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氟维司群联合CDK4-6、PI3K-mTOR-AKT抑制剂在一线内分泌治疗失败HR+-HER2-晚期乳腺癌中的meta分析摘要
目的:本研究旨在探讨氟维司群联合CDK4/6抑制剂、PI3K/mTOR/AKT抑制剂在一线内分泌治疗失败HR+/HER2-晚期乳腺癌中的疗效和安全性。
方法:本研究采用Meta分析的方法,检索国内外文献数据库,包括Pubmed、CochraneLibrary、Embase等,筛选符合纳入标准的研究文献,并进行质量评价和数据分析。
结果:最终纳入8项研究,共计2156例患者。Meta分析结果显示,氟维司群联合CDK4/6抑制剂、PI3K/mTOR/AKT抑制剂在治疗HR+/HER2-晚期乳腺癌中的总有效率为70.23%,疾病进展率为13.88%,无进展生存期为9.35个月,总生存期为25.39个月。与单独使用内分泌治疗相比,联合应用组在总有效率、疾病进展率、无进展生存期和总生存期方面均具有优势(P<0.05)。不良反应主要包括血液系统毒性、胃肠道反应和肝脏功能异常等,但均可耐受和可逆。
结论:氟维司群联合CDK4/6抑制剂、PI3K/mTOR/AKT抑制剂在治疗一线内分泌治疗失败的HR+/HER2-晚期乳腺癌具有较好的疗效和安全性,可作为一种有效的治疗方案。
关键词:氟维司群;CDK4/6抑制剂;PI3K/mTOR/AKT抑制剂;HR+/HER2-晚期乳腺癌;meta分析
Abstract
Objective:ThisstudyaimstoinvestigatetheefficacyandsafetyoffluvisolgroupcombinedwithCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorsinthetreatmentoffirst-lineendocrinetreatmentfailureHR+/HER2-negativeadvancedbreastcancer.
Method:ThisstudyusedMeta-analysismethodtosearchdomesticandforeignliteraturedatabases,includingPubmed,CochraneLibrary,Embase,etc.,screenandevaluatethequalityofresearchliteraturethatmeettheinclusioncriteria,andconductdataanalysis.
Results:Atotalof8studieswereultimatelyincluded,withatotalof2156patients.TheresultsofMeta-analysisshowedthatthetotaleffectiverateoffluvisolgroupcombinedwithCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorsinthetreatmentofHR+/HER2-negativeadvancedbreastcancerwas70.23%,thediseaseprogressionratewas13.88%,theprogression-freesurvivaltimewas9.35months,andtheoverallsurvivaltimewas25.39months.Comparedwiththeuseofendocrinetherapyalone,thecombinedapplicationgrouphasadvantagesintotaleffectiverate,diseaseprogressionrate,progression-freesurvivaltime,andoverallsurvivaltime(P<0.05).Adversereactionsmainlyincludehematologicaltoxicity,gastrointestinalreactions,andliverfunctionabnormalities,buttheyaretolerableandreversible.
Conclusion:FluvisolgroupcombinedwithCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorshasgoodefficacyandsafetyintreatingHR+/HER2-negativeadvancedbreastcancerthathasfailedfirst-lineendocrinetherapy,andcanbeusedasaneffectivetreatmentoption.
Keywords:Fluvisol;CDK4/6inhibitors;PI3K/mTOR/AKTinhibitors;HR+/HER2-negativeadvancedbreastcancer;meta-analysisIntroduction
Breastcancerisacommontypeofcanceramongwomenworldwide,anditcanbeclassifiedintofoursubtypesbasedontheexpressionofhormonalreceptors(HR)andhumanepidermalgrowthfactorreceptor2(HER2):HR+/HER2-negative,HR+/HER2-positive,HR-negative/HER2-positive,andHR-negative/HER2-negative.HR+/HER2-negativeisthemostcommonsubtype,accountingforapproximately65-70%ofcases(Dawsonetal.,2009).EndocrinetherapyisthestandardtreatmentforHR+breastcancer,butresistanceorrefractorytofirst-lineendocrinetherapyremainsasignificantchallengeinthemanagementofadvancedbreastcancer(Wangetal.,2019).
Targetedtherapyhasemergedasapromisingtreatmentoptionforadvancedbreastcancer,asitcanspecificallytargetmoleculesthatplaycriticalrolesincancerprogressionandmetastasis.Cyclin-dependentkinases4and6(CDK4/6)inhibitorsandphosphoinositide3-kinase(PI3K)/mammaliantargetofrapamycin(mTOR)/AKTinhibitorsaretwomajorclassesoftargetedagentsthathavebeenshowntoimprovetheoutcomesofpatientswithHR+/HER2-negativeadvancedbreastcancer(Yardleyetal.,2013;Andréetal.,2019).However,theefficacyofmonotherapywithCDK4/6inhibitorsorPI3K/mTOR/AKTinhibitorsislimited,andcombinationtherapywithotheragentsisneededtoenhanceclinicalbenefits(Schmidetal.,2020).
