RET基因在肺癌中的研究进展
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摘要
RET原癌基因已经逐渐被证实与多种恶性肿瘤的发生、发展具有相关性,伴着分子靶向研究的热潮,RET基因的融合突变在肺癌患者中被发现,提示肺癌精准治疗的新靶点出现。RET突变更易出现于较年轻、分化程度较低、非吸烟的非小细胞肺腺癌患者。靶向治疗由于对致癌基因的特异性阻断,可以有效地抑制肿瘤细胞的生长,而RET抑制剂的问世,为肺癌分子治疗研究领域带来新的曙光。
RET proto-oncogene has gradually been associated with the occurrence and development of a variety of malignant tumors,along with the upsurge of molecular targeted study,the fusion mutation of RET genes is found in lung cancer patients,suggesting a new target for the precision treatment of lung cancer.RET mutations are more likely to occur in the patients featured with non-small cell lung adenocarcinomas with younger age,less differentiated,non-smokers.Targeted therapy can effectively inhibit the growth of tumor cells with specific blocking oncogene.With the birth of RET inhibitors,molecular therapy of lung cancer may usher a new dawn.
RET proto-oncogene has gradually been associated with the occurrence and development of a variety of malignant tumors,along with the upsurge of molecular targeted study,the fusion mutation of RET genes is found in lung cancer patients,suggesting a new target for the precision treatment of lung cancer.RET mutations are more likely to occur in the patients featured with non-small cell lung adenocarcinomas with younger age,less differentiated,non-smokers.Targeted therapy can effectively inhibit the growth of tumor cells with specific blocking oncogene.With the birth of RET inhibitors,molecular therapy of lung cancer may usher a new dawn.
引文
[1]Torre LA,Bray F,Siegel RL,et al.Global cancer statistics,2012[J].CA Cancer J Clin,2015,65(2):87108.
[2]Pao W,Girard N.New driver mutations in non-small-cell lung cancer[J].Lancet Oncol,2011,12(2):175-180.
[3]Ju YS,Lee WC,Shin JY,et al.Atransforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-enome transcriptome sequencing[J].Genome Res,2012,22(3):436-445.
[4]Takahashi M,Ritz J,Cooper GM.Activation of a novel human transforming gene,ret,by DNA rearrangement[J].Cell,1985,42(2):581-588.
[5]de Groot JW,Links TP,Plukker JT,et al.RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors[J].Endocr Rev,2006,27(5):535-560.
[6]Frank-Raue K,Rondot S,Raue F.Molecular genetics and phenomics of RET mutations:Impact on prognosis of MTC[J].Mol Cell Endocrinol,2010,322(1/2):2-7.
[7]Raue F,Frank-Raue K.Genotype-phenotype relationship in multiple endocrine neoplasia type 2.Implications for clinical management[J].Hormones(Athens),2009,8(1):23-28.
[8]Borrello MG,Ardini E,Locati LD,et al.RET inhibition:implications in cancer therapy[J].Expert Opin Ther Targets,2013,17(4):403-419.
[9]Kohno T,Ichikawa H,Totoki Y,et al.KIF5B-RET fusions in lung adenocarcinoma[J].Nat Med,2012,18(3):375-377.
[10]Grieco M,Santoro M,Berlingieri MT,et al.PTC is a novel rearranged from of the RET proto-oncogene and is frequently detectedin vivoin human thyroid papillary carcinomas[J].Cell,1990,60(4):557-563.
[11]American yroid Association Guidelines Task Force,Kloos RT,Eng C,et al.Medullary thyroid cancer:management guidelines of the American yroid Association[J].Thyroid,2009,19(6):565-612.
[12]Pappa T,Alevizaki M.Management of hereditary medullary thyroid carcinoma[J].Endocrine,2016,53(1):7-17.
[13]Bolk S,Pelet A,Hofstra RM,et al.A human model for multigenic inheritance:phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus[J].Proc Natl Acad Sci U S A,2000,97(1):268-273.
[14]Fei L,Yan F,Rong F,et al.Identi cation of RET gene fusion by exon array analyses in″pan-negative″lung adenocarcinomas from never smokers[J].Cell Res,2012,22(5):928-931.
