乳腺癌的新輔助治療

OPENISSUESINMULTIDISCIPLINARYBREASTCANCERMANAGEMENTNEOADJUVANTTHERAPYLuciaMentucciaOncologiaMedica,SoraToimprovesurgicaloutcomesandoptionsForoperablebreastcancer,theaimistoincreasethechanceofbreastconservingsurgeryinpatientswhowouldotherwiserequiremastectomyForinoperablelocallyadvancedbreastcancers,theaimistoachieveoperabilityTogaininformationontumorresponseTodefineshort-termsurrogatemarkersofresponse

GoalsofNeoadjuvantTheapy

inBreastCancer1523ptswithclinicalT1-3,N0-N1breastcancerStratification?Age?ClinicalTumorSize?ClinicalNodalStatusOperationOperationNSABPB-18WolmarkNtal;JNatlCancerInstMonogr.2001ACx4ACx436%20%43%cCR(249pts)cPR(296pts)cSD+cPD(140pts)23%4%9%pInv(160pts)pNon-Inv(26pts)pCR(63pts)NSABPB-18:ClinicalandPathologicBreastTumorResponseWolmarkNtal;JNatlCancerInstMonogr.2001NSABPB-18:

SurgeryPerformed100806040200%P<0.01MastLump60406832Preop-ChemoPostop-ChemoWolmarkNtal;JNatlCancerInstMonogr.2001WolmarkNtal;JNatlCancerInstMonogr.2001NSABPB-27

PtswithT1c-3N0orT1-3N1breastcancerRandomizationACx4TamX5YrsACx4TamX5YrsACx4TamX5YrsSurgeryTaxoterex4SurgerySurgeryTaxoterex42411ptsBearHD,etal.JClinOncol.2006;24(13):2019-2027.NSABPB-27PathologicCompleteResponseinBreast

BearHD,etal.JClinOncol.2006;24(13):2019-2027.Diseasefree-survivalOverallSurvivalpCRtoNeoadjuvantChemotherapyiscorrelatedwithimprovedDFS&OS(NSABPB-27)BearHD,etal.JClinOncol.2006;24(13):2019-2027.NSABPB-27:OverallSurvivalNodalStatusPtswithoutpCRPtswithpCRNSABPB-27:OS,DFS,RFSPreoperativevspostoperative,OverallSurvivalTheCochraneLibrary,Issue3,2008pCRvsresidualdisease,OverallSurvivalTheCochraneLibrary,Issue3,2008Intrinsicsub-typeshavedifferentprognosisand

differentresponsetoprimaryCT0102030405060708090100Christofanillietal2006,n=30Binesetal2003,n=32Bursteinetal2003,n=40Kellyetal2006,n=37Harrisetal2003,n=40Hurleyetal2002,n=48Griggsetal2005,n=18Limentanietal2007,n=31Giannietal2007,n=115Lybaertetal2006,n=89Coudertetal2005,n=33Buzdaretal2007,n=64Pernasetal2006,n=16ResponseRateswithNeoadjuvantTrastuzumabpCR(%)T+L(IBConly)D+HT+H(includingIBC)AC→T+H(includingIBC)V+H(includingIBC)D+cisplatin+H(includingIBC)D+HD+V+T(includingIBC)X+D+HAT→T→CMF+HD+HT→FEC+HT→FEC+HStudyL,lapatinib;V,vinorelbine;X,capecitabine;

FEC,5-fluorouracil,epirubicin,cyclophosphamideAT→T→CMF+H(IBConly)Baselgaetal2007,n=31TrastuzumabNOAH,IBConlyLapatinibNOAH,allpatientsPaclitaxelq3wkx4+Hx12N=23FECx4+Hx12RPaclitaxelq3wkx4N=19FECx4BCptsM0,T1-3,No-1,HER2+(FISHorICH3+)N=42FEC,5-fluorouracil,epirubicin,cyclophosphamideH,trastuzumabTheMDAndersonStudyBuzdarAU,ClinCancerRes2007Additional22pts66%26%T-FECT-FEC+Tras0205075%ofpatientspCRwithCTTrastuzumabBuzdarAU,ClinCancerRes2007MDAndersonNeoadjuvantTrial

DFSat72monthsFUBuzdarAetalASCOBreast2009BuzdarAU,ClinCancerRes2007CMF

q4wx3cyclesNOAHHER2-positiveLABC

(IHC3+orFISH+)AT

q3wx3cyclesT

q3wx4cyclesH+AT

q3wx3cyclesH+T

q3wx4cyclesHq3wx4cycles

+CMFq4wx3cyclesHcontinuedq3w

toweek52(n=115)(n=113)AT

q3wx3cyclesT

q3wx4cyclesCMF

q4wx3cyclesHER2-negativeLABC

(IHC0/1+)Surgeryfollowedby

radiotherapya(n=99)Surgeryfollowedby

radiotherapyaSurgeryfollowedby

radiotherapya19crossedovertoHGianniLetal.Lancet2010;375:377–84Patients(%)39%20%01020304050WithHWithoutHHER2positivep=0.002pCRratesintheNOAHtrial:

intent-to-treatpopulationGianniLetal.Lancet2010;375:377–84EFS:HER2-positivepopulationL.Giannietal.,TheLancet,2010…FutureClinicalPractice….Anti-HER2Treatment:mechanismsofactionThreeNeoadjuvantTrialsUsingTargetedTherapiesforHER-2PositiveBCLAPATINIBVSTRASTUZUMABINCOMBINATIONWITHNEOADJUVANTANTHRACYCLINE-TAXANE-BASEDCHEMOTHERAPY:

