THELATESTINBREASTCANCERR教學(xué)講解課件

What’sPositiveaboutTripleNegativeBreastCancer?JulieR.Gralow,M.D.JillProfessorEndowedProfessorofBreastCancerDirector,BreastMedicalOncologySeattleCancerCareAllianceUniversityofWashingtonSchoolofMedicineFredHutchinsonCancerResearchCenter.BreastCancer:ClassicPrognosticandPredictiveFactorsEstrogenReceptor(ER)+75%ofBreastCancerHER-2+20-25%ofBreastCancer.TripleNegativeBreastCancerNoexpressionofER,PR,ER215%ofbreastcancersAggressive,higherrecurrenceratesChemotherapyiscurrentlymaintreatmentoptionMorecommonin:YoungwomenAfricanAmericansHispanicsBRCA1+(80%).RacialDistributionofTripleNegativeBreastCancer

SteadLA,etal,BreastCancerResearch11:R18,2009

.TimingofRecurrenceinTripleNegativeBreastCancervs.OtherSubtypes

Dentetal.ClinCanRes2007;13:4429.GeneExpressionProfilinginBreastCancerOverthelastdecade,geneexpressionprofilinghasgivenusinsightsintothebiologicalcomplexityofbreasttumorsClinicallyapplicablegeneexpression-basedassayshavebeenandarebeingdevelopedforpredictionofprognosisand/ortreatmentbenefit.MolecularClassificationofBreastCancer:

BreastCancerisNOTOneDisease!

TheCancerGenomeAtlasNetwork.Nature490,2012

LuminalALuminalBHER-2+Basal

Normal

Breast–likeIndividualgenesIndividualpatientsReddots:Genesare“turnedup”incancercellscomparedtonormalcells“HeatMap”.BasalSubtypeLowexpressionofluminalandHER2geneclustersTypicallyER-,PR-,andHER-2-negative,butupto30percentdiscordanceHighexpressionofproliferationclustergenes,virtuallyalwayshighgrade,widespreadgenomicinstabilityHighexpressionofEGFRanduniquebasalclustergenes(basalepithelialcytokeratins5,14,and17)p53mutationscommonOtherreceptorsandpathwayscanbealtered(c-kit,c-met,RAS-MAPK,mTOR/PI3K)StrongassociationwithcancersinBRCA1mutationcarriers(over80percentbasal-like)AssociatedwithDNArepairdefectsPARP1commonlyincreased.AgendiaMammaprint70-GenePrognosticSignatureAssayGenomicHealthOncotypeDx21-GeneRecurrenceScoreAssayClinicallyAvailableGenomicAssaysinBreastCancerOncotypeDXandMammaprintprovideprognosticinformationinearlybreastcancerOncotypeDXprovidespredictiveinformationofbenefitfromadjuvantchemotherapyinER-positivedisease.PAM50BreastCancerIntrinsicClassifierAssayPAM50classifieridentifiesthefourmajorbiologicsubtypesofbreastcancerreferredtoasLuminalA,LuminalB,HER2-enriched,andBasal-likeMeasures50classifiergenesand5controlgenesthroughRT-qPCRInvestigationalinUSClinicalvalidationstudiesongoing.NotallTripleNegativeBreastCancersareBasalSubtype,andNotallBasalBreastCancersareTripleNegative

PratAetal,Oncologist2013epubaheadofprintClinicalstatus(bystandardpathologytesting):TripleNegativeSubtypestatus(bygenomicprofiling):Basal.TripleNegativeBreastCancer:SubtypesandTherapeuticTargets

LehmannB,JCI2011;PietenpolJ.SABCS2012

GenomicProfilingofTNBC:6SubtypesIdentified!Analysisof21publicdatasetsIdentified587TNBCs386intrainingset201invalidationsetDifferentialsensitivityofTNBCcelllinestotargetedagentsduetodistinctexpressionpatterns,expressionofkeymutationsinoncogenesandtumorsuppressors.Specificchemotherapyagents(e.g.platinums)Anti-angiogenics(bloodvesselblockers)PolyADPribosepolymerase(PARP)inhibitorsTreatmentApproachesforTripleNegativeBreastCancer.PreoperativeChemotherapywithPlatinumCompounds:PhaseIITrialsGarberCDDP→SurgN=28

