大四下乳腺多学科治疗选修课

乳腺癌的治疗

从外科走向多学科沈坤炜上海交通大学医学院附属瑞金医院乳腺疾病诊治中心BreastCancerisChangingFace2007TrendsofIncidencebyAgein5-yearIntervalPeriods,1973-2007inShanghaiTwopeaksbegantomergeintooneAgeneralelevationamong45-80LocalRecurrenceRatesColumbiaClinicalClassification

FIVEGRAVESIGNSEdemaofskin(<1/3)SkinulcerationFixationoftumortochestwallMassiveaxillarylymphnodeinvolvement(2.5cm)Fixationofaxillarynodes1915-1942HaagensenInoperableBreastCancerTwoormoregravesignsExtensiveedemaofskin(>1/3)SatelliteskinnodulesInflammatorycarcinomaSupraclavicularlymphnodesInternalmammary/parasternaltumorEdemaofarmDistantmatastasesMultidisciplinaryManagementofBreastCancerUmbertoVeronesiHeadoftheNationalCancerInstituteinMilanThedirectoroftheEuropeanInstituteofOncology

ComparingRadicalMastectomywithQuadrantectomy,-AxillaryDissection,andRadiotherapyinPatientswithSmallCancersoftheBreastNewEnglandJournalofMedicine1981;305:6-11701patientsCALN(—)T≤2cm(1973-1980)Halstedmastectomy(349pts)Q.+ALND+RT(352pts)Result:NSin7.5yearssurvivalrateNSABPB-061976-1984N=1,851MultidisciplinaryManagementofBreastCancerBreastReconstructionMultidisciplinaryManagementofBreastCancerLymphaticMappingandSentinelNodeBiopsyThe“sentinel”nodeisthefirstnodetoreceivelymphaticdrainagefromaprimarytumor.Thus,itisthefirstnodetowhichatumorwillmetastasize.Ifthesentinelnodeisnegativeformetastaticdisease,theremainingnodesinthelymphaticbasinarealsolikelytobenegative.SentinelLymphNodeBiopsyMultidisciplinaryManagementofBreastCancerBonadonna:CMFTrial Total Failures

ControlGroup 179 43 CMF 207 1 p=0.00002GBonadonnaetal.NEJM1976,updated:NEJM19951970’sCMF1980’sAC1990’sACT2000’sACTdd2000’sTAC2009TACvTCvTCB

EBCTCGMeta-Analysis2005-06

BreastCancerMortalityPetoRonbehalfoftheEarlyBreastCancerTrialists’CollaborativeGroup(EBCTCG).PresentedatSABCS2007,December13,2007.SanAntonio,TX.Deathrates(%/year:total–rateinwomenwithoutrecurrence)&logrankanalysesTaxanes>Anthra.>CMF>NoChemo.MultidisciplinaryManagementofBreastCancerSurrogateDefinitionsOfIntrinsicSubtypesOfBreastCancer2011ER,PR,HER,andKi67Surrogatedefinitionsofintrinsicsubtypes2013IntrinsicsubtypeClinico-pathologicsurrogatedefinitionNotesLuminalAER&PRposHER2negKi-67lowRecurrencerisklow*AlevelofKi-67<14%bestcorrelatedwiththegene-expressiondefinitionofLuminalA.PRcut-pointof≥20%bestcorrespondtoLuminalAsubtype.LuminalBHER2neg:ERposHER2negOneof:Ki-67high/PRnegorlow/Recurrenceriskhigh*HER2pos:ERposHER2

posEitherahighKi-67valueoralowPRvaluemaybeusedtodistinguishbetween‘LuminalA-like’and‘LuminalB-like(HER2negative)’.Erb-B2overexpressionHER2posER&PRnegBasal-likeER&PRnegHER2neg80%overlapbetween‘TN’andintrinsic‘basal-like’subtype.‘TN’alsoincludessomespecialhistologicaltypessuchasadenoidcysticcarcinoma.SystemicTreatmentmendationsforSubtypesSystemictreatmentmendations2013SubtypeTypeoftherapyNotesontherapyLuminalAET:mostcriticalandoftenusedaloneRelativeindicationsforcytotoxics(amajority)(i)high21-geneRS(i.e.>25);(ii)70-genehighriskstatus;(iii)grade3;(iv)≥4LN(aminorityrequiredonlyonenode).LuminalB(HER2neg)ETforall,CTformostLuminalB(HER2pos)CT+anti-HER2+ETNodataareavailabletosupporttheomissionofcytotoxicsinthisgroup.HER2pos(non-luminal)CT+anti-HER2Thresholdforuseofanti-HER2therapywasdefinedaspT1borlargertumourornode-positivity.Triplenegative(ductal)CT‘Specialhistologicaltypes’A.EndoresponsiveB.Endonon-responsiveETCTAdenoidcysticcarcinomasmaynotrequireanyadjuvantcytotoxics(ifnodenegative).MultidisciplinaryManagementofBreastCancerBreastCancerDiseases–201…AllBreastCancersER+65-75%HER2+15-20%Triplenegative15%HER3+IGFR1+p95+4%P53mut30-40%FGFR1Ampl8%PTENloss30-50%PI3Kmut10%BRCAMut8%BiochimicaetBiophysicaActa1795(2009)62–81