PRIMARYEFFICACYENDPOINTANALYSISOFTHE

GEPARQUINTOSTUDY(GBG44)

UntchM,LoiblS,BischoffJ,EidtmannH,KaufmannM,BlohmerJU,HilfrichJ,StrumbergD,FaschingP,KreienbergR,TeschH,HanuschC,GerberB,RezaiM,JackischC,HuoberJ,KühnT,NekljudovaV,vonMinckwitzGforthe

GBG/AGOstudygroup

Thispresentationistheintellectualpropertyoftheauthor/presenter

Contactthemforpermissiontoreprintand/ordistribute.SanAntonioBreastCancerSymposium-CancerTherapyandResearchCenteratUTHealthScienceCenter–December8-12,2010ConclusionsfromRun-inPhase

(N=60)NeutropeniaGradeIII/IVin82%G-CSFmademandatorytogetherwithL

Treatmentdiscontinuationsin34.5%Ldosereducedfrom1250to1000mg/d

DiarrheaGradeIII/IVin6.9%Loperamidegivenasstand-bymedicationforL*vonMinckwitz,M.Untchetal,AnnOncol2010BreastConservationRateConclusionsAnthracycline-taxanebasedCT+TachievedapCR(ypT0/isypN-/+)rateof50%inHER2-positivepatients,confirmingourpreviousfindings(TECHNO,GeparQuattro)CT+L(1250/1000mg)resultedinasignificantlylowerpCRrateof35%(Caveat:10%morediscontinuationswithL).ComplianceofLwithECandDocetaxelwaslowerthanwithT.Resultsshouldbeseeninthecontextofotherstudieslike

Neo-ALTTO,whichuses

ahigherdoseofL(1500mg/d)butashorterpre-operativetreatmentduration.FirstresultsoftheNeo-ALTTOtrial(BIG01-06/EGF106903):AphaseIII,randomized,openlabel,neoadjuvantstudyoflapatinib,trastuzumab,andtheircombinationpluspaclitaxelinwomenwithHER2-positiveprimarybreastcancerJoséBaselga,IanBradbury,HolgerEidtmann,SerenaDiCosimo,ClaudiaAura,EvandrodeAzambuja,HenryGomez,PhuongDinh,KarineFauria,VeerleVanDooren,PaoloPaoletti,AronGoldhirsch,Tsai-WangChang,IstvanLang,MichaelUntch,RichardD.GelberandMartinePiccart-GebhartonbehalfoftheNeo-ALTTOStudyTeamDecember10,2010StudyDesignStratification:T≤5cmvs.T>5cmERorPgR+vs.ER&PgR–N0-1vs.N≥2ConservativesurgeryornotInvasiveoperableHER2+BCT>2cm(inflammatoryBCexcluded)LVEF

50%N=45034weeks52

weeksofanti-HER2therapylapatinibtrastuzumablapatinibtrastuzumabFECX3SURG

ERYRANDOMIZElapatinibtrastuzumablapatinibtrastuzumabpaclitaxelpaclitaxelpaclitaxel+12wks6wksEfficacy–pCRandtpCREfficacy–Overall(Clinical)Response

at6weeks(w/ochemo)andatsurgeryL:lapatinib;T:trastuzumab;L+T:lapatinibplustrastuzumabSafetyNomajorcardiacdysfunctionOnedeathinL+TimmediatelyafterendoftreatmentL

(N=154)T

(N=149)L+T

(N=152)Diarrhea36(23%)3(2%)32(21%)Hepatic*20(13%)2(1%)13(9%)Neutropenia24(16%)4(3%)13(9%)Skindisorders10(7%)4(3%)10(7%)Number(%)ofpatientswithAEsatGrade≥3L:lapatinib;T:trastuzumab;L+T:lapatinibplustrastuzumab*Includes2patientswithHy’sLawcriteriainT,andonepatientinL