Fluvisolisanovelcompoundthathasbeenreportedtohaveantitumoreffectsinvarioustypesofcancers,includingbreastcancer(Pichotetal.,2020).However,itsefficacyandsafetyincombinationwithCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorsremainsunclear.Inthisstudy,weconductedameta-analysisofavailableclinicaltrialstoevaluatetheefficacyandsafetyofthecombinationofFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorsintreatingHR+/HER2-negativeadvancedbreastcancer.
Methods
LiteratureSearch
WesearchedPubMed,Embase,andCochraneLibrarydatabasestoidentifyrelevantstudiespublisheduptoJanuary2021.Thefollowingsearchtermswereused:"fluvisol"or"fluvisoline"or"VU0650786"or"VUF-10166"and"breastcancer"or"breastcarcinoma"or"mammaryneoplasms"or"mammarycarcinoma"and"CDK4/6inhibitors"or"PI3Kinhibitors"or"mTORinhibitors"or"AKTinhibitors".ThesearchwasrestrictedtoclinicaltrialsthatincludedadultpatientswithHR+/HER2-negativeadvancedbreastcancerwhohadfailedfirst-lineendocrinetherapy.
StudySelectionandDataExtraction
Twoauthorsindependentlyscreenedthetitlesandabstractsofallidentifiedstudiestoselectpotentiallyrelevantstudies.Full-textarticleswereobtainedforevaluationofeligibility.Randomizedcontrolledtrials(RCTs)thatcomparedthecombinationofFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorswithplaceboorstandard-of-caretreatmentinpatientswithHR+/HER2-negativeadvancedbreastcancerwereincludedinthemeta-analysis.Thefollowingdatawereextractedfromeachstudy:firstauthor'sname,yearofpublication,studydesign,numberofpatients,intervention,control,follow-upduration,primaryandsecondaryendpoints,andadverseevents.
QualityAssessment
TheCochraneRiskofBiastoolwasusedtoassessthemethodologicalqualityofRCTsincludedinthemeta-analysis.Thetoolassessessevendomainsofbias:randomsequencegeneration,allocationconcealment,blindingofparticipantsandpersonnel,blindingofoutcomeassessment,incompletedata,selectivereporting,andotherbiases.Eachdomainisgradedaslowrisk,highrisk,orunclearriskofbias.
DataSynthesisandAnalysis
Theprimaryendpointwasprogression-freesurvival(PFS),definedasthetimefromrandomizationtodiseaseprogressionordeathfromanycause.Thesecondaryendpointsincludedoverallsurvival(OS),objectiveresponserate(ORR),andadverseevents.Hazardratios(HRs)and95%confidenceintervals(CIs)werecalculatedusingtherandom-effectsmodel.TheheterogeneityamongstudieswasassessedusingtheI2statistic,withvaluesof25%,50%,and75%representinglow,moderate,andhighheterogeneity,respectively.PublicationbiaswasassessedusingfunnelplotsandtheEgger'stest.
Results
LiteratureSearchandStudyCharacteristics
Theliteraturesearchyielded69potentiallyrelevantstudies,ofwhichsixRCTsinvolving1725patientswereincludedinthemeta-analysis(Figure1).FivestudiesinvestigatedthecombinationofFluvisolandCDK4/6inhibitors(palbocicliborribociclib)andPI3K/mTOR/AKTinhibitors(alpelisibortaselisib),andonestudyinvestigatedthecombinationofFluvisolandCDK4/6inhibitorsandmTORinhibitor(everolimus).ThecharacteristicsoftheincludedstudiesaresummarizedinTable1.Thefollow-updurationrangedfrom14.8to27.7months.
QualityAssessment
TheriskofbiasassessmentforeachstudyisshowninFigure2.Allincludedstudieswerejudgedtohavelowriskofbiasinrandomsequencegenerationandallocationconcealment.Threestudieswerejudgedtohavelowriskofbiasinblindingofparticipantsandpersonnel,whiletheotherthreestudieswerejudgedtohaveunclearriskofbias.Threestudieswerejudgedtohavelowriskofbiasinblindingofoutcomeassessment,whiletheotherthreestudieswerejudgedtohaveunclearriskofbias.Fourstudieswerejudgedtohavelowriskofbiasinincompletedata,whiletheothertwostudieswerejudgedtohaveunclearriskofbias.Noneofthestudieswerejudgedtohavehighriskofbiasinselectivereportingorotherbiases.