GronwaldCDDP→SurgN=25

TorrisiECF→P→SurgN=30

RyanCDDP/BEV→SurgN=51

1.GarberJE,etal.BreastCancerResTreat.2006;100(Suppl1):Abstract3074.2.RyanPD,etal.JClinOncol.2009;27(15S):Abstract551.3.TorrisiR,etal.CancerChemotherPharmacol.2008;62(4):667-672.4.GronwaldJ,etal.JClinOncol.2009;27(15S):Abstract502.PtCharacteristics22154072TripleNegativeTripleNegativeTripleNegativeBRCA-1Mutation%pCR806040200.TBCRC009:PhaseIIStudyofCisplatinorCarboplatininMetastaticTNBC

IsakoffSJetal,ASCO2011abstract#1025Patients:86metastaticTNBCTreatment:RandomizedtocisplatinorcarboplatinResults:ResponseRate30%overallCisplatin37%Carboplatin23%1stlineRR32%,2ndline20%Conclusion:Bothactiveandwell-toleratedEvaluatingp63/73forpredictionofresponse.PhaseIIITrialofEribulinvsCapecitabineforMetastaticBreastCancer

KaufmanPetal,SABCS2012Abstract#S6-6

Eribulinhasdemonstratedsurvivalbenefitinheavilypre-treatedmetastaticbreastcancerCapecitabineapprovedfortreatmentofmetastaticbreastcancerfollowingexposuretoanthracycline/taxaneLineoftherapy20%1stline50%2ndline30%>3rdlineCo-primaryendpointOSandPFS.PhaseIIITrialofEribulinvsCapecitabineforMetastaticBreastCancer

KaufmanPetal,SABCS2012Abstract#S6-6NosignificantdifferencebetweeneribulinandcapecitabineExploratoryanalysissuggestspossibleincreasedbenefitforeribulinincertainsubsets(ER-,TNBC)TNBC:Overallsurvival14.4monthseribulin,9.4monthscapecitabineOverallsurvivalbyreceptorstatus.AngiogenesisInhibition:AgentsTargetingtheVEGFPathwayBLOODVESSELCELLVEGFReceptorVEGFBevacizumab(Avastin)Anti-VEGFAntibody:bindstoVEGFandblockstumorbloodvesselgrowthCANCERCELLOtherVEGF/VEGFRinhibitors:sunitinibsorafenibaxitinibpazopanib.Eligibility:-NopriorchemoformetsAdjuvanttaxaneif>12mos.HER-2+onlyifpriortrastuzumabRANDOMIZEPaclitaxel+bevacizumabPaclitaxel1st-LineBevacizumabE2100:Paclitaxel+/-BevacizumabinStageIVBreastCancer

MillerKDetal,NEJM2007Accrual:68528-daycycle:

Paclitaxel90mg/m2d1,8,and15Bevacizumab10mg/kgd1and15.Paclitaxel+/-BevacizumabinMetastaticBreastCancer

MillerKDetal,NEJM357:2666-76,2007PaclitaxelalonePaclitaxel+Bevacizumab%16%38%6112528months.E2100:Paclitaxel+/-BevacizumabinStageIVBreastCancer

MillerKDetal,NEJM2007Toxicities(grade3,4)

Paclitaxel

Paclitaxel+BevHTN 2% 15% p<0.001Thrombosis 4% 2%Bleeding 0% 2% p=0.02Proteinuria 0% 2% p=0.002AcceleratedFDAapprovalin2008.FDARevokedApprovalofBevacizumabinBreastCancerFDAremovedmetastaticbreastcancerfrombevacizumablabelNosurvivalbenefitToxicBiologicreality?Reboundeffect?Lackoftargetingtoappropriatepopulation?Whichpatients?Whichtumors?.2nd-LineBevacizumab

PhaseIIIRIBBON2TrialofChemo/Bevacizumabin2nd-lineHER2-NegativeMetastaticBreastCancer

Brufsky

Aetal,JClinOncol2011

*Taxaneallowed:q3weeklydocetaxel,paclitaxel,oralbumin-boundpaclitaxelChemotherapy(taxane*,gemcitabine,vinorelbine,orcapecitabine)Bevacizumab10mg/kgq2weeksor15mg/kgq3weeksChemotherapy(taxane*,gemcitabine,vinorelbine,orcapecitabine)Placeboq2weeksorq3weeksRANDOMIZEPDPD2:1Inclusioncriteria:1priorchemotherapyHER2negative(n=684).RIBBON2:EfficacyChemotherapy/

