非小细胞肺癌术后患者ERCC1、β-TubulinⅢ表达的临床意义以及ERCC1基因多态性与晚期非小细胞肺癌含铂化疗方案疗效及生存的相关性研究

非小细胞肺癌术后患者ERCC1、β-TubulinⅢ表达的临床意义以及ERCC1基因多态性与晚期非小细胞肺癌含铂化疗方案疗效及生存的相关性研究摘要：

目的：研究非小细胞肺癌（NSCLC）术后患者ERCC1、β-TubulinⅢ表达的临床意义，探讨ERCC1基因多态性与晚期NSCLC含铂化疗方案疗效及生存的相关性。

方法：利用免疫组织化学法检测术后NSCLC患者手术标本中ERCC1、β-TubulinⅢ的表达情况，并进行分析比较。同时，对晚期NSCLC患者进行含铂化疗，观察ERCC1基因多态性与药物疗效及生存的相关性。

结果：ERCC1、β-TubulinⅢ在NSCLC组织中高表达，与患者的临床病理参数密切相关，尤其是分化程度、TNM分期和淋巴结转移等。调查结果表明，ERCC1基因多态性与NSCLC含铂化疗后生存期呈显著相关，差异具有统计学意义（P<0.05）。

结论：NSCLC术后患者ERCC1、β-TubulinⅢ表达的增高提示了患者的肿瘤侵袭程度和预后，可协助临床医生制定更加有效的治疗方案。ERCC1基因多态性与NSCLC含铂化疗后疗效及生存有关系，可能与铂类药物的代谢有关，对于NSCLC患者的个性化治疗具有重要的参考价值。

关键词：非小细胞肺癌；ERCC1；β-TubulinⅢ；含铂化疗；基因多态性

Abstract:

Objective:ToinvestigatetheclinicalsignificanceofERCC1andβ-TubulinIIIexpressioninpatientswithnon-smallcelllungcancer(NSCLC)aftersurgery,andtoexplorethecorrelationbetweenERCC1genepolymorphismandtheefficacyandsurvivalofplatinum-containingchemotherapyinpatientswithadvancedNSCLC.

Methods:ImmunehistochemicalstainingwasusedtodetectERCC1andβ-TubulinIIIexpressioninsurgicalspecimensofNSCLCpatientsaftersurgery,andtoanalyzeandcomparethem.Atthesametime,platinum-containingchemotherapywasperformedonpatientswithadvancedNSCLC,andthecorrelationbetweenERCC1genepolymorphismanddrugefficacyandsurvivalwasobserved.

Results:ERCC1andβ-TubulinIIIwerehighlyexpressedinNSCLCtissues,andwerecloselyrelatedtotheclinicalpathologicalparametersofpatients,especiallydifferentiationdegree,TNMstagingandlymphnodemetastasis.TheinvestigationshowedthatERCC1genepolymorphismwassignificantlycorrelatedwiththesurvivalperiodofNSCLCpatientsafterplatinum-containingchemotherapy,andthedifferencewasstatisticallysignificant(P<0.05).

Conclusion:TheincreasedexpressionofERCC1andβ-TubulinIIIinpatientswithNSCLCaftersurgeryindicatesthedegreeoftumorinvasionandprognosisofpatients,andcanassistcliniciansinformulatingmoreeffectivetreatmentplans.ERCC1genepolymorphismisrelatedtotheefficacyandsurvivalofNSCLCpatientsafterplatinum-containingchemotherapy,whichmayberelatedtothemetabolismofplatinum-baseddrugs,andhasimportantreferencevalueforpersonalizedtreatmentofNSCLCpatients.

Keywords:Non-smallcelllungcancer;ERCC1;β-TubulinIII;Platinum-containingchemotherapy;GenepolymorphismNon-smallcelllungcancer(NSCLC)isacommontypeoflungcancerandistheleadingcauseofcancer-relateddeathsworldwide.Platinum-basedchemotherapyisoneofthemaintreatmentsforNSCLC,butitsefficacyvariesamongpatients.Therefore,thereisaneedtoidentifybiomarkersthatcanpredicttreatmentoutcomesandguidepersonalizedtreatment.

OnesuchbiomarkeristheERCC1(excisionrepaircross-complementationgroup1)gene,whichencodesaproteininvolvedinDNArepair.ERCC1genepolymorphismhasbeenfoundtobecorrelatedwiththeresponsetoplatinum-containingchemotherapyinNSCLCpatients.Specifically,patientswiththeTTgenotypeoftheERCC1C118Tpolymorphismhavebeenshowntohaveabetterresponsetoplatinum-containingchemotherapyandlongersurvivalthanthosewiththeCCorCTgenotype(1,2).

Themechanismbehindthiscorrelationisnotfullyunderstood,butitisthoughtthatERCC1playsaroleinthemetabolismofplatinum-baseddrugs.Platinumagents,suchascisplatinandcarboplatin,formDNAadductsthatinterferewithcelldivisionandeventuallyleadtocelldeath.ERCC1isinvolvedintherepairoftheseadducts,anditsexpressionlevelsareknowntoaffectthesensitivityofcancercellstoplatinumdrugs(3).

AnotherbiomarkerthathasbeenstudiedinNSCLCisβ-tubulinIII,aproteininvolvedincelldivisionandmotility.β-tubulinIIIoverexpressionhasbeenassociatedwithpoorprognosisandresistancetochemotherapyinNSCLCpatients(4,5).However,therelationshipbetweenβ-tubulinIIIexpressionandtheresponsetoplatinum-containingchemotherapyisstillunclear.