[15]Matsubara D,Kanai Y,Ishikawa S,et al.Identi cation of CCDC6-RET fusion in the human lung adenocarcinoma cell line,LC-2/ad[J].Jorac Oncol,2012,7(12):1872-1876.
[16]Drilon A,Wang L,Hasanovic A,et al.Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas[J].Cancer Discov,2013,3(6):630-635.
[17]Gainor JF,Shaw AT.Novel targets in non-small cell lung cancer:ROS1 and RET fusions[J].Oncologist,2013,18(7):865-875.
[18]Cai W,Su C,Li X,et al.KIF5B-RET fusions in Chinese patients with non-small cell lung cancer[J].Cancer,2013,119(8):1486-1494.
[19]Yoo SS,Jin G,Jung HJ,et al.RET Fusion Genes in Korean NonSmall Cell Lung Cancer[J].J Korean Med Sci,2013,28(10):1555-1558.
[20]Johnson JL,Pillai S,Chellappan SP.Genetic and biochemical alterations in non-small cell lung cancer[J].Biochem Res Int,2012,2012:940405.
[21]Takeuchi K,Soda M,Togashi Y,et al.RET,ROS1 and ALK fusions in lung cancer[J].Nat Med,2012,18(3):378-381.
[22]刘光源,朱江,文彦,等.非小细胞肺癌ALK、ROS1及RET融合基因检测与临床特性的相关性分析[J].中国胸心血管外科临床杂志,2014,21(4):522-526.
[23]Okamoto I,Sakai K,Morita S,et al.Multiplex genomic profiling of non-small cell lung cancers from the LETS phaseⅢtrial of rstline S-1/carboplatin versus paclitaxel/carboplatin:results of a West Japan Oncology Group study[J].Oncotarget,2014,5(8):2293-2304.
[24]潘放,任庆兰.酪氨酸激酶ALK、ROS1、RET融合基因与肺癌临床特征的关系分析[J].实用癌症杂志,2015,30(7):958-960.
[25]Dong Y,Ren W,Qi J,et al.EGFR,ALK,RET,KRAS and BRAF alterations in never-smokers with non-small cell lung cancer[J].Oncol Lett,2016,11(4):2371-2378.
[26]Wang R,Hu H,Pan Y,et al.RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer[J].J Clin Oncol,2012,30(35):4352-4359.
[27]Lipson D,Capelletti M,Yelensky R,et al.Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies[J].Nat Med,2012,18(3):382-384.
[28]Yokota K,Sasaki H,Okuda K,et al.KIF5B/RET fusion gene in surgically-treated adenocarcinoma of the lung[J].Oncol Rep,2012,28(4):1187-1192.
[29]Lin C,Wang S,Xie W,et al.The RET fusion gene and its correlation with demographic and clinicopathological features of nonsmall cell lung cancer:a meta-analysis[J].Cancer Biol Ther,2015,16(7):1019-1028.
[30]Kim JO,Lee J,Shin JY,et al.KIF5B-RET Fusion gene may coincide oncogenic mutations of EGFR or KRAS gene in lung adenocarcinomas[J].Diagn Pathol,2015,10:143.
[31]Lu H,Xu H,Xie F,et al.1p/19q codeletion and RET rearrangements in small-cell lung cancer[J].Onco Targets Ther,2016,9:3571-3577.
[32]Zupan A,Glavaˇc D.The development of rapid and accurate screening test for RET hotspot somatic and germline mutations in MEN2 syndromes[J].Exp Mol Pathol,2015,99(3):416-425.
[33]Wells SA Jr,Robinson BG,Gagel RF,et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer:a randomized,double-blind phaseⅢtrial[J].J Clin Oncol,2012,30(2):134-141.
[34]Aziz N,Zhao Q,Bry L,et al.College of American Pathologists'laboratory standards for next-generation sequencing clinical tests[J].Arch Pathol Lab Med,2015,139(4):481-493.
[35]Karnes HE,Duncavage EJ,Bernadt CT.Targeted next-generation sequencing using fine-needle aspirates from adenocarcinomas of the lung[J].Cancer Cytopathol,2014,122(2):104-113.
