表皮生长因子受体酪氨酸激酶抑制剂治疗非小细胞肺癌脑转移的研究进展
摘要
肺癌为最常见的恶性肿瘤之一,其发病率呈逐年上升趋势,约有30%的非小细胞肺癌(NSCLC)患者发生脑转移,严重影响患者的生活质量和预后。表皮生长因子受体(EGFR)属于酪氨酸激酶受体家族的一种,在多种恶性肿瘤中高表达或异常表达,突变后能活化肿瘤细胞内酪氨酸激酶,参与肿瘤细胞的增殖、生长、分化。近年来,随着精准靶向治疗技术的不断发展,EGFR酪氨酸激酶抑制剂(TKI)对EGFR突变的NSCLC脑转移显示出较好的治疗效果。本文就EGFR-TKI治疗NSCLC脑转移的研究进展加以综述。
引文
[1]范怡畅,陈兆鑫,俞静,等.表皮生长因子受体信号转导通路中的基因改变与其抑制剂疗效相关性研究进展[J].中国医院用药评价与分析,2018,18(4):438-442.
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[3]郭芷汛,刘欢,李艳,等.表皮生长因子受体-酪氨酸激酶抑制剂在治疗非小细胞肺癌方面的研究进展[J].实用医院临床杂志,2018,18(1):208-210.
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[5]KIM B,JANG Y J,PARK S,et al.Histopathologic analysis of brain metastasis in pulmonary adenocarcinoma:necrosis is a new risk factor[J].Pathol Res Pract,2019,215(4):807-815.
[6]PEDROSA R M S M,MUSTAFA D A M,AERTS J G J V,et al.Potential molecular signatures predictive of lung cancer brain metastasis[J].Front Oncol,2018,8:159.
[7]KIM R,KEAM B,KIM S,et al.Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients:therapeutic implications for immune checkpoint inhibitors[J].BMC Cancer,2019,19(1):19.
[8]SUN G,DING X,BI N,et al.Molecular predictors of brain metastasisrelated microRNAs in lung adenocarcinoma[J].PLo S Genet,2019,15(2):e1007888.
[9]唐菲,周麟,卢铀.非小细胞肺癌脑转移的治疗策略与相关问题[J].中国肿瘤临床,2015,42(19):947-952.
[10]HAN G,BI J,TAN W,et al.A retrospective analysis in patients with EGFR-mutant lung adenocarcinoma:is EGFR mutation associated with a higher incidence of brain metastasis[J].Oncotargets,2016,7(35):56998-57010.
[11]LI L,LUO S,LIN H,et al.Correlation between EGFR mutation status and the incidence of brain metastases in patients with nonsmall cell lung cancer[J].J Thorac Dis,2017,9(8):2510-2520.
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[13]WU Y L,ZHAO Q,DENG L,et al.Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer[J].Lung Cancer,2019,127:1-5.
[14]冯佳,魏学燕,李闯,等.肺腺癌细胞EGFR基因过表达和突变通过介导CXCR4/CXCL12信号通路表达导致肿瘤生物学行为改变的机制研究[J].中国肺癌杂志,2018,21(7):503-512.
[15]张永芹,孙秀锦,左云,等.肺癌脑转移患者中不同EGFR突变状态下的临床及影像学特点[J].临床神经外科杂志,2018,15(3):179-183.
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[18]ARBOUR K C,KRIS M G,RIELY G J,et al.Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases[J].Cancer,2018,124(1):105-109.
[19]SOLCA F,DAHL G,ZOEPHEL A,et al.Target binding properties and cellular activity of afatinib(BIBW 2992),an irreversible Erb B family blocker[J].J Pharmacol Exp Ther,2012,343(2):342-350.
[20]LI D,AMBROGIO L,SHIMAMURA T,et al.BIBW2992,an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models[J].Oncogene,2008,27(34):4702-4711.
[21]SEQUIST L V,YANG J C,YAMAMOTO N,et al.Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations[J].J Clin Oncol,2013,31(27):3327-3334.
