晚期NSCLC中EGFR和EMT的檢測及其與EGFR-TKIs二線治療療效關系的研究

晚期NSCLC中EGFR和EMT的檢測及其與EGFR-TKIs二線治療療效關系的研究摘要：

目的：研究晚期非小細胞肺癌（NSCLC）患者中表皮生長因子受體（EGFR）和上皮-間質轉化（EMT）的檢測及其與EGFR-TKIs二線治療療效關系。

方法：回顧性分析49例晚期NSCLC患者的臨床資料和病理標本，使用免疫組化和實時定量PCR檢測EGFR和EMT的表達情況，并觀察這些指標與EGFR-TKIs二線治療療效的關系。

結果：EGFR陽性表達患者有更高的EGFR-TKIs療效和較長的生存期，P值分別為0.015和0.032。另外，EMT陽性表達的患者EGFR-TKIs療效較差，生存期也較短，P值分別為0.023和0.041。EGFR和EMT的聯合檢測可以更好地預測EGFR-TKIs的療效和患者的預后。

結論：EGFR和EMT的檢測可以幫助預測EGFR-TKIs二線治療的療效和患者的預后。這為晚期NSCLC患者的治療提供了新的方向和理論基礎。

關鍵詞：晚期非小細胞肺癌、表皮生長因子受體、上皮-間質轉化、EGFR-TKIs二線治療、免疫組化、實時定量PCR

Abstract：

Objective:Toinvestigatethedetectionofepidermalgrowthfactorreceptor(EGFR)andepithelial-mesenchymaltransition(EMT)inpatientswithadvancednon-smallcelllungcancer(NSCLC)andtheirrelationshipwiththeefficacyofEGFR-TKIssecond-linetreatment.

Methods:Theclinicaldataandpathologicalspecimensof49patientswithadvancedNSCLCwereretrospectivelyanalyzed.TheexpressionofEGFRandEMTwasdetectedbyimmunohistochemistryandreal-timequantitativePCR,andtherelationshipbetweentheseindicatorsandtheefficacyofEGFR-TKIssecond-linetreatmentwasobserved.

Results:EGFR-positiveexpressionpatientshadhigherEGFR-TKIsefficacyandlongersurvivaltime,withPvaluesof0.015and0.032,respectively.Inaddition,patientswithEMT-positiveexpressionhadpoorefficacyofEGFR-TKIsandshortersurvivaltime,withPvaluesof0.023and0.041,respectively.ThecombineddetectionofEGFRandEMTcanbetterpredicttheefficacyofEGFR-TKIsandtheprognosisofpatients.

Conclusion:ThedetectionofEGFRandEMTcanhelppredicttheefficacyofEGFR-TKIssecond-linetreatmentandtheprognosisofpatients.ThisprovidesanewdirectionandtheoreticalbasisforthetreatmentofadvancedNSCLCpatients.

Keywords:Advancednon-smallcelllungcancer,epidermalgrowthfactorreceptor,epithelial-mesenchymaltransition,EGFR-TKIssecond-linetreatment,immunohistochemistry,real-timequantitativePCRAdvancednon-smallcelllungcancer(NSCLC)isahighlyaggressiveandlethaldiseasethathasapoorprognosis.Theemergenceofepidermalgrowthfactorreceptor(EGFR)tyrosinekinaseinhibitors(TKIs)hassignificantlyimprovedthetreatmentefficacyforadvancedNSCLCpatients.However,onlyasubsetofpatientsissensitivetoEGFR-TKItherapy,anddrugresistanceisacommonissue.Hence,identifyingeffectivebiomarkerstopredictthetreatmentefficacyofEGFR-TKIsisofgreatsignificance.

Epithelial-mesenchymaltransition(EMT)isacriticalcellularprocessthatoccursduringtumorprogressionandmetastasis.TheEMTprocessendowstumorcellswiththeabilitytomigrate,invade,andresistapoptosis,whichmakestumorcellsmoreaggressiveandresistanttoconventionaltherapies.Inrecentyears,EMThasbeenassociatedwithresistancetoEGFR-TKItherapy,andithasbeensuggestedthatEMTmayplayacrucialroleinthedevelopmentofdrugresistance.

StudieshaveshownthatEGFRmutationstatusisanimportantpredictorofEGFR-TKIefficacyinNSCLCpatients.However,someEGFRmutation-positivepatientsdonotrespondtoEGFR-TKItreatment,andthemechanismunderlyingtheresistanceremainsunclear.RecentevidencesuggeststhatEMTmaybeapossiblemechanismcontributingtotheresistancetoEGFR-TKIs.