PlaceboChemotherapy/

BevacizumabOverallResponseRate30%39.5%P=0.0193MedianProgression-FreeSurvival5.1months7.2monthsHR0.78(95%CI,0.64-0.93);P

=0.0072MedianOverallSurvival(Interim)16.4months18monthsHR0.90(95%CI,0.71-1.14);P=0.3741Responserate,PFShigherwithbevacizumab;OSnotstatisticallydifferent.RIBBON2:ProgressionFreeSurvivalinTripleNegativeSubgroupBrufskyAetal,BreastCancerResTreatment2012Time(months)Estimatedprobability2.76.0PFSBEV+CT

(N=112)PLA+CT

(N=47)Events,n(%)94(84)42(89)Median,months6.02.7HR0.494Log-ranktestp=0.000605101520251.00.80.60.40.20.0.RIBBON2:InterimOverallSurvivalinTripleNegativeSubgroupBrufskyAetal,BreastCancerResTreatment2012Time(months)Estimatedprobability12.617.9OSBEV+CT

(N=112)PLA+CT

(N=47)Events,n(%)52(46)29(62)Median,months17.912.6HR0.624Log-ranktestp=0.05340510152025301.00.80.60.40.20.0.BEATRICE:PhaseIIITrialofAdjuvantBevacizumabinTripleNegativeBreastCancer

CameronDetal,SABCS2012,Abstract#

S6-5

EligibilityResectedinvasivebreastcancerNegativeforER,PR,HER2(centrallyconfirmed)N=2,59163%lymphnodenegativeChemotherapyoptionsTaxanebased>4cyclesAnthracycllinebased>4cyclesAnthracycline+Taxane(3-4cycleseach)Primaryendpoint:invasivedisease-freesurvivalInvestigator’schoiceofstandardchemo(4-8cycles)ObservationInvestigator’schoiceofstandardchemo(4-8cycles)BEV(5mg/kg/wkequivalent)BEVmonotherapy

(totalduration1yr).BEATRICE:PhaseIIITrialofAdjuvantBevacizumabinTripleNegativeBreastCancerNoimprovementinDFSorOSforadditionofbevacizumabInterimOS(59%ofevents)PrimaryEndpoint:IDFS.BEATRICE:PhaseIIITrialofAdjuvantBevacizumabinTripleNegativeBreastCancerDisappointing1strandomizedPhaseIIIadjuvanttrialspecificallyfortriplenegativepopulation3yearsurvivalbetterthananticipatedNosignificantimprovementinDFS/OSwithadditionofbevacizumabAdverseeventprofileconsistentwiththatpreviouslyseen.RecentlyReportedPreoperativeTrialsofBevacizumabinBreastCancerNSABPB-40(BearHetal)NEJM2012Preopanthracycline/taxanechemotherapy+/-bevacizumabImprovedpathologicCompleteResponse(pCR)withbevacizumab:28.4%vs34.5%,p=0.027Geparquinto(VonMickwitzGetal)NEJM2012Preopanthracycline/taxanechemotherapy+/-bevacizumabOverall(HER2-):pCR15%vs17.5%p=nsTriplenegativesubset:pCR27.8%(nobev)vs36.4%(withbev)p=0.21WillthistranslateintoimprovedDFSandOSintheadjuvanttrials?Possiblereasonforoptimism?.TheHumanEpidermalGrowthFactorFamilyofReceptorsHER1EGFRHER2HER3HER4TumorCellTrastuzumabPertuzumabLapatinibErlotinibGefitinibCetuximab.EGFRTargetedTherapyinUnselectedMetastaticBreastCancer

n

RR

CB

TTPGefitinibRobertson(2003) 33 7% 30% ? Baselga(2003)

32 0% 6% 8wksAlbain(2002)

63 2% 5% 8wksErlotinib Winer(2002)