ERsignalingpathwayEstrogensignalingpathwayOsborneCK,SchiffR.Annu.Rev.Med.201162:233-47.geneamplification

overexpression

ofHER2protein

(10-foldto100-fold)NORMALCELLTUMORCELLHER2geneHER2proteinHerceptin

monoclonalantibody

selectivelytargets

theextracellular

domainofthe

HER2proteinNUCLEOLUSCELLSURFACEWITHEXTRACELLULARDOMAINS

OFHER2PROTEINHER2HER2HER2HER2HER2HER2HER2HER2Herceptin®MechanismofActionConstitutiveactivationofdownstreamsignalingpathways5-yrTAMvs.NotinER+BreastCancerEBCTCG,Lancet,2005:1687-717TrastuzumabintheTreatmentofBreastCancerGabrielN.Hortobagyi,M.D.Theresultsaresimplystunning.Clearly,theresultsreportedinthisissueofthejournalarenotevolutionarybutrevolutionary.Trastuzumabandthetworeportsinthisissuewillcompletelyalterourapproachtothetreatmentofbreastcancer.Editorial,Oct20,2005EarlyDetectionTrendsinincidenceofbreastcancerinselectedcountriesTrendsinmortalityfrombreastcancerinselectedcountriesFerlayJ,etal.IntJCancer2010TrendsinMortalityandIncidencefromBreastCancerMultidisciplinaryManagementofBreastCancerMultidisciplinaryManagementofBreastCancerBreastCancerMultidisciplinaryManagement:MultidisciplinaryClinicMultidisciplinaryConference——thestandardcareofbreastcancer.MultidisciplinaryManagementofBreastCancerComprehensiveBreastHealthCenter

ShanghaiRuijinHospital

门诊日间化疗“一站式”服务病房MultidisciplinaryConferenceMultidisciplinaryConferenceGoal:TreatmentIndividualization!Movingawayfromonesizefitsall!PersonalizedRxforBreastCancer:Hope/Hype?EdithA.Perez,M.D.DeputyDirector,MayoClinicComprehensiveCancerCenterGroupViceChair,Alliancefor

ClinicalTrialsinOncologySereneM.andFrancesC.DurlingProfessorofMedicineMayoClinic

Jacksonville,FloridaPersonalizedRxforBreastCancerHype–yesHope–YES!THANKYOU“Conventional”WisdomofYesterday…BreastcancerisonediseaseOne-size-fits-alltreatmentapproachBystage,nodalstatus,andhormonereceptorstatus“ConventionalWisdom”ofToday…Breastcancerisaheterogeneousdiseasecomprisedofdifferentmolecularsubtypesbasedongene/proteinexpressionprofilingOutlineGenerallandscapeofclinicalresearchinbreastcancerProspectivebiomarkervalidation:AfielddrivenbylargeconsortiumandtrialsAdjuvanttrialsEarlydrugdevelopment:newdesignsCohorts:Anemergingresearchtoolinbreastcancerarea?TAILORxTrialMINDACTTrialRxPondersTrialIndividualizedTherapyDecisionSupportSystemClinicallyandMolecularlyAppropriateTherapyMultidisciplinaryGenomicsRoundsMoussesConfidentialMolecularPathwayKnowledgeMining

InformedConsentonUSONIRB-approvedprotocolN=1CLIACLIAvalidationIdentifyingTherapeuticTargetsonWGSofmTNBCCancerIntegratedAnalysisTumorDNA/RNAandgermlineDNALifeSOLiD4O’ShaugnessyetalProcSA2011Mole