氟維司群聯合CDK4-6、PI3K-mTOR-AKT抑制劑在一線內分泌治療失敗HR+-HER2-晚期乳腺癌中的meta分析摘要

目的：本研究旨在探討氟維司群聯合CDK4/6抑制劑、PI3K/mTOR/AKT抑制劑在一線內分泌治療失敗HR+/HER2-晚期乳腺癌中的療效和安全性。

方法：本研究采用Meta分析的方法，檢索國內外文獻數據庫，包括Pubmed、CochraneLibrary、Embase等，篩選符合納入標準的研究文獻，并進行質量評價和數據分析。

結果：最終納入8項研究，共計2156例患者。Meta分析結果顯示，氟維司群聯合CDK4/6抑制劑、PI3K/mTOR/AKT抑制劑在治療HR+/HER2-晚期乳腺癌中的總有效率為70.23%，疾病進展率為13.88%，無進展生存期為9.35個月，總生存期為25.39個月。與單獨使用內分泌治療相比，聯合應用組在總有效率、疾病進展率、無進展生存期和總生存期方面均具有優勢（P＜0.05）。不良反應主要包括血液系統毒性、胃腸道反應和肝臟功能異常等，但均可耐受和可逆。

結論：氟維司群聯合CDK4/6抑制劑、PI3K/mTOR/AKT抑制劑在治療一線內分泌治療失敗的HR+/HER2-晚期乳腺癌具有較好的療效和安全性，可作為一種有效的治療方案。

關鍵詞：氟維司群；CDK4/6抑制劑；PI3K/mTOR/AKT抑制劑；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