69 3% 6% 6wksConclusions:Minimalclinicalactivityinheavilypretreated,unselectedbreastcancerpatientsPharmacodynamicresultswereseen:EGFRsignalingpathwayisaffectedintumorandskinPossiblerolein“triplenegative”population?.Eligibility:MetastaticTNBC102patientsRANDOMIZECarboplatin+CetuximabCetuximabTBCRC001:RandomizedPhaseIIStudyofCetuximabinCombinationwithCarboplatininStageIVTNBC

CareyLAetal,JClinOncol30,2012Cetuximab+CarboplatinPD.TBCRC001:RandomizedPhaseIIStudyofCetuximabinCombinationwithCarboplatininStageIVTNBC

CareyLAetal,JClinOncol30,2012CetuxumabCetuxCetux+CarboCetux+CarboCompleteResponse001.4%PartialResponse6%17%15%StableDisease16%25%23%ProgressiveDisease77%50%52%OverallResponse6%17%17%ClinicalBenefitRate10%25%31%.TBCRC001:RandomizedPhaseIIStudyofCetuximabinCombinationwithCarboplatininStageIVTNBC

CareyLAetal,JClinOncol30,2012Despitestrongpreclinicaldata,combinationcetuximabpluscarboplatininmetastaticTNBCproducedresponsesinfewerthan20%ofpatientsEGFRpathwayanalysisshowedthatmostTNBCsinvolvedactivationHowever,cetuximabblockedexpressionoftheEGFRpathwayinonlyaminority,suggestingthatmosthadalternatemechanismsforpathwayactivation.OngoingStudyatUW:CombinedTargetedTherapiesforTNBC:PhaseIITrialofWeeklyNab-PaclitaxelandBevacizumabFollowedbyMaintenanceBevacizumabandErlotinib

PI:JSpechtLocallyrecurrentormetastaticER/PR/HER2negativebreastcancer;>6mosfromweeklypaclitaxel(n=63)Nab-paclitaxel100mg/m2IVQwkx24+Bevacizumab10mg/kgIVQ2wkx8Bevacizumab10mg/kgIVQ2wk+Erlotinib150mgPOdailyCR,PR,SDPrimaryobjective:PFSSecondaryobjectives:RR,OS,Safety,EGFR,SPARCexpressioninprimarytumor,CTC,CEC.PARPasaTargetforTherapyPARP

EnzymewithroleinDNArepairIncreasedlevelsintriplenegativebreastcancerAllowscancercellstobemoreresistanttochemotherapyandradiationtherapyeffectsNeededforsurvivalofBRCA-deficientcells.

PARPisanImportantEnzymeinDNARepairofNormalCellsasWellasCancerCellsDNADAMAGECellDeathEnvironmentalfactors(UV,radiation,chemicals)Normalphysiology(DNAreplication)Chemotherapy,RadiotherapyDNAREPAIRPATHWAYSSingleStrandBreaksBaseexcisionrepairPARP1ReplicationLesionsBaseexcisionrepairPARP1DoubleStrandBreaksHomologousrecombinationBRCA1/BRCA2DNAAdducts/BaseDamageBaseexcisionrepairPARP1.PARPInhibitorsasTherapyinBreastCancerPARPinhibitorsPotentiateeffectsofchemotherapy-inducedDNAdamageSingleagentactivityinBRCA1/2deficienttumorsCurrentlybeingevaluatedinclinicaltrialsPARPinhibitorswithreportedclinicaldatatodate:Iniparib(BSI-201)Veliparib(ABT-888)Olaparib(AZD2281).OralPARPInhibitorOlaparibinBRCA-deficientAdvancedBreastCancer

TuttAetal,ASCO2009,abstract#501

Patients:BRCA1/BRCA2+advanced,chemotherapyrefractorybreastcancerTreatment:Cohort1:olaparib400mgpoBID(27patients)Cohort2:olaparib100mgpoBID(27patients)Results: –Objectiveresponserate41% –MedianPFS:5.7monthsRaregrade3nausea,fatigue,vomiting.RandomizedPhaseIIvsPhaseIIITrialResults

Gemcitabine/Carboplatin+/-IniparibinTripleNegativeMetastaticBreastCancer

O’Shaughnessyetal,NEJM2011andASCO2011,abstract1007ChemoaloneChemo+PARPinhibitor3.36.97.712.2monthsP=0.0054.15.111.111.8monthsP=0.28P=0.027RandomizedPhaseIIstudyRandomizedPhaseIIIstudyFarlessimpressiveInipariboriginallythoughttobePARPinhibitor,nowuncertain.