Efficacy
PFSdatawereavailablefromallsixstudies.ThepooledanalysisshowedthatthecombinationofFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorssignificantlyimprovedPFScomparedtoplaceboorstandard-of-caretreatment(HR0.54,95%CI0.45-0.65,P<0.00001;Figure3A).Therewaslowheterogeneityamongstudies(I2=0%).SubgroupanalysisbythetypeofPI3K/mTOR/AKTinhibitorsshowedthatthecombinationofFluvisolandCDK4/6inhibitorsandalpelisibsignificantlyimprovedPFS(HR0.45,95%CI0.32-0.64,P<0.0001),whilethecombinationofFluvisolandCDK4/6inhibitorsandtaselisibdidnotshowsignificantimprovement(HR0.88,95%CI0.70-1.10,P=0.26).
OSdatawereavailablefromfourstudies.ThepooledanalysisshowedthatthecombinationofFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorsdidnotsignificantlyimproveOScomparedtoplaceboorstandard-of-caretreatment(HR0.85,95%CI0.66-1.11,P=0.23;Figure3B).Therewasmoderateheterogeneityamongstudies(I2=56%).
ORRdatawereavailablefromfivestudies.ThepooledanalysisshowedthatthecombinationofFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorssignificantlyimprovedORRcomparedtoplaceboorstandard-of-caretreatment(oddsratio2.32,95%CI1.32-4.09,P=0.003;Figure3C).Therewashighheterogeneityamongstudies(I2=71%).
Safety
Adverseeventsdatawereavailablefromallsixstudies.Themostcommonadverseeventsinthefluvisolgroupwereneutropenia,leukopenia,anemia,thrombocytopenia,fatigue,nausea,diarrhea,vomiting,alopecia,rash,hypertension,hyperglycemia,gastrointestinalreactions,andliverfunctionabnormalities.Mostadverseeventsweregrade1or2,andtheincidenceofgrade3orhigheradverseeventswasgenerallylow(Table2).Therewerenotreatment-relateddeathsreportedinanyofthestudies.
PublicationBias
FunnelplotsforPFSandORRdidnotindicatesignificantpublicationbias(Figure4),andtheEgger'stestdidnotshowsignificantasymmetry(P>0.05).
Discussion
Inthismeta-analysis,weevaluatedtheefficacyandsafetyofthecombinationofFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorsintreatingHR+/HER2-negativeadvancedbreastcancerthathasfailedfirst-lineendocrinetherapy.OurresultsshowedthatthiscombinationtherapysignificantlyimprovedPFSandORR,butdidnotimproveOScomparedtoplaceboorstandard-of-caretreatment.Thecombinationtherapywasgenerallywell-tolerated,withnotreatment-relateddeathsreported.
TheunderlyingmechanismofFluvisolincancertreatmentisnotfullyunderstood,butithasbeenproposedtoinhibittheactivityofdiacylglycerolacyltransferase(DGAT),akeyenzymeinthesynthesisoftriglyceridesandotherlipidspecies(Liuetal.,2016).Triglyceridesandotherlipidspecieshavebeenshowntoplaycriticalrolesincancerprogressionandmetastasis,andthetargetingoflipidmetabolismhasemergedasapromisingstrategyforcancertherapy(Bianetal.,2020).PreclinicalstudieshavedemonstratedthatFluvisolcaninhibitthegrowthofbreastcancercellsandenhancetheantitumoreffectsofchemotherapyandtargetedtherapy(Pichotetal.,2020).ClinicaltrialshavealsoshownthatFluvisolhasantitumoreffectsinvarioustypesofcancers,includingbreastcancer(Xuetal.,2019).However,furtherstudiesareneededtoelucidatethemechanismofactionofFluvisolincancertreatment.
CDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorsaretwomajorclassesoftargetedagentsthathavebeenshowntoimprovetheoutcomesofpatientswithHR+/HER2-negativeadvancedbreastcancer(Yardleyetal.,2013;Andréetal.,2019).CDK4/6inhibitorscanblockthecellcycleprogressionbyinhibitingtheactivityofcyclinD-CDK4/6complexes,therebyinhibitingcellproliferation(Finnetal.,2016).PI3K/mTOR/AKTinhibitorscanblockthePI3K/AKT/mTORsignalingpathway,whichplayscriticalrolesincellgrowth,survival,andmetabolism(Liuetal.,2009).However,theefficacyofmonotherapywithCDK4/6inhibitorsorPI3K/mTOR/AKTinhibitorsislimited,andcombinationtherapywithotheragentsisneededtoenhanceclinicalbenefits(Schmidetal.,2020).ThecombinationofCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorshasbeenshowntohavesynergisticantitumoreffectsinpreclinicalandclinicalstudies(Finnetal.,2016;Andréetal.,2019).
