AdjuvantEndocrineTherapyinPremenopausalWomenEricP.Winer,MDDana-FarberCancerInstituteHarvardMedicalSchoolBoston,USAIntheUnitedStates…Approximately25-30%ofbreastcancerarisesinpremenopausalwomenOver60%areER+Decisionsaboutadjuvantendocrinetherapycanhaveamajorimpactonbreastcancerdiseasecontrol,mortality,andqualityoflifeinpremenopausalwomenInthepast,itwasverysimple…

Tamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsTamoxifenx5yearsOutcomeat15yearswithTamoxifen

inPremenopausalWomenwithorwithoutChemotherapyEBCTCG,Lancet2011ER+disease,entryage<45years,79%chemotherapy(n-2614)OvarianAblationvsNil

NoChemotherapy

66.6%72.7%62.7%54.3%46.3%56.7%10.4%(SE3.1)8.3%(SE3.0)6.1%(SE2.9)Reductionintheriskof:Recurrence31%DeathfromBC31%Mortality28% NobenefitseenwhenOSaddedtochemotherapyNodatafromoverviewofOS+tamoxifeninadjuvantsettingEBCTCG,Lancet2005TheAdjuvantBreastCancerTrialsCollaborativeGroupJ.Natl.CancerInst.200799:516-525Relapse-freeSurvivalintheAdjuvantBreastCancerOASTrialConfoundedby:Age;median43yearsERstatus:18%negative,42%unknownChemotherapyadministration:80%NoncompliancewithOFS:12%NSABPB-30:OverallSurvivalandDisease-freeSurvivalbyTreatmentInducedAmenorrheaSwainSMetal.NEnglJMed2010;362:2053-2065“Amenorrheawasassociatedwithimprovedsurvivalregardlessofthetreatmentandestrogen-receptorstatus.”ABCSG-12TrialDesignRecruitment1999-20061.803premenopausalpatientsStageI&II,<10posnodes,ER+and/orPgR+Durationoftreatment:3yearsPre-operativeChemoallowedBonestudyuntilJuni2003Randomize1:1:1:1Surgery(+RT)Tamoxifen20mg/dGoserelin3.6mgq28dAnastrozol1mg/d+ZoledronicAcid4mgq6m

Anastrozol1mg/dTamoxifen20mg/d+ZoledronicAcid4mgq6m

8GnantM,etal.LancetOncol2008;9:840-849GnantM,etal.NEnglJMed2009;360:679-691PrimaryEndPoint:Disease-FreeSurvival

NoSignificantDifferenceBetweenTAMandANA1009080706050403020100012243648607284Timesincerandomization,monthsDisease-freesurvival,% No. Hazardratio(95%CI) ofevents vsTAM PvalueANA 72/903 1.096(0.78to1.53) .593TAM 65/900Patientsatrisk9008407365804392641416090384974355843627115159TAMANA

9Gnantetal,AnnOncol2014MichaelGnant,BrigitteMlineritsch,HerbertStoeger,GeroLuschin-Ebengreuth,DietmarHeck,ChristianMenzel...

AdjuvantEndocrineTherapyPlusZoledronicAcidinPremenopausalWomen:62-monthResultsFromtheABCSG-12RandomizedTrialTheLancetOncology,Volume12,Issue7,2011,631-641/10.1016/S1470-2045(11)70122-XTEXTandSOFTDesignsEnrolled11/03-4/11Premenopausal<12weeksaftersurgeryPlannedOFSNoplannedchemoORplannedchemoPremenopausal<12weeksaftersurgeryNochemoORRemainpremenopausal<8mosafterchemoRANDOMIZERANDOMIZETEXT:2672SOFT:3047JointAnalysisN=4690MedianFU5.7yearsPaganietal,ASCO2014+NEJM2014,Francisetal,SABCS2014+NEJM2014SOFTPrimaryAnalysisN=2033MedianFU5.6yearsTamoxifen+OFSx5yrExemestane+OFSx5yrTamoxifenx5yrs

