肉瘤样癌转化：一种少见的肺腺癌EGFR靶向治疗耐药表现.pdf 5页

'中国科技论文在线http://www.paper.edu.cnSarcomatoidcarcinomatransformation:araremanifestationofEGFRTKIdrugresistanceinapatient#5withlungadenocarcinoma112112XUSong,LIURenwang,LIUXia,SHITao,LIXiongfei,ZHONGDiansheng,211*WANGYan,CHENGang,CHENJun(1.DepartmentofLungCancerSurgery,TianjinMedicalUniversityGeneralHospital;2.DepartmentofMedicalOncology,TianjinMedicalUniversityGeneralHospital)10Abstract:Objective:AlmostallEGFR-mutantlungcancersdevelopresistancetoEGFRtyrosinekinaseinhibitors(EGFR-TKIs).Severalmechanismsforthisacquiredresistancehavebeenidentified,includingdevelopmentofanEGFRT790Mmutation,METamplification,hepatocytegrowthfactor(HGF)overexpression,lossofPTENexpression,epithelialtomesenchymaltransitionandtransformationtosmallcelllungcancer.Herein,wepresentedalungcancerpatientwithEGFRexon1519deltionwhowasresistanttoEGFRTKItreatment.Method:Tofurtherexploretheunderlyingmechanisms,weperformedagenemutationprofilingbynextgenerationsequencing(NGS).Results:Themechanismofdrugresistanceisveryrare.SomeadenocarcinoamacellsaquiredT790MmutationinEGFRexon20,andotheradenocarcinoamacellstransformedintosarcomatoidcarcinoma.Conclusion:Thiscaseinspiresusagaintheimportanceoftissuere-biopsyoncetheacquiredresistance20occursafterTKIconsistantpressure.SarcomatoidcarcinomatransformationisararemanifestationofEGFRTKIdrugresistanceinapatientwithlungadenocarcinoma.Keywords:drugresistance;adenocarcinoma;sarcomatoidcarcinoma;EGFR-TKI0Introduction25Drugresistanceisthemosttroublesomeproblemforepidermalgrowthfactorreceptortyrosinekinaseinhibitors(EGFR-TKIs)treatmentinnon-smallcelllungcancer(NSCLC)patients.ThemajormechanismswhichcontributetowardsEGFRTKIresistanceinNSCLChavebeendemonstrated,includingsecondarymuationofEGFRT790M,METamplification,epithelialtomesenchymaltransition,activationofalternativeoncogenicpathwaysandtransformationtosmall30celllungcancer(SCLC)[1-5].Herein,wepresentedararecaseoftransformationtosarcomatoidcarcinomaafterEGFR-TKItreatment.1CaseReportAnon-smoker60-year-oldwomanwasdiagnosedwithleftupperlungadenocarcinomabysupraclavicularlymphnodesbiopsyin2012December.GenemutationtestindicatedEGFRexon3519deletion.Aftertwocyclesofgemcitabinpluscisplatinchemotherapy,abdominalCTscanshowedlivermetastasisandshestartedtotakeerlotinibsince2013January.Metastastictumorsinliverandsupraclavicularlymphnodesalldisappearedandlungtumorconstantlyshrinkedfollowingwitherlotinibtreatmentuntil2015October.Theoriginallungtumorstartedtoenlargeandbredasecondarygrowingnoduleadjacently(Figure1).Althoughdrugresistancewas40appeared,thepatientrefusedtoreceiveothertreatmentsbutcontinuouslytookerlotinib.In2016July,aleftupperlobectomyplussystematicmediastinallymphadenectomybyVATSwasperformedafterawholebodyevaluationwhichhadnosignofextrapulmonaryabnormalities.Thepathologicaldiagnosisoftheoriginallungtumorwasconfirmedtobeadenocarcinoma,andthesecondarylungtumorwassarcomatoidcarcinoma(Figure2).N1butnotN2lymphnodeswereFoundations:SpecializedResearchFundfortheDoctoralProgramofHigherEducation(20131202120004);NationalNaturalScienceFoundationofChina(81301812)Briefauthorintroduction:XUSong(1982),Male,Associateprofessor,Lungcancer.E-mail:xusong198@hotmail.com-1- 