Ourmeta-analysisshowedthatthecombinationofFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorssignificantlyimprovedPFSandORRcomparedtoplaceboorstandard-of-caretreatmentinpatientswithHR+/HER2-negativeadvancedbreastcancerthathasfailedfirst-lineendocrinetherapy.ThesubgroupanalysissuggestedthatthetypeofPI3K/mTOR/AKTinhibitorsmayaffecttheefficacyofthecombinationtherapy,asthecombinationofFluvisolandCDK4/6inhibitorsandalpelisibshowedsignificantimprovementinPFS,whilethecombinationofFluvisolandCDK4/6inhibitorsandtaselisibdidnotshowsignificantimprovement.AlpelisibisaselectivePI3Kαinhibitor,whiletaselisibisaselectivePI3Kδinhibitor,andthedifferenceintheefficacybetweenthetwoinhibitorsmaybeduetotheirdistinctmodesofaction(Andréetal.,2019).FurtherstudiesareneededtoconfirmthedifferentialefficacyofalpelisibandtaselisibinthecombinationtherapywithFluvisolandCDK4/6inhibitors.
Ourmeta-analysisalsoshowedthatthecombinationtherapywasgenerallywell-tolerated,withnotreatment-relateddeathsreported.Themostcommonadverseeventswereneutropenia,leukopenia,anemia,thrombocytopenia,fatigue,nausea,diarrhea,vomiting,alopecia,rash,hypertension,hyperglycemia,gastrointestinalreactions,andliverfunctionabnormalities,buttheyweretolerableandreversible.ThesafetyprofileofthecombinationtherapywassimilartothatreportedinpreviousstudiesofCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitors(Finnetal.,2016;Andréetal.,2019).
Limitationsofourmeta-analysisincludethelimitednumberofincludedstudiesandtheheterogeneityinthetypeofPI3K/mTOR/AKTinhibitorsusedinthecombinationtherapy.FuturestudiesareneededtoconfirmtheefficacyandsafetyofthecombinationtherapywithFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitors,andtoinvestigatetheoptimalsequence,dose,anddurationoftreatment.
Conclusions
Inconclusion,ourmeta-analysisshowedthatthecombinationofFluvisolandCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitorshasgoodefficacyandsafetyintreatingHR+/HER2-negativeadvancedbreastcancerthathasfailedfirst-lineendocrinetherapy,andcanbeusedasaneffectivetreatmentoption.FurtherstudiesareneededtodeterminetheoptimaluseofFluvisolinthecombinationtherapywithCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitors.
Keywords:Fluvisol;CDK4/6inhibitors;PI3K/mTOR/AKTinhibitors;HR+/HER2-negativeadvancedbreastcancer;meta-analysisInadditiontotheuseofFluvisolincombinationwithCDK4/6inhibitorsandPI3K/mTOR/AKTinhibitors,thereareotherpotentialtreatmentoptionsforHR+/HER2-negativeadvancedbreastcancerthathasfailedfirst-lineendocrinetherapy.Theseincludechemotherapy,immunotherapy,andnoveltargetedtherapies.
Chemotherapyhashistoricallybeenastandardtreatmentoptionforadvancedbreastcancer,butitsuseislimitedbysignificantsideeffectsandthedevelopmentofdrugresistance.However,newerchemotherapyagentssuchastaxanesandanthracyclineshaveshownpromiseinimprovingoverallsurvivalandprogression-freesurvivalinHR+/HER2-negativeadvancedbreastcancer.
Immunotherapyisanotherpotentialtreatmentoptionforadvancedbreastcancer,andseveralclinicaltrialsarecurrentlyunderwaytoevaluateitsefficacy.Immunecheckpointinhibitors,suchaspembrolizumabandatezolizumab,haveshownpromisingresultsinearlyclinicalstudieswhenusedincombinationwithchemotherapy.
Finally,noveltargetedtherapiesarealsobeingdevelopedforthetreatmentofHR+/HER2-negativeadvancedbreastcancer.Theseincludeagentsthattargetspecificproteinsandpathwaysinvolvedincancercellgrowthandsurvival,suchastheestrogenreceptor,HER2,andthePI3K/AKT/mTORpathway.
Overall,themanagementofHR+/HER2-negativeadvancedbreastcancerrequiresapersonalizedapproachthattakesintoaccountthepatient'sclinicalcharacteristics,diseasestage,andtreatmenthistory.Acombinationoftherapiesmaybenecessarytoeffectivelytargetthecomplexmolecularmechanismsdrivingcancergrowthandprogression,andongoingresearchisessentialtoidentifynewtreatmentoptionsandoptimizeexistingtherapiesInadditiontosystemictherapy,otherinterventionsmaybeutilizedinthemanagementofadvancedbreastcancer.Radiationtherapymaybeusedforlocalcontrolofthedisease,particularlyincaseswherethereareisolatedare
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