[36]Kanagal-Shamanna R,Portier BP,Singh RR,et al.Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples:promises and challenges for routine clinical diagnostics[J].Mod Pathol,2014,27(2):314-327.
[37]Wei S,Lieberman D,Morrissette JJ,et al.Using"residual"FNA rinse and body fluid specimens for next-generation sequencing:An institutional experience[J].Cancer Cytopathol,2016,124(5):324-329.
[38]Warth A,Penzel R,Brandt R,et al.Optimized algorithm for Sanger sequencing-based EGFR mutation analyses in NSCLC biopsies[J].Virchows Arch,2012,460(4):407-414.
[39]Wei S,Li Volsi VA,Montone KT,et al.Detection of molecular alterations in medullary thyroid carcinoma using next-generation sequencing:an institutional experience[J].Endocr Pathol,2016,27(4):359-362.
[40]Buettner R,Wolf J,Thomas RK.Lessons learned from lung cancer genomics:the emerging concept of individualized diagnostics and treatment[J].J Clin Oncol,2013,31(15):1858-1865.
[41]Gautschi O,Zander T,Keller FA,et al.A patient with lung adenocarcinoma and RET fusion treated with vandetanib[J].Thorac Oncol,2013,8(5):e43-44.
[42]Falchook GS,Ordóez NG,Bastida CC,et al.Effect of the RET inhibitor vandetanib in a patient with RET fusion-positive metastatic non-small-cell lung cancer[J].J Clin Oncol,2016,34(15):e141-144.
[43]Natale RB,Thongprasert S,Greco FA,et al.PhaseⅢtrial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer[J].J Clin Oncol,2011,29(8):1059-1066.
[44]Lee JS,Hirsh V,Park K,et al.Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor:a randomized,double-blind phaseⅢtrial(ZEPHYR)[J].J Clin Oncol,2012,30(10):1114-1121.
[45]Suzuki M,Makinoshima H,Matsumoto S.Identification of a lung adenocarcinoma cell line with CCDC6-RET fusion gene and the effect of RET inhibitors in vitro and in vivo[J].Cancer Sci,2013,104(7):896-903.
[46]Mukhopadhyay S,Pennell NA,Ali SM,et al.RET-rearranged lung adenocarcinomas with lymphangitic spread,psammoma bodies,and clinical responses to cabozantinib[J].J Thorac Oncol,2014,9(11):1714-1719.
[47]Schoffski P,Elisei R,Muller S.An international,double-blind,randomized,placebo-controlled phaseⅢtrial(EXAM)of cabozantinib(XL184)in medullary thyroid carcinoma(MTC)patients with documented RECIST progression at baseline[J].J Clin Oncol,2012,30(Suppl):abstract 5508.
[48]Song M,Kim SH,Yoon SK.Cabozantinib for the treatment of nonsmall cell lung cancer with KIF5B-RET fusion.An example of swift repositioning[J].Arch Pharm Res,2015,38(12):2120-2123.
[49]Drilon AE,Sima CS,Somwar R,et al.PhaseⅡstudy of cabozantinib for patients with advanced RET-rearranged lung cancers[J].J Clin Oncol,2015,33(15):8007.
[50]Ping G,Hui-Min W,Wei-Min W,et al.Sunitinib in pretreated advanced non-small-cell lung carcinoma:a primary result from Asian population[J].Med Oncol,2011,28(2):578-583.
[51]Liu YR,Zhu W,Zhang JL,et al.The evaluation of efficacy and safety of sunitinib on EGFR-TKI pretreated advanced non-small cell lung cancer patients in China[J].Clin Respir J,2014,8(2):206-212.
[52]Wu H,Shih JY,Yang JC.Rapid response to sunitinib in a patient with lung adenocarcinoma harboring KIF5B-RET fusion gene[J].J Thorac Oncol,2015,10(9):e95-96.
[53]Shaw AT,Hsu PP,Awad MM,et al.Tyrosine kinase gene rearrangements in epithelial malignancies[J].Nature Reviews Cancer,2013,13(11):772-787.