中国科技论文在线http://www.paper.edu.cn45involved.Nextgenerationsequencing(NGS)testconfirmedthattheoriginallungadenocarcinoamahadEGFRexon19deletionbutalsofoundT790MmutationinEGFRexon20.ThesecondarysarcomatoidcarcinomashowedEGFRexon19deletionaswell.Besides,sarcomatoidcarcinomahadgeneticmutationonFANCLandBCL2L2,andamplificationonCDK4,MDM2,APFRP1,GNAS,CIC,FANCE,Notch4andAKT2(Table1).Thepostoperative50ctDNA(circulatingtumorDNA)testdidnotshowanydrivergenemutationintheblood,includingEGFRexon20T790Mmutationorexon19deletion(BurningRockDx,Guangzhou,China).Moreover,apostoperativeCTC(circulatingtumorcells)analysisshowCTCvalueis4.29(cut-off8.70FU)(Geno,Shanghai,China).Therefore,thepatientcontinueserlotinibtreatmentandisgivenintensivefollow-up.55Fig.1:CTscanandgrossspecimen.Bluearrow:sarcomatoidcarcinoma;redarrow:adenocarcinoma.2Discussion60TwopulmonarytumorsofthispatienthaveverydistinctphenotypesafterEGFRTKItreatment.TheadeonocarcinomaparthadEGFRexon20T790Mmutation,whichcanexplainwhytheprimarypulmonarytumorreplaseaftererlotinibtreatmentsince2015October.However,anewpulmonarynoduleoccurredadjacentlyandgrewmoreprogressivelycomparedtoadenocarcinoma,whichwasconfirmedassarcomatoidcarcinomabyCTguidedbiopsyand65surgery.ThroughNGSanalysis,weareconvincedthatsarcomatoidcarcinomaistransformedfromthepre-existingTKI-sensitiveadeonocarcinoma,butdoesnotrepresentasecondprimarylungcancer.-2- 中国科技论文在线http://www.paper.edu.cn70Fig.2Histologyofprimaryadenocarcinomaandsecondarylungsarcomatoidcarcinoma.TransformationtosarcomatoidcarcinomaafterEGFR-TKItreatmentisveryrare,andwedidnotfindanysimilarpublicationpreviously.Thepathophysiologicalmechanismunderlyingtransformationtosarcomatoidcarcinomaisnotwellunderstood,andwepostulatedthatthere75mightbetwopossibilities:1.Tumorheterogeneity.ThecomponentofsarcomatoidcarcinomamaybealreadypresentandgraduallybecomedominantafterEGFR-TKItherapy.2.Directtransformation.Toexplorethereasonfromgeneticclue,wehenceperformedaNGSanalysiswithabroadgenepanel.FromtheNGSdata,wecanexplicitlyseethatsarcomatoidcarcinomasharedsamegeneticphenotypeincludingEGFR19del(withcomparablemutationfrequency)andthree80othergenesastheprimaryadenocarcinomapossessed.Fromthispoint,wecanpresumelogicallythatsarcomatoidcarcinomamightbeswitcheddirectlyfomadeonocarcinomaafteraquiringaseriesofgenealternations,eg.SMO,CDK4,MDM2,butnotbecauseofthetumorheterogeneity.Inaddition,wecanalsoseethatthetheprimaryadenocarcinomahassecondaryEGFRT790Mmutation.85-3- 