(1018)Tamoxifen+OFSx5yr(1015)Exemestane+OFSx5yr(1014)SanAntonioBreastCancerSymposium,December9-13,2014OvarianSuppression+AI

vsOvarianSupression+TAMPremeno.ER10%and/orPgR10%Patientswithestradiol(E2)inthepremenopausalrangeeitherafterCTorwithoutCTRA

N

D

O

M

I

Z

ETx5yOFS+Tx5yOFS+Ex5yAnyCTPremenopausalNoCTStrata*Paganietal,ASCO2014andNEJM2014TEXTTrialResultsPaganietalNEJM2014Nodifferenceoverallsurvival,HR1.14ResultsoftheCoxProportional-HazardsModelfortheComparisonofDisease-freeSurvival,AccordingtoTreatmentGroup,amongAllPatientsandAccordingtoPatientCohort.PaganiOetal.NEnglJMed2014;371:107-118.ExemestaneBetterInAllSubgroupsAdverseEventsonTEXTSimilarnumberofgrade3or4eventsMostfrequent:hotflashes,musculskeletalsymptoms,hypertensionDepressionin50%,grade3or4only4.1%Osteoporosis13.2%onexemestane;6.4%tamoxifenExemestanearmhadmorefractures,musculoskeletalsymptoms,vaginaldryness,libido,dyspareuniaTamoxifenhasmorethromboembolicevents,hotflashes,sweating,urinaryincontinencePaganietalNEJM2014RA

N

D

O

M

I

Z

ETamoxifenx5yOFS=ovarianfunctionsuppression(GnRHtriptorelin,oophorectomyorirradiation)3047PatientsRandomizedinITT,Dec2003-Jan2011Medianfollow-up5.6yearsSOFT:SUPPRESSIONofOVARIANFUNCTIONTRIAL

PremenopausalER+veand/orPR+veBreastCancerExemestane+OFSx5yTamoxifen+OFSx5yNoChemotherapyPriorChemotherapyPremenopausal,within12weeksofsurgery(Mediantimesincesurgery=1.8months)Premenopausal*aftercompletingchemotherapy;Randomizationwithin8monthsofcompletion(Mediantimesincesurgery=8.0months)(n=1018)(n=1015)PrimaryAnalysis(n=2033)TwoPatientCohorts(stratified)(n=1014)*Accordingtolocally-determinedE2levelinpremenopausalrange(47%)(53%)SOFT:PrimaryAnalysis:Disease-freeSurvivalPrimaryanalysisinoverallpopulationnotsignificant(p=0.10)MultivariableCoxmodelHR=0.78(95%CI0.62-0.98)p=0.03Francisetal,NEJM2015T+OFSvT:19%relativereductioninBCrecurrence,p=0.09E+OFSvT:36%relativereductioninBCrecurrence,5yBCFI>90%SecondaryObjectivesPremenopausalNoChemotherapyCohortselectedforlowriskclinicopathologicfeatures90%≥age40yr,91%nodenegative,85%tumor≤2cm,41%grade1PremenopausalafterPriorChemotherapyT+OFSvT:Absoluteimprovementin5-yrBCFIof4.5%E+OFSvT:Absoluteimprovementin5-yrBCFIof7.7%and5-yrDRFIof4.2%350patients(11.5%)underage3594%receivedchemotherapyinthisagegroupAllwomen<35yearsofageHowtoInterpretSOFTandTEXT?TamoxifenaloneLowerriskdisease(nodenegativeand/orlimitednodalinvolvementOlder(butstillpremenopausalNochemotherapygivenLowriskbygeneprofile??HowtoInterpretSOFTandTEXT?OvariansuppressionplustamorAIHigheranatomicriskbasedonsizeandnodalstatusChemotherapyadministered(presumablybecauseofsize