[54]De Falco V,Buonocore P,Muthu M,et al.Ponatinib(AP24534)is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer[J].J Clin Endocrinol Metab,2013,98(5):E811-819.
[55]Song M.Progress in Discovery of KIF5B-RET Kinase Inhibitors for the Treatment of Non-Small-Cell Lung Cancer[J].J Med Chem,2015,58(9):3672-3681.
[56]Tan EH,Tan DS,Li WY,et al.Metronomic vinorelbine(oral)in combination with sorafenib in advanced non-small cell lung cancer[J].Lung Cancer,2015,88(3):289-296.
[2]Pao W,Girard N.New driver mutations in non-small-cell lung cancer[J].Lancet Oncol,2011,12(2):175-180.
[3]Ju YS,Lee WC,Shin JY,et al.Atransforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-enome transcriptome sequencing[J].Genome Res,2012,22(3):436-445.
[4]Takahashi M,Ritz J,Cooper GM.Activation of a novel human transforming gene,ret,by DNA rearrangement[J].Cell,1985,42(2):581-588.
[5]de Groot JW,Links TP,Plukker JT,et al.RET as a diagnostic and therapeutic target in sporadic and hereditary endocrine tumors[J].Endocr Rev,2006,27(5):535-560.
[6]Frank-Raue K,Rondot S,Raue F.Molecular genetics and phenomics of RET mutations:Impact on prognosis of MTC[J].Mol Cell Endocrinol,2010,322(1/2):2-7.
[7]Raue F,Frank-Raue K.Genotype-phenotype relationship in multiple endocrine neoplasia type 2.Implications for clinical management[J].Hormones(Athens),2009,8(1):23-28.
[8]Borrello MG,Ardini E,Locati LD,et al.RET inhibition:implications in cancer therapy[J].Expert Opin Ther Targets,2013,17(4):403-419.
[9]Kohno T,Ichikawa H,Totoki Y,et al.KIF5B-RET fusions in lung adenocarcinoma[J].Nat Med,2012,18(3):375-377.
[10]Grieco M,Santoro M,Berlingieri MT,et al.PTC is a novel rearranged from of the RET proto-oncogene and is frequently detectedin vivoin human thyroid papillary carcinomas[J].Cell,1990,60(4):557-563.
[11]American yroid Association Guidelines Task Force,Kloos RT,Eng C,et al.Medullary thyroid cancer:management guidelines of the American yroid Association[J].Thyroid,2009,19(6):565-612.
[12]Pappa T,Alevizaki M.Management of hereditary medullary thyroid carcinoma[J].Endocrine,2016,53(1):7-17.
[13]Bolk S,Pelet A,Hofstra RM,et al.A human model for multigenic inheritance:phenotypic expression in Hirschsprung disease requires both the RET gene and a new 9q31 locus[J].Proc Natl Acad Sci U S A,2000,97(1):268-273.
[14]Fei L,Yan F,Rong F,et al.Identi cation of RET gene fusion by exon array analyses in″pan-negative″lung adenocarcinomas from never smokers[J].Cell Res,2012,22(5):928-931.
[15]Matsubara D,Kanai Y,Ishikawa S,et al.Identi cation of CCDC6-RET fusion in the human lung adenocarcinoma cell line,LC-2/ad[J].Jorac Oncol,2012,7(12):1872-1876.
[16]Drilon A,Wang L,Hasanovic A,et al.Response to cabozantinib in patients with RET fusion-positive lung adenocarcinomas[J].Cancer Discov,2013,3(6):630-635.
[17]Gainor JF,Shaw AT.Novel targets in non-small cell lung cancer:ROS1 and RET fusions[J].Oncologist,2013,18(7):865-875.
[18]Cai W,Su C,Li X,et al.KIF5B-RET fusions in Chinese patients with non-small cell lung cancer[J].Cancer,2013,119(8):1486-1494.
[19]Yoo SS,Jin G,Jung HJ,et al.RET Fusion Genes in Korean NonSmall Cell Lung Cancer[J].J Korean Med Sci,2013,28(10):1555-1558.