中国科技论文在线http://www.paper.edu.cnTable1:Geneanalysisofprimaryadenocarcinomaandsecondarylungsarcomatoidcarcinoma.locationFrequency(%)GeneMutationtypeSarcomatoidAdenocarcinoamacarcinomaEGFRexon19E746_A750deletionmut27.7028.90BCL2L2exon3A65Tmissensemut16.6049.30FANCLexon1S30Lmissensemut15.5051.30ARFRP120q13.33cn_amplification6.1916.99EGFRexon20T790Mmissensemut15.20TGFBR2exon8R553Hmissensemut29.10TRRAPexon43V2098Amissensemut24.70FLT1exon13V211synonymousmut17.40NF1exon17A208synonymousmut8.80TBX3exon12P63synonymousmut7.00SMOexon7F252synonymousmut23.10CDK412q14.1cn_amplification11.38MDM212q15cn_amplification18.66AKT219q13.2cn_amplification3.8CIC19q13.2cn_amplification4.31GNAS20q13.32cn_amplification6.76FANCE6p21.31cn_amplification4.12NOTCH46p21.32cn_amplification3.8790Green:Genealterationsthatadenocarcinomaandsarcomatoidcarcinomabothpossess.Blue:Genealterationsthatadenocarcinomapossesses.Pink:Genealterationsthatsarcomatoidcarcinomapossesses.3Conclusion95Inthispaper,wereportedthepatienthastwomajormechanismsforEGFRTKIdrugresistance,namelyEGFRexon20T790Mmutationandsarcomatoidcarcinomatransformation.Thiscaseinspiresusagaintheimportanceoftissuere-biopsyoncetheacquiredresistanceoccursafterTKIconsistantpressure.SarcomatoidcarcinomatransformationisararemanifestationofEGFRTKIdrugresistanceinapatientwithlungadenocarcinoma.Sincesarcomatoidcarcinomais100notsensitivetochemo-orradio-therapy,acompletesurgicalresectionmightbethebestalternative.Acknowledgements(Optional)ThisworkwassupportedbygrantsfromNationalNaturalScienceFoundationofChina(81301812),SpecializedResearchFundfortheDoctoralProgramofHigherEducation105(20131202120004),ScientificResearchFoundationfortheReturnedOverseasChineseScholarsofStateEducationMinistry.-4- 中国科技论文在线http://www.paper.edu.cnReferences110[1]KobayashiS,BoggonTJ,DayaramT,JännePA,KocherO,MeyersonM,JohnsonBE,EckMJ,TenenDG,HalmosB.EGFRmutationandresistanceofnon-small-celllungcancertogefitinib.NEnglJMed2005;352:786-92.[2]EngelmanJA,ZejnullahuK,MitsudomiT,SongY,HylandC,ParkJO,LindemanN,GaleCM,ZhaoX,ChristensenJ,KosakaT,HolmesAJ,RogersAM,CappuzzoF,MokT,LeeC,JohnsonBE,CantleyLC,JännePA.115METamplificationleadstogefitinibresistanceinlungcancerbyactivatingERBB3signaling.Science2007;316:1039-43.[3]SudaK,TomizawaK,FujiiM,MurakamiH,OsadaH,MaeharaY,YatabeY,SekidoY,MitsudomiT.Epithelialtomesenchymaltransitioninanepidermalgrowthfactorreceptor-mutantlungcancercelllinewithacquiredresistancetoerlotinib.JThoracOncol.2011;6:1152-61.120[4]AhsanA.MechanismsofresistancetoEGFRtyrosinekinaseinhibitorsandtherapeuticapproaches:anupdate.AdvExpMedBiol.2016;893:137-53.[5]WatanabeS1,SoneT,MatsuiT,YamamuraK,TaniM,OkazakiA,KurokawaK,TamboY,TakatoH,OhkuraN,WasedaY,KatayamaN,KasaharaK.Transformationtosmall-celllungcancerfollowingtreatmentwithEGFRtyrosinekinaseinhibitorsinapatientwithlungadenocarcinoma.LungCancer.2013;82:370-2.125肉瘤样癌转化：一种少见的肺腺癌EGFR靶向治疗耐药表现112112211徐嵩，刘仁旺，刘夏，石涛，李雄飞，钟殿胜，王燕，陈钢，陈军130（1.天津医科大学总医院肺部肿瘤外科；2.天津医科大学总医院肿瘤内科）摘要：目的：几乎所有EGFR突变患者都会出现耐药。获得性耐药的机制包括T790M二次突变，MET扩增，HGF扩增，PTEN表达丧失，EMT，小细胞转化等。我们报道了一例EGFR突变患者的少见耐药机制。方法：我们采用二代测序方法检测耐药患者组织和血液135基因突变情况，并通过免疫组化等方法鉴定。结果：我们发现EGFR靶向治疗耐药患者有EGFR20外显子T790M二次突变，同时出现肉瘤样癌转变。结论：液体活检是EGFR靶向治疗耐药有效的检测方法，但是通过组织活检检测细胞转化机制仍是不可取代的。关键词：耐药；腺癌；肉瘤样癌；EGFR-TKI中图分类号：R78140-5-'