[22]WU Y L,ZHOU C,HU C P,et al.Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations(LUX-Lung 6):an open-label,randomised phase 3 trial[J].Lancet Oncol,2014,15(2):213-222.
[23]YANG J C H,SEQUIST L V,GEATER S L,et al.Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations:a combined post-hoc analysis of LUX-Lung 2,LUX-Lung 3,and LUX-Lung 6[J].Lancet Oncol,2015,16(7):830-838.
[24]SCHULER M,WU Y L,HIRSH V,et al.First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases[J].J Thorac Oncol,2016,11(3):380-390.
[25]YANG J C H,WU Y L,SCHULER M,et al.Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma(LUX-Lung 3 and LUX-Lung 6):analysis of overall survival data from two randomised,phase 3 trials[J].Lancet Oncol,2015,16(2):141-151.
[26]FAN Y,HUANG Z,FANG L,et al.Chemotherapy and EGFR tyrosine kinase inhibitors for treatment of brain metastases from non-smallcell lung cancer:survival analysis in 210 patients[J].Onco Targets Ther,2013,6:1789-1803.
[27]HOFFKNECHT P,TUFMAN A,WEHLER T,et al.Efficacy of the irreversible Erb B family blocker afatinib in epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease[J].J Thorac Oncol,2015,10(1):156-163.
[28]SU P L,WU Y L,CHANG W Y,et al.513P Preventing and treating brain metastases with three first-line EGFR-tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced non-small cell lung cancer[J].Ther Adv Med Oncol,2018,29(9):425.
[29]MOK T S,WU Y L,AHN M J,et al.Osimertinib or platinumpemetrexed in EGFR T790M-positive lung cancer[J].N Engl JMed,2017,376(7):629-640.
[30]YANG J C,AHN M J,KIM D W,et al.Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer:AURAstudy phase II extension component[J].J Clin Oncol,2017,35(12):1288-1296.
[31]GOSS G,TSAI C M,SHEPHERD F A,et al.Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer(AURA2):a multicentre,open-label,single-arm,phase 2 study[J].Lancet Oncol,2016,17(12):1643-1652.
[32]GOSS G,TSAI C M,SHEPHERD F A,et al.CNS response to osimertinib in patients with T790M-positive advanced NSCLC:pooled data from two phase II trials[J].Ann Oncol,2017,29(3):687-693.
[33]WU Y L,AHN M J,GARASSINO M C,et al.CNS Efficacy of osimertinib in patients with T790M-positive advanced non-smallcell lung cancer:data from a randomized phaseⅢtrial(AURA3)[J].J Clin Oncol,2018,36(26):2702-2709.
[34]YANG Z,GUO Q,WANG Y,et al.AZD3759,a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases[J].Sci Transl Med,2016,8(368):368ra172.
[35]AHN M J,KIM D W,CHO B C,et al.Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNSmetastases(BLOOM):a phase 1,open-label,dose-escalation and dose-expansion study[J].Lancet Respir Med,2017,5(11):891-902.
[36]HEON S,YEAP B Y,BRITT G J,et al.Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib[J].Clin Cancer Res,2010,16(23):5873-5882.
[37]HEON S,YEAP B Y,LINDEMAN N I,et al.The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations[J].Clin Cancer Res,2012,18(16):4406-4414.
[38]BERGER L A,RIESENBERG H,BOKEMEYER C,et al.CNSmetastases in non-small-cell lung cancer:current role of EGFR-TKI therapy and future perspectives[J].Lung Cancer,2013,80(3):242-248.
[39]BALLARD P,YATES J W,YANG Z,et al.Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLCbrain metastases models,and early evidence of clinical brain metastases activity[J].Clin Cancer Res,2016,22(20):5130-5140.
[2]HUANG L,FU L.Mechanisms of resistance to EGFR tyrosine kinase inhibitors[J].Acta Pharm Sin B,2015,5(5):390-401.
[3]郭芷汛,刘欢,李艳,等.表皮生长因子受体-酪氨酸激酶抑制剂在治疗非小细胞肺癌方面的研究进展[J].实用医院临床杂志,2018,18(1):208-210.
