detection using droplet digital PCR[J].Oncotarget,2017,8(4):5861-5873.
[33]HUANG Z,WANG Z,BAI H,et al.The detection of EG-FR mutation status in plasma is reproducible and can dynamically predict the efficacy of EGFR-TKI[J].Thorac Cancer,2012,3(4):334-340.
[34]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.
[35]冷再君,徐傲,徐修才,等.多途径标本(下转第1691页)检测aNSCLC患者EGFR基因突变[J].安徽医科大学学报,2014,49(9):1320-1324.
[36]白桦,赵军,王书航,等.变性高效液相色谱法检测非小细胞肺癌患者外周血及肿瘤组织表皮生长因子受体突变[J].中华结核和呼吸杂志,2008,31(12):891-896.
[37]邹敏,周韶璋,于起涛,等.非小细胞肺癌患者肿瘤组织和血清表皮生长因子受体第19、21外显子的检测及其临床特征的分析[J].中国病理生理杂志,2013,29(5):839-844.
[38]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.
[39]陈祥娜.晚期非小细胞肺癌靶向治疗中循环DNA检测EGFR基因突变应用价值[J].中外医疗,2014,33(32):53-54.
[40]ELLISON G,DONALD E,MCWALTER G,et al.Acomparison of ARMS and DNA sequencing for mutation analysis in clinical biopsy samples[J].J Exp Clin Cancer Res,2010,29:132.
[41]YANG X,ZHUO M,YE X,et al.Quantification of mutant alleles in circulating tumor DNA can predict survival in lung cancer[J].Oncotarget,2016,7(15):20810-20824.
[42]XIE F,ZHANG Y,MAO X,et al.Comparison of genetic profiles among primary lung tumor,metastatic lymph nodes and circulating tumor DNA in treatment-naive advanced non-squamous non-small cell lung cancer patients[J].Lung Cancer,2018,87(121):54-60.
[43]CAI X,JANKU F,ZHAN Q,et al.Accessing Genetic Information with Liquid Biopsies[J].Trends Genet,2015,31(10):564-575.
[44]VALLEE A,MARCQ M,BIZIEUX A,et al.Plasma is a better source of tumor-derived circulating cell-free DNAthan serum for the detection of EGFR alterations in lung tumor patients[J].Lung Cancer,2013,82(2):373-374.
[2]PAO W,MILLER V A,POLITI K A,et al.Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain[J].PLoS Med,2005,2(3):e17.
[3]BAI H,WANG Z,CHEN K,et al.Influence of chemotherapy on EGFR mutation status among patients with non-small-cell lung cancer[J].J Clin Oncol,2012,30(25):3077-3083.
[4]JANNE P A.Challenges of detecting EGFR T790Min gefitinib/erlotinib-resistant tumours[J].Lung Cancer,2008,60(Suppl 2):S3-S9.
[5]SEQUIST L V,HEIST R S,SHAW A T,et al.Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice[J].Ann Oncol,2011,22(12):2616-2624.
[6]OVERMAN M J,MODAK J,KOPETZ S,et al.Use of research biopsies in clinical trials:are risks and benefits adequately discussed?[J].J Clin Oncol,2013,31(1):17-22.
[7]GERLINGER M,ROWAN A J,HORSWELL S,et al.Intratumor heterogeneity and branched evolution revealed by multiregion sequencing[J].N Engl J Med,2012,366(10):883-892.
[8]WAN J,MASSIE C,GARCIA-CORBACHO J,et al.Liquid biopsies come of age:towards implementation of circulating tumour DNA[J].Nat Rev Cancer,2017,17(4):223-238.
[9]POLIVKA J J,PESTA M,JANKU F.Testing for oncogenic molecular aberrations in cell-free DNA-based liquid biopsies in the clinic:are we there yet?[J].Expert Rev Mol Diagn,2015,15(12):1631-1644.