UW/SCCAPhaseITrialofCisplatin/VinorelbinewithPARPInhibitorABT-888(Veliparib)inMetastaticBreastCancerRodlerEetal,SABCS2011,abstractP1-17-04PatientswithmetastaticTNBCand/orBRCAmutationassociatedbreastcancerCisplatin75mg/m2IVDay1Vinorelbine25mg/m2Days1,8VeliparibDays1-14Doseescalationevery21days.UW/SCCAPhaseITrialofCisplatin/VinorelbinewithABT-888(Veliparib)

MaximumTumorResponse(%)fromBaseline36patientsenrolledtodateCurrentlyatdoselevel7ofveliparib.

TripleNegativeBreastCanceris

aHighlyDiverseGroupofCancersLehmannBD,etal.JClinInvest121:2750-67,20116subtypesofTNBCidentifiedbygeneexpressionarray!.Basal-like1and2(BL1,BL2)HighexpressionofcellcycleandDNAresponsegenesMoreresponsivetoplatinumchemotherapyImmunomodulatory(IM)Mesenchymal(M)andMesenchymal-stemLike(MSL)Enrichedforgenesassociatedwithepilthelial-mesenchymaltransitionResponsivetomTOR,PI3K,abl-srcpathwaydrugsLuminalAndrogenReceptor(LAR)Sensitivetoandrogenreceptordrugs6TypesofTripleNegativeBreastCancer.TNBCLARSubtype

NotYetReportedTBCRC011:TargetingAndrogenReceptorfortheTreatmentofAR+/ER-/PR-MetastaticBreastCancer

GulcapAetal,ASCO2011,abstract#12210-20%ofTNBCareAndrogenReceptorPositiveDrugstargetingARaretypicallyusedintreatingprostatecancerBicalutamide(Casodex)Enzalutamide(Xtandi)TBCRC011:TreatmentwithbicalutamideStudy:230TNBCpatientstested,27AR+Noresultstodate.Claudin-lowSubtype5-10%oftumorsTypicallyER-,PR-,HER2-Lowexpressionofcell-celljunctionproteinsLymphocyteinfiltratesStemcell+EMTfeaturesHER2BasalLuminalProliferationBasalClaudin-low.TNBCM/MSLandClaudin-lowSubtypes

MetaplasticBreastCancerSubtypeoftriplenegativebreastcancerRare,butincreasingincidenceDistinctsubtypebymolecularprofilingClaudin-lowEnrichedforepithelial-to-mesenchymaltransition(EMT)markers~50%oftumorshavePI3KmutationsorlossinPTENIncreasedVEGFproductionChemorefractory<10%pCRratewithneoadjuvantchemotherapyLittledataregardingresponseinmetastaticsetting.

DATinAdvancedCancersCancer

MoroneyJetal,ClinCancerRes18,2012136patientswithadvancedcancer29breastcancer(12metaplastic)RegimenLiposomaldoxorubicin(Doxil)30mg/m2IVevery3weeksBevacizumab(Avastin)15mg/kgIVevery3weeksTemsirolimus(Torisel)25mgIVweeklyResultsResponseinmetaplasticbreastcancer:5/12(42%).TNBCM/MSLandClaudin-lowSubtypes

ProposedSWOGClinicalTrial:DATforMetaplasticTripleNegativeBreastCancer

PI:SMoulderTriplenegative,metastaticbreastcancerHighgrademetaplastic,spindlecell,ormyoepithelialhistologyVimentinpositive‘Claudin-low’orMesenchymal-liketumorsbyprofilingRegimen:DATvsliposomaldoxorubicinLiposomaldoxorubicin(Doxil)30mg/m2IVevery3weeksBevacizumab(Avastin)15mg/kgIVevery3weeksTemsirolimus(Torisel)25mgIVweekly.114clinically-definedTNBCpatientswithresidualdiseaseafterpreopchemoImmunohistochemistryKi67,ER,PR,HER2,AR112/114Nanostringdigitalexpressionanalysis450genes89/114Nextgenerationsequencing182oncogenesandtumorsuppressorsMolecularCharacterizationofResidualTripleNe