[20]Johnson JL,Pillai S,Chellappan SP.Genetic and biochemical alterations in non-small cell lung cancer[J].Biochem Res Int,2012,2012:940405.
[21]Takeuchi K,Soda M,Togashi Y,et al.RET,ROS1 and ALK fusions in lung cancer[J].Nat Med,2012,18(3):378-381.
[22]刘光源,朱江,文彦,等.非小细胞肺癌ALK、ROS1及RET融合基因检测与临床特性的相关性分析[J].中国胸心血管外科临床杂志,2014,21(4):522-526.
[23]Okamoto I,Sakai K,Morita S,et al.Multiplex genomic profiling of non-small cell lung cancers from the LETS phaseⅢtrial of rstline S-1/carboplatin versus paclitaxel/carboplatin:results of a West Japan Oncology Group study[J].Oncotarget,2014,5(8):2293-2304.
[24]潘放,任庆兰.酪氨酸激酶ALK、ROS1、RET融合基因与肺癌临床特征的关系分析[J].实用癌症杂志,2015,30(7):958-960.
[25]Dong Y,Ren W,Qi J,et al.EGFR,ALK,RET,KRAS and BRAF alterations in never-smokers with non-small cell lung cancer[J].Oncol Lett,2016,11(4):2371-2378.
[26]Wang R,Hu H,Pan Y,et al.RET fusions define a unique molecular and clinicopathologic subtype of non-small-cell lung cancer[J].J Clin Oncol,2012,30(35):4352-4359.
[27]Lipson D,Capelletti M,Yelensky R,et al.Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies[J].Nat Med,2012,18(3):382-384.
[28]Yokota K,Sasaki H,Okuda K,et al.KIF5B/RET fusion gene in surgically-treated adenocarcinoma of the lung[J].Oncol Rep,2012,28(4):1187-1192.
[29]Lin C,Wang S,Xie W,et al.The RET fusion gene and its correlation with demographic and clinicopathological features of nonsmall cell lung cancer:a meta-analysis[J].Cancer Biol Ther,2015,16(7):1019-1028.
[30]Kim JO,Lee J,Shin JY,et al.KIF5B-RET Fusion gene may coincide oncogenic mutations of EGFR or KRAS gene in lung adenocarcinomas[J].Diagn Pathol,2015,10:143.
[31]Lu H,Xu H,Xie F,et al.1p/19q codeletion and RET rearrangements in small-cell lung cancer[J].Onco Targets Ther,2016,9:3571-3577.
[32]Zupan A,Glavaˇc D.The development of rapid and accurate screening test for RET hotspot somatic and germline mutations in MEN2 syndromes[J].Exp Mol Pathol,2015,99(3):416-425.
[33]Wells SA Jr,Robinson BG,Gagel RF,et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer:a randomized,double-blind phaseⅢtrial[J].J Clin Oncol,2012,30(2):134-141.
[34]Aziz N,Zhao Q,Bry L,et al.College of American Pathologists'laboratory standards for next-generation sequencing clinical tests[J].Arch Pathol Lab Med,2015,139(4):481-493.
[35]Karnes HE,Duncavage EJ,Bernadt CT.Targeted next-generation sequencing using fine-needle aspirates from adenocarcinomas of the lung[J].Cancer Cytopathol,2014,122(2):104-113.
[36]Kanagal-Shamanna R,Portier BP,Singh RR,et al.Next-generation sequencing-based multi-gene mutation profiling of solid tumors using fine needle aspiration samples:promises and challenges for routine clinical diagnostics[J].Mod Pathol,2014,27(2):314-327.
[37]Wei S,Lieberman D,Morrissette JJ,et al.Using"residual"FNA rinse and body fluid specimens for next-generation sequencing:An institutional experience[J].Cancer Cytopathol,2016,124(5):324-329.
[38]Warth A,Penzel R,Brandt R,et al.Optimized algorithm for Sanger sequencing-based EGFR mutation analyses in NSCLC biopsies[J].Virchows Arch,2012,460(4):407-414.
[39]Wei S,Li Volsi VA,Montone KT,et al.Detection of molecular alterations in medullary thyroid carcinoma using next-generation sequencing:an institutional experience[J].Endocr Pathol,2016,27(4):359-362.