Inconclusion,ERCC1genepolymorphismisapromisingbiomarkerforpredictingtheefficacyandsurvivalofNSCLCpatientstreatedwithplatinum-containingchemotherapy.β-tubulinIIImayalsohavepredictivevalue,butfurtherstudiesareneededtoconfirmitsclinicalsignificance.PersonalizedtreatmentstrategiesbasedonthesebiomarkerscouldimprovetheoutcomesofNSCLCpatientsandreduceunnecessarytreatment-relatedtoxicityPossibledirectionforfutureresearch:

-InvestigatingthecombinationofmultiplebiomarkerstoenhancethepredictivepoweroftreatmentefficacyandsurvivalinNSCLCpatientsreceivingplatinum-containingchemotherapy.

-ExploringtheunderlyingmechanismsofhowERCC1andβ-tubulinIIIaffectthesensitivityofNSCLCcellstoplatinumdrugsandwhethertheyinteractwithothermolecularpathwayssuchasDNArepair,apoptosis,andcellcycleregulation.

-Developingnon-invasivemethodsfordetectingERCC1andβ-tubulinIIIexpressionlevels,suchascirculatingtumorcellsorcirculatingtumorDNA,tofacilitatetheirclinicaltranslationaspredictivebiomarkers.

-ConductingprospectiveclinicaltrialstovalidatetheclinicalutilityofthesebiomarkersinguidingtreatmentdecisionsandimprovingpatientoutcomesindifferentsubsetsofNSCLCpatients,includingthosewithdifferenthistologicalsubtypes,stages,andgeneticprofiles.

-ExploringthepotentialofcombiningplatinumdrugswithotherchemotherapeuticagentsortargetedtherapiesthatcanselectivelyenhancethesensitivityofNSCLCcellswithhighERCC1orβ-tubulinIIIexpressionorovercometheirresistancemechanismsInrecentyears,precisionmedicinehasgainedmomentuminthetreatmentofNSCLCpatients,leadingtotheadventofnumeroustargetedtherapiesandimmunotherapiesthathaveshownpromisingclinicaloutcomes.However,despitetheseadvances,asignificantproportionofNSCLCpatientsstillreceivechemotherapyasastandardofcare,especiallythosewithadvancedormetastaticdisease.Therefore,identifyingpredictivebiomarkersthatcanguidetreatmentdecisionsandfacilitatepersonalizedchemotherapyregimensiscrucialinimprovingpatientoutcomes.

TwobiomarkersthathaveemergedaspotentialpredictorsofchemotherapyresponseinNSCLCareERCC1andβ-tubulinIII.ERCC1isaDNArepairenzymethatplaysacriticalroleinthenucleotideexcisionrepairpathway,whichisresponsibleforrepairingplatinum-inducedDNAdamage.SeveralstudieshaveshownthatNSCLCpatientswithhighERCC1expressionlevelsarelessresponsivetoplatinum-basedchemotherapyandhavepooreroverallsurvivalratescomparedtothosewithlowERCC1expression(Olaussenetal.,2006;Gautschietal.,2007).β-tubulinIII,ontheotherhand,isamicrotubuleproteinthatisinvolvedincelldivisionandisthetargetoftaxanes,aclassofchemotherapeuticagentscommonlyusedinNSCLCtreatment.Overexpressionofβ-tubulinIIIhasbeenassociatedwithtaxaneresistanceandaworseprognosisinNSCLCpatients(Seveetal.,2015).

Basedonthisevidence,severalclinicaltrialsandmeta-analyseshavebeenconductedtovalidatetheclinicalutilityofERCC1andβ-tubulinIIIaspredictivebiomarkersinNSCLC.Inameta-analysisof25studiescomprisingover3000NSCLCpatients,highERCC1expressionwasassociatedwithalowerresponserateandoverallsurvivalinpatientsreceivingplatinum-basedchemotherapy(Ouetal.,2012).Similarly,ameta-analysisof17studiesinvolvingover1600patientsfoundthathighβ-tubulinIIIexpressionwassignificantlyassociatedwithpoorerresponsetotaxanesandworseoverallsurvival(Wangetal.,2014).However,thesestudiesalsohighlightedtheheterogeneityinthemethodologyandcut-offvaluesusedforERCC1andβ-tubulinIIIexpressionanalysis,emphasizingtheneedforstandardizationandvalidationinfuturestudies.

OnepotentialapplicationofERCC1andβ-tubulinIIIbiomarkersisinguidingtheselectionofchemotherapyregimens.Forexample,NSCLCpatientswithlowERCC1expressionmaybenefitfromplatinum-basedchemotherapy,whilethosewithhighERCC1expressionmayderivemorebenefitfromnon-platinum-basedregimensoralternativestrategiessuchasimmunotherapyortargetedtherapies.Similarly,patientswithlowβ-tubulinIIIexpressionmaybenefitfromtaxane-basedchemotherapyasafirst-linetreatment,whilethosewithhighexpressionmayrequirealternativechemotherapyregimensorcombinationtherapywithtargetedtherapiesthatcanovercometaxaneresistance.

AnotherpotentialapplicationofthesebiomarkersisinidentifyingsubsetsofNSCLCpatientswhomaybenefitfromcombinationtherapywithchemotherapyandtargetedagents.Forinstance,preclinicalstudieshaveshownthatcombiningplatinum-basedchemotherapywithEGFRorALKinhibitorscanenhancethesensitivityofNSCLCcellswithhighERCC1orβ-tubulinIIIexpressionandovercometheirresistancemechanisms(Sudaetal.,2014;Schuleretal.,2016).Similarly,combiningtaxane-basedchemotherapywithanti-angiogenicagentsorimmunecheckpointinhibitorsmayimprovethetherapeuticefficacyinNSCLCwithhighβ-tubulinIIIexpression(Campbel