[10]ROLFO C,CASTIGLIA M,HONG D,et al.Liquid biopsies in lung cancer:the new ambrosia of researchers[J].Biochim Biophys Acta,2014,1846(2):539-546.
[11]ABBOSH C,BIRKBAK N J,WILSON G A,et al.Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution[J].Nature,2017,545(7655):446-451.
[12]BREVET M,JOHNSON M L,AZZOLI C G,et al.Detection of EGFR mutations in plasma DNA from lung cancer patients by mass spectrometry genotyping is predictive of tumor EGFR status and response to EGFR inhibitors[J].Lung Cancer,2011,73(1):96-102.
[13]SACHER A G,PAWELETZ C,DAHLBERG S E,et al.Prospective Validation of Rapid Plasma Genotyping for the Detection of EGFR and KRAS Mutations in Advanced Lung Cancer[J].JAMA Oncol,2016,2(8):1014-1022.
[14]JIANG B,LIU F,YANG L,et al.Serum detection of epidermal growth factor receptor gene mutations using mutant-enriched sequencing in Chinese patients with advanced non-small cell lung cancer[J].J Int Med Res,2011,39(4):1392-1401.
[15]SHI C,ZHENG Y,LI Y,et al.Association between clinical characteristics and the diagnostic accuracy of circulating single-molecule amplification and resequencing technology on detection epidermal growth factor receptor mutation status in plasma of lung adenocarcinoma[J].J Clin Lab Anal,2018,32(2):1-8.
[16]QUE D,XIAO H,ZHAO B,et al.EGFR mutation status in plasma and tumor tissues in non-small cell lung cancer serves as a predictor of response to EGFR-TKI treatment[J].Cancer Biol Ther,2016,17(3):320-327.
[17]苏飞,郑可,付祎云,等.不同治疗对肺癌患者血液循环游离DNA检测EGFR基因突变的影响及预后分析[J].中国肺癌杂志,2018,21(5):389-396.
[18]XU F,WU J,XUE C,et al.Comparison of different methods for detecting epidermal growth factor receptor mutations in peripheral blood and tumor tissue of nonsmall cell lung cancer as a predictor of response to gefitinib[J].Onco Targets Ther,2012,5:439-447.
[19]ZHU G,YE X,DONG Z,et al.Highly Sensitive Droplet Digital PCR Method for Detection of EGFR-Activating Mutations in Plasma Cell-Free DNA from Patients with Advanced Non-Small Cell Lung Cancer[J].J Mol Diagn,2015,17(3):265-272.
[20]DUAN H,LU J,LU T,et al.Comparison of EGFR mutation status between plasma and tumor tissue in non-small cell lung cancer using the Scorpion ARMS method and the possible prognostic significance of plasma EGFR mutation status[J].Int J Clin Exp Pathol,2015,8(10):13136-13145.
[21]KIMURA H,SUMINOE M,KASAHARA K,et al.Evaluation of epidermal growth factor receptor mutation status in serum DNA as a predictor of response to gefitinib(IRESSA)[J].Br J Cancer,2007,97(6):778-784.
[22]ZHANG H,LIU D,LI S,et al.Comparison of EGFR signaling pathway somatic DNA mutations derived from peripheral blood and corresponding tumor tissue of patients with advanced non-small-cell lung cancer using liquidchip technology[J].J Mol Diagn,2013,5(6):819-826.
[23]杜俊,王征,杨丽,等.肺腺癌患者血浆和肿瘤标本中表皮生长因子受体基因T790M位点突变检测一致性研究[J].中华肿瘤杂志,2018,40(1):35-39.
[24]DOUILLARD J Y,OSTOROS G,COBO M,et al.Firstline gefitinib in Caucasian EGFR mutation-positive NSCLC patients:aphase-Ⅳ,open-label,single-arm study[J].Br J Cancer,2014,110(1):55-62.
[25]MA M,SHI C,QIAN J,et al.Comparison of plasma and tissue samples in epidermal growth factor receptor mutation by ARMS in advanced non-small cell lung cancer[J].Gene,2016,591(1):58-64.