RANDOMIZATIONLapatinib1000mg/dailyLapatinib1500mg/dailyCOREBIOPSYSURGERY

ChemotherapyABCTXL80mg/m2Trastuzumab2mg/kg5FU600mg/m2Epi75mg/m2CTX600mg/m2CHERLOBTrial:studyplanGuarneriV,ASCO2011121pazpCR(breast&axilla)NodenegativityBreastconservation0102030405060708090ArmA:CT+trastuzumabArmB:CT+lapatinibArmC:CT+trastuzumab/lapatinibCHER-LOB:EFFICACYOUTCOMESGuarneriV,ASCO2011NeoSphere:studydesignTHP(n=107)

docetaxel+trastuzumab+

pertuzumabHP(n=107)

trastuzumab+pertuzumabTP(n=96)

docetaxel+pertuzumabSURGERYdocetaxelq3wx4→FECq3wx3trastuzumabq3wcycles5–17FECq3wx3trastuzumabq3wcycles5–17FECq3wx3trastuzumabq3wcycles5–17FECq3wx3trastuzumabq3wcycles5–21Studydosing:q3wx4TH(n=107)

docetaxel+trastuzumabPatientswithoperableor

locallyadvanced/inflammatory*

HER2-positiveBC

Chemo-na?ve&

primarytumors

>2cm(N=417)BC,breastcancer;FEC,5-fluorouracil,epirubicinandcyclophosphamide

*Locallyadvanced=T2–3,N2–3,M0orT4a–c,anyN,M0;operable=T2–3,N0–1,M0;inflammatory=T4d,anyN,M0

H,trastuzumab;P,pertuzumab;T,docetaxelGianniLetal.SABCS2010

H,trastuzumab;P,pertuzumab;T,docetaxelNeoSpherepCRrates:ITTpopulationsummaryp=0.014150403020100THTHPHPTPpCR,%95%CIp=0.0198p=0.00329.045.816.824.06GianniLetal.SABCS2010010203040506070THTHPHPTPERorPRposERandPRneg20.026.017.436.829.130.063.25.9pCR,%95%CI

H,trastuzumab;P,pertuzumab;T,docetaxelGianniLetal.SABCS2010NEOSPHERE:pCRandhormonereceptorsstatusL:lapatinib;T:trastuzumab;L+T:lapatinibplustrastuzumabpCRpathologiccompleteresponseHR:hormonereceptors

pCRbyhormonereceptorstatusBaselgaJetal.SABCS2010T:trastuzumab;L:lapatinib;T+L:trastuzumabpluslapatinibCHER-LOB:pCRratebyHR25%22.7%0102030405060ArmA(CT+T)ArmB(CT+L)ArmC(CT+T+L)26.6%35.7%56.2%35.7%HR+HR+HR+HR-HR-HR-Trial/authorpts#RegimenHR+%%pCRHR-HR+Kemeny54FACVb6620.07.7Ring435CMF,A/E7121.68.1Bear1211AC5913.65.7Bear565AC+T5722.814.1GEPARDO250ddAD+/-T5615.41.1GEPARDUO913ddAD/CA-D7422.86.2GEPARTRIO286TAC/TAC-NX6836.610.1Guarneri1731FAC+/-P6823.87.8Gianni438A+/P/CMF6342.211.6Guarneri201FEC/ET/GET7416.63.5Colleoni399ECF/EC/ET/ViFuP6833.37.6HORMONERECEPTORSTATUSANDpCRNeoadjuvanttherapyinHER2+operablebreastcancer:KeyFindingsPatientselectionismandatoryfortheintegrationofnovelagentsincancertreatmentChemotherapy+trastuzumabisthegoldstandardDouble-HER2blockadeincreasesthepCRrateEndocrinepathwayisstillimportanteveninpresenceofHER2co-expressionThepreoperativesettingisidealtotestnewcombinationsthroughthe“windowofopportunitymodel”ShouldneoadjuvantregimensforHER2-positivediseasealwayscontainanti-HER2drug?YesNoAIs

dual

HER2-targetingareasonableoptionforthepreoperativesettingforHER2disease?YesNoA8.5%87.2%4.3%67.4%21.7%10.9%NeoAdjuvantSystemicTherapyStGallen2011VonMinckwitzG,SABCS2010VonMinckwitzG,SABCS2010VonMinckwitzG,SABCS2010OBJECTIVESVonMinckwitzG,SABCS2010VonMinckwitzG,SABCS2010CHARACTERISTICSOFPATIENTSVonMinckwitzG,SABCS2010NeoadjuvantBevacizumabandAnthracycline-TaxaneBasedChemotherapyin684TripleNegativePrimaryBreastCancers:SecondaryEndpointAnalysisoftheGEPARQUINTOStudy(GBG44)GerberBetal.ProcASCO2011;Abstract1006.GerberBetal.ProcASCO2011;Abstract1006.GerberBetal.ProcASCO2011;Abstract1006.GEPARQUINTO:BenefitofBevacizumab

AddedtoNeoadjuvantChemotherapyin

TNBCSubgroupGerberBetal.ProcASCO2011;Abstract1006.BenefitofbevlimitedtoTNBCsubgrouppCRbreast(withbevvswithoutbev)*TNBCpatients:36.4vs27.8%(p=0.021)Allpatie