[4]YASUDA H,PARK E,YUN C H,et al.Structural,biochemical,and clinical characterization of epidermal growth factor receptor(EGFR)exon 20 insertion mutations in lung cancer[J].Sci Transl Med,2013,5(216):216ra177.
[5]KIM B,JANG Y J,PARK S,et al.Histopathologic analysis of brain metastasis in pulmonary adenocarcinoma:necrosis is a new risk factor[J].Pathol Res Pract,2019,215(4):807-815.
[6]PEDROSA R M S M,MUSTAFA D A M,AERTS J G J V,et al.Potential molecular signatures predictive of lung cancer brain metastasis[J].Front Oncol,2018,8:159.
[7]KIM R,KEAM B,KIM S,et al.Differences in tumor microenvironments between primary lung tumors and brain metastases in lung cancer patients:therapeutic implications for immune checkpoint inhibitors[J].BMC Cancer,2019,19(1):19.
[8]SUN G,DING X,BI N,et al.Molecular predictors of brain metastasisrelated microRNAs in lung adenocarcinoma[J].PLo S Genet,2019,15(2):e1007888.
[9]唐菲,周麟,卢铀.非小细胞肺癌脑转移的治疗策略与相关问题[J].中国肿瘤临床,2015,42(19):947-952.
[10]HAN G,BI J,TAN W,et al.A retrospective analysis in patients with EGFR-mutant lung adenocarcinoma:is EGFR mutation associated with a higher incidence of brain metastasis[J].Oncotargets,2016,7(35):56998-57010.
[11]LI L,LUO S,LIN H,et al.Correlation between EGFR mutation status and the incidence of brain metastases in patients with nonsmall cell lung cancer[J].J Thorac Dis,2017,9(8):2510-2520.
[12]BAEK M Y,AHN H K,PARK K R,et al.Epidermal growth factor receptor mutation and pattern of brain metastasis in patients with non-small cell lung cancer[J].Korean J Intern Med,2018,33(1):168-175.
[13]WU Y L,ZHAO Q,DENG L,et al.Leptomeningeal metastasis after effective first-generation EGFR TKI treatment of advanced non-small cell lung cancer[J].Lung Cancer,2019,127:1-5.
[14]冯佳,魏学燕,李闯,等.肺腺癌细胞EGFR基因过表达和突变通过介导CXCR4/CXCL12信号通路表达导致肿瘤生物学行为改变的机制研究[J].中国肺癌杂志,2018,21(7):503-512.
[15]张永芹,孙秀锦,左云,等.肺癌脑转移患者中不同EGFR突变状态下的临床及影像学特点[J].临床神经外科杂志,2018,15(3):179-183.
[16]NCCN.NCCN clinical practice guidelines in oncology:non-small cell lung cancer(version 2.2019)[EB/OL].Fort Washington:NCCN,2019[2018-11-21].http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
[17]GROMMES C,OXNARD G R,KRIS M G,et al."Pulsatile"highdose weekly erlotinib for CNS metastases from EGFR mutant nonsmall cell lung cancer[J].Neuro Oncol,2011,13(12):1364-1369.
[18]ARBOUR K C,KRIS M G,RIELY G J,et al.Twice weekly pulse and daily continuous-dose erlotinib as initial treatment for patients with epidermal growth factor receptor-mutant lung cancers and brain metastases[J].Cancer,2018,124(1):105-109.
[19]SOLCA F,DAHL G,ZOEPHEL A,et al.Target binding properties and cellular activity of afatinib(BIBW 2992),an irreversible Erb B family blocker[J].J Pharmacol Exp Ther,2012,343(2):342-350.
[20]LI D,AMBROGIO L,SHIMAMURA T,et al.BIBW2992,an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models[J].Oncogene,2008,27(34):4702-4711.
[21]SEQUIST L V,YANG J C,YAMAMOTO N,et al.Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations[J].J Clin Oncol,2013,31(27):3327-3334.
[22]WU Y L,ZHOU C,HU C P,et al.Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations(LUX-Lung 6):an open-label,randomised phase 3 trial[J].Lancet Oncol,2014,15(2):213-222.