[26]VAZQUEZ S,CASAL J,AFONSO A F,et al.EGFR testing and clinical management of advanced NSCLC:a Galician Lung Cancer Group study(GGCP 048-10)[J].Cancer Manag Res,2016,8:11-20.
[27]YUNG T K,CHAN K C,MOK T S,et al.Single-molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non-small cell lung cancer patients[J].Clin Cancer Res,2009,15(6):2076-2084.
[28]LI X,REN R,REN S,et al.Peripheral blood for epidermal growth factor receptor mutati detection in non-small cell lung cancer patients[J].Transl Oncol,2014,7(3):341-348.
[29]LIU X,LU Y,ZHU G,et al.The diagnostic accuracy of pleural effusion and plasma samples versus tumour tissue for detection of EGFR mutation in patients with advanced non-small cell lung cancer:Comparison of methodologies[J].J Clin Pathol,2013,66(12):1065-1069.
[30]ZHANG X,CHANG N,YANG G,et al.A comparison of ARMS-Plus and droplet digital PCR for detecting EGFRactivating mutations in plasma[J].Oncotarget,2017,8(67):112014-112023.
[31]ZHAO X,HAN R B,ZHAO J,et al.Comparison of epidermal growth factor receptor mutation statuses in tissue and plasma in stageⅠ-Ⅳnon-small cell lung cancer patients[J].Respiration,2013,85(2):119-125.
[32]ZHANG Y,XU Y,ZHONG W,et al.Total DNA input is a crucial determinant of the sensitivity of plasma cell-free DNA EGFR mutation detection using droplet digital PCR[J].Oncotarget,2017,8(4):5861-5873.
[33]HUANG Z,WANG Z,BAI H,et al.The detection of EG-FR mutation status in plasma is reproducible and can dynamically predict the efficacy of EGFR-TKI[J].Thorac Cancer,2012,3(4):334-340.
[34]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.
[35]冷再君,徐傲,徐修才,等.多途径标本(下转第1691页)检测aNSCLC患者EGFR基因突变[J].安徽医科大学学报,2014,49(9):1320-1324.
[36]白桦,赵军,王书航,等.变性高效液相色谱法检测非小细胞肺癌患者外周血及肿瘤组织表皮生长因子受体突变[J].中华结核和呼吸杂志,2008,31(12):891-896.
[37]邹敏,周韶璋,于起涛,等.非小细胞肺癌患者肿瘤组织和血清表皮生长因子受体第19、21外显子的检测及其临床特征的分析[J].中国病理生理杂志,2013,29(5):839-844.
[38]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.
[39]陈祥娜.晚期非小细胞肺癌靶向治疗中循环DNA检测EGFR基因突变应用价值[J].中外医疗,2014,33(32):53-54.
[40]ELLISON G,DONALD E,MCWALTER G,et al.Acomparison of ARMS and DNA sequencing for mutation analysis in clinical biopsy samples[J].J Exp Clin Cancer Res,2010,29:132.
[41]YANG X,ZHUO M,YE X,et al.Quantification of mutant alleles in circulating tumor DNA can predict survival in lung cancer[J].Oncotarget,2016,7(15):20810-20824.
[42]XIE F,ZHANG Y,MAO X,et al.Comparison of genetic profiles among primary lung tumor,metastatic lymph nodes and circulating tumor DNA in treatment-naive advanced non-squamous non-small cell lung cancer patients[J].Lung Cancer,2018,87(121):54-60.
[43]CAI X,JANKU F,ZHAN Q,et al.Accessing Genetic Information with Liquid Biopsies[J].Trends Genet,2015,31(10):564-575.
[44]VALLEE A,MARCQ M,BIZIEUX A,et al.Plasma is a better source of tumor-derived circulating cell-free DNAthan serum for the detection of EGFR alterations in lung tumor patients[J].Lung Cancer,2013,82(2):373-374.