[40]Buettner R,Wolf J,Thomas RK.Lessons learned from lung cancer genomics:the emerging concept of individualized diagnostics and treatment[J].J Clin Oncol,2013,31(15):1858-1865.
[41]Gautschi O,Zander T,Keller FA,et al.A patient with lung adenocarcinoma and RET fusion treated with vandetanib[J].Thorac Oncol,2013,8(5):e43-44.
[42]Falchook GS,Ordóez NG,Bastida CC,et al.Effect of the RET inhibitor vandetanib in a patient with RET fusion-positive metastatic non-small-cell lung cancer[J].J Clin Oncol,2016,34(15):e141-144.
[43]Natale RB,Thongprasert S,Greco FA,et al.PhaseⅢtrial of vandetanib compared with erlotinib in patients with previously treated advanced non-small-cell lung cancer[J].J Clin Oncol,2011,29(8):1059-1066.
[44]Lee JS,Hirsh V,Park K,et al.Vandetanib Versus placebo in patients with advanced non-small-cell lung cancer after prior therapy with an epidermal growth factor receptor tyrosine kinase inhibitor:a randomized,double-blind phaseⅢtrial(ZEPHYR)[J].J Clin Oncol,2012,30(10):1114-1121.
[45]Suzuki M,Makinoshima H,Matsumoto S.Identification of a lung adenocarcinoma cell line with CCDC6-RET fusion gene and the effect of RET inhibitors in vitro and in vivo[J].Cancer Sci,2013,104(7):896-903.
[46]Mukhopadhyay S,Pennell NA,Ali SM,et al.RET-rearranged lung adenocarcinomas with lymphangitic spread,psammoma bodies,and clinical responses to cabozantinib[J].J Thorac Oncol,2014,9(11):1714-1719.
[47]Schoffski P,Elisei R,Muller S.An international,double-blind,randomized,placebo-controlled phaseⅢtrial(EXAM)of cabozantinib(XL184)in medullary thyroid carcinoma(MTC)patients with documented RECIST progression at baseline[J].J Clin Oncol,2012,30(Suppl):abstract 5508.
[48]Song M,Kim SH,Yoon SK.Cabozantinib for the treatment of nonsmall cell lung cancer with KIF5B-RET fusion.An example of swift repositioning[J].Arch Pharm Res,2015,38(12):2120-2123.
[49]Drilon AE,Sima CS,Somwar R,et al.PhaseⅡstudy of cabozantinib for patients with advanced RET-rearranged lung cancers[J].J Clin Oncol,2015,33(15):8007.
[50]Ping G,Hui-Min W,Wei-Min W,et al.Sunitinib in pretreated advanced non-small-cell lung carcinoma:a primary result from Asian population[J].Med Oncol,2011,28(2):578-583.
[51]Liu YR,Zhu W,Zhang JL,et al.The evaluation of efficacy and safety of sunitinib on EGFR-TKI pretreated advanced non-small cell lung cancer patients in China[J].Clin Respir J,2014,8(2):206-212.
[52]Wu H,Shih JY,Yang JC.Rapid response to sunitinib in a patient with lung adenocarcinoma harboring KIF5B-RET fusion gene[J].J Thorac Oncol,2015,10(9):e95-96.
[53]Shaw AT,Hsu PP,Awad MM,et al.Tyrosine kinase gene rearrangements in epithelial malignancies[J].Nature Reviews Cancer,2013,13(11):772-787.
[54]De Falco V,Buonocore P,Muthu M,et al.Ponatinib(AP24534)is a novel potent inhibitor of oncogenic RET mutants associated with thyroid cancer[J].J Clin Endocrinol Metab,2013,98(5):E811-819.
[55]Song M.Progress in Discovery of KIF5B-RET Kinase Inhibitors for the Treatment of Non-Small-Cell Lung Cancer[J].J Med Chem,2015,58(9):3672-3681.
[56]Tan EH,Tan DS,Li WY,et al.Metronomic vinorelbine(oral)in combination with sorafenib in advanced non-small cell lung cancer[J].Lung Cancer,2015,88(3):289-296.