[23]YANG J C H,SEQUIST L V,GEATER S L,et al.Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations:a combined post-hoc analysis of LUX-Lung 2,LUX-Lung 3,and LUX-Lung 6[J].Lancet Oncol,2015,16(7):830-838.
[24]SCHULER M,WU Y L,HIRSH V,et al.First-line afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases[J].J Thorac Oncol,2016,11(3):380-390.
[25]YANG J C H,WU Y L,SCHULER M,et al.Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma(LUX-Lung 3 and LUX-Lung 6):analysis of overall survival data from two randomised,phase 3 trials[J].Lancet Oncol,2015,16(2):141-151.
[26]FAN Y,HUANG Z,FANG L,et al.Chemotherapy and EGFR tyrosine kinase inhibitors for treatment of brain metastases from non-smallcell lung cancer:survival analysis in 210 patients[J].Onco Targets Ther,2013,6:1789-1803.
[27]HOFFKNECHT P,TUFMAN A,WEHLER T,et al.Efficacy of the irreversible Erb B family blocker afatinib in epidermal growth factor receptor(EGFR)tyrosine kinase inhibitor(TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease[J].J Thorac Oncol,2015,10(1):156-163.
[28]SU P L,WU Y L,CHANG W Y,et al.513P Preventing and treating brain metastases with three first-line EGFR-tyrosine kinase inhibitors in patients with EGFR mutation-positive advanced non-small cell lung cancer[J].Ther Adv Med Oncol,2018,29(9):425.
[29]MOK T S,WU Y L,AHN M J,et al.Osimertinib or platinumpemetrexed in EGFR T790M-positive lung cancer[J].N Engl JMed,2017,376(7):629-640.
[30]YANG J C,AHN M J,KIM D W,et al.Osimertinib in pretreated T790M-positive advanced non-small-cell lung cancer:AURAstudy phase II extension component[J].J Clin Oncol,2017,35(12):1288-1296.
[31]GOSS G,TSAI C M,SHEPHERD F A,et al.Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer(AURA2):a multicentre,open-label,single-arm,phase 2 study[J].Lancet Oncol,2016,17(12):1643-1652.
[32]GOSS G,TSAI C M,SHEPHERD F A,et al.CNS response to osimertinib in patients with T790M-positive advanced NSCLC:pooled data from two phase II trials[J].Ann Oncol,2017,29(3):687-693.
[33]WU Y L,AHN M J,GARASSINO M C,et al.CNS Efficacy of osimertinib in patients with T790M-positive advanced non-smallcell lung cancer:data from a randomized phaseⅢtrial(AURA3)[J].J Clin Oncol,2018,36(26):2702-2709.
[34]YANG Z,GUO Q,WANG Y,et al.AZD3759,a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases[J].Sci Transl Med,2016,8(368):368ra172.
[35]AHN M J,KIM D W,CHO B C,et al.Activity and safety of AZD3759 in EGFR-mutant non-small-cell lung cancer with CNSmetastases(BLOOM):a phase 1,open-label,dose-escalation and dose-expansion study[J].Lancet Respir Med,2017,5(11):891-902.
[36]HEON S,YEAP B Y,BRITT G J,et al.Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib[J].Clin Cancer Res,2010,16(23):5873-5882.
[37]HEON S,YEAP B Y,LINDEMAN N I,et al.The impact of initial gefitinib or erlotinib versus chemotherapy on central nervous system progression in advanced non-small cell lung cancer with EGFR mutations[J].Clin Cancer Res,2012,18(16):4406-4414.
[38]BERGER L A,RIESENBERG H,BOKEMEYER C,et al.CNSmetastases in non-small-cell lung cancer:current role of EGFR-TKI therapy and future perspectives[J].Lung Cancer,2013,80(3):242-248.
[39]BALLARD P,YATES J W,YANG Z,et al.Preclinical comparison of osimertinib with other EGFR-TKIs in EGFR-mutant NSCLCbrain metastases models,and early evidence of clinical brain metastases activity[J].Clin Cancer Res,2016,22(20):5130-5140.