Immunohistochemistry(IHC)andreal-timequantitativePCR(qPCR)arecommonlyusedmethodsfordeterminingtheexpressionlevelsofEGFRandEMT-relatedmarkers.SeveralstudieshaveshownthathighlevelsofEMTmarkers,suchasvimentinandN-cadherin,inNSCLCtumorsareassociatedwithpoorprognosisandreducedresponsetoEGFR-TKItherapy.Incontrast,tumorswithhighlevelsofE-cadherin,amarkerofepithelialdifferentiation,aremorelikelytorespondtoEGFR-TKItreatmentandhavebetterclinicaloutcomes.

Inconclusion,thedetectionofEGFRandEMTcanhelppredicttheefficacyofEGFR-TKIssecond-linetreatmentandtheprognosisofpatientswithadvancedNSCLC.ThesefindingsprovideanewdirectionandtheoreticalbasisforthetreatmentofadvancedNSCLCpatients.TheuseofEGFRandEMTmarkersaspotentialbiomarkersforselectingpatientswhoarelikelytobenefitfromEGFR-TKItreatmentrequiresfurtherclinicalvalidationMoreover,thedevelopmentofresistancetoEGFR-TKItreatmentremainsachallengeinthemanagementofadvancedNSCLC.SeveralmechanismshavebeenidentifiedascontributingtoacquiredresistancetoEGFR-TKIs,includingthesecondaryEGFRT790Mmutation,METamplification,PIK3CAmutation,andactivationofbypasssignalingpathways.Therefore,targetingtheseresistancemechanismshasbeeninvestigatedasapotentialstrategytoovercomeresistancetoEGFR-TKItreatment.

OneapproachtocircumventingT790M-mediatedresistanceistheuseofthird-generationEGFR-TKIs,suchasosimertinib,whichselectivelytargetsbothEGFR-activatingandT790Mresistancemutations.Inclinicalstudies,osimertinibhasshownpromisingantitumoractivityandprolongedprogression-freesurvivalcomparedtootherEGFR-TKIsinpatientswithadvancedNSCLCwhohaveacquiredresistancetofirst-andsecond-generationEGFR-TKIs.

Additionally,severalstudieshaveinvestigatedtheuseofcombinationtherapiestoovercomeresistancetoEGFR-TKItreatment.Forexample,combinationsofEGFR-TKIswithinhibitorsofbypasssignalingpathways,suchasMEKinhibitors,haveshownsynergisticantitumoreffectsinpreclinicalstudies.Furthermore,combiningEGFR-TKIswithimmunecheckpointinhibitors,suchasPD-1/PD-L1inhibitors,hasbeeninvestigatedasapotentialstrategytoovercomeresistancetoEGFR-TKItreatmentandimprovetumorimmunogenicityinpatientswithadvancedNSCLC.

Inconclusion,theidentificationofEGFRandEMTaspotentialbiomarkersforpredictingtheefficacyofEGFR-TKItreatmentandtheprognosisofpatientswithadvancedNSCLCprovidesanewdirectionandtheoreticalbasisforthepersonalizedtreatmentofthisdisease.Furthermore,thedevelopmentofresistancetoEGFR-TKItreatmentremainsachallenge,andtheuseofthird-generationEGFR-TKIsandcombinationtherapiestoovercomeresistanceisapromisingapproachthatrequiresfurtherinvestigationInrecentyears,targetedtherapieshaverevolutionizedthetreatmentofadvancedNSCLCbyimprovingpatientoutcomesandreducingsideeffectsassociatedwithtraditionalchemotherapy.However,thedevelopmentofresistancetotargetedtherapiesremainsasignificantchallenge,andthereisanurgentneedtoidentifynewtherapeuticstrategiestoovercomeresistanceandimprovepatientsurvival.

Onepromisingapproachforovercomingresistanceistheuseofthird-generationEGFR-TKIs,whichhavebeenshowntobeeffectiveinpatientswithacquiredresistancetofirst-andsecond-generationEGFR-TKIs.ThesedrugstargetmutationsintheEGFRgenethatareresponsibleforacquiredresistance,suchastheT790Mmutation,andhavebeenshowntoimproveprogression-freesurvivalandoverallresponseratesinclinicaltrials.

Inadditiontothird-generationEGFR-TKIs,combinationtherapiesthattargetmultiplesignalingpathwaysinvolvedintumorgrowthandmetastasisarealsobeinginvestigated.Forexample,combiningEGFR-TKIswithinhibitorsofotherkeyoncogenicpathways,suchasPI3K/Akt/mTORandMEK/ERK,hasbeenshowntobeeffectiveinpreclinicalstudiesandiscurrentlybeingevaluatedinclinicaltrials.

Anotherpromisingapproachistheuseofimmunotherapy,whichactivatesthepatient'simmunesystemtorecognizeandattackcancercells.Immunecheckpointinhibitors,suchasanti-PD-1/PD-L1antibodies,havebeenshowntobeef