乳腺癌新辅助治疗临床思路PPT课件.pptx

乳腺癌新辅助治疗临床思路,1,Neoadjuvantoftreatmentforbreastcancer,2,Thefirstgenerationofneoadjuvantclinicaltrials-NSABP18,3,Thesecondgenerationofneoadjuvantclinicaltrials-NSABP27,4,NSABP-B18/27Neoadjuvantvsadjuvant“AC”,RastogietalJCO2008,1,Neo-adjuvant=Adjuvant,2,pCRisagoodsurrogatemarkerforlong-termoutcome,3,NSABP-27showedthattheadditionofpreoperativetaxanestoACimprovetheresponse,5,Question,Inthesecondgenerationofneoadjuvantclinical,althoughadditionoftaxanesgenerallyledtohigherpCRrates,aclinicallymeaningfulimprovementinlong-termoutcomeswasnotshownconsistentlyearlyimprovementsinpCRratescannotyetactassurrogateendpointsmostneoadjuvanttrialsundertakensofarhaveenrolledunselectedpopulationsofpatients.,6,Part:Proposalforthestandardcharacterisationofthepopulationtotreat,GianniLEW,SemiglazovV,etal.SABC2008(abstract31/LeoneJPetal.JClinOncol27:15s,2009(suppl;abstr625)ChangHRetal.JClinOncol26:2008(May20suppl;abstr604),thegenomiccomplexityofbreastcancerhasstartedtobeappreciated,withseveralsubtypeswithspecificmolecularprofiles,7,SubtypesbyIHC-ASCO/CAPguidelines,8,ShanghaiBreastCancerSurvivalStudydatas,Suetal.BMCCancer2011,11:292,9,HER2positive4cyclesNeoTH,LuminalB4cyclesNeoXT,Tripenegative4cyclesNeoTP,Pathology,IHC,subtypesLuminalAsubtype：ER+orPR+，HER2-,Ki6716%LuminalBsubtype,Her2+:HER2+subtype：ER-PR-，HER2+TNBC：ER-、PR-、HER2-,NeoadjuvantinBC-phasetrial,10,213patients(medianfollowup24months),11,Results,12,Allpatients6377,EligiblewithknownHER2-status4387,HER2negative3060,HER2positivew/otrastuzumab665,HER2positivewithtrastuzumab662,pCR454,pCR119,pCR181,nopCR2606,nopCR546,nopCR481,pCR-Rate*14.8%,pCR-Rate*17.9%,pCR-Rate*27.3%,*ypT0ypN0,AGO,13,OSanalysisbypCR,NopCR,pCR,n=662HER2+withtrastuzumabn=3060HER2negativen=665HER2+;notrastuzumab,Log-rankvsp=0.058vsp=0.134,vsp=0.295vsp=0.384,14,ClinicalT网站显示全球目前正在进行中的总共有15项乳腺癌新辅助化疗的III期临床试验其中有7项是基于分子分型的试验，受试对象为三阴性乳腺癌或HER2阳性乳腺癌未进行分子分型的试验8项，其中5项新药试验，3项寻求验证新的分子标志物的指导意义的试验，1项研究双膦酸盐疗效的试验已经没有正在进行中的非基于分子分型的标准化疗的乳腺癌新辅助化疗临床试验,15,Part:ProposalforUseofthefunctionalandmolecularimagineasendpoint?,MRI-Ultrasonography-Mammography-PET-CT-Mammography,Iscontroversialwithrespecttobothassessmentofdiseaseextentandresponsetotreatment.False-positivefindingsonbreastMRIcanariseafterneoadjuvantchemotherapy.Itcouldoverestimatetheextentofresidualdisease.FindingssuggestthatthevalueofMRIcouldbeofparticularimportanceforsomeBCsubtype.MRItobethemostpromisingresearchimagingmethodtoinvestigateintheneoadjuvantsettingatpresent,tendstooverestimateresidualtumourvolumeand,comparedwithmammographyandMRI,ithasthehighestrateoffalse-positivefindingsandlowspecificity,specificityofmammographyislowandpredictionofpathologicaloutcomeispoor,especiallywhencalcificationsarepresent.,Resultsavailableonuseof(FDG)PET-CTintheneoadjuvantsettingarecontradictory,16,Part:ProposalforUseofthefunctionalandmolecularimagineasendpoint?,PETCT-haveshownthatmetabolicinformationobtainedfromFDG-PETprovidesareliablemarkeroftumourviabilityandtreatmentresponse,beingassociatedwithresponsetoneoadjuvantchemotherapyatanearlystage,andaccuratelyvisualisinglymph-nodemetastases2CurrentguidelinesdonotsupportuseofFDG-PETorFDG-PETwithCTforstagingofbreastcancerbecauseofthehighfalse-negativeratefordetectionoflesionsthataresmall(1cm)orlowgrade,therelativelylowsensitivityfordetectionofaxillarynodalmetastases,1,NationalCancerInstitute.Breastcancertreatment(PDQ).Nov21,20112,DuchJ,etal.EurJNuclMedMolImaging2009;36:155157.3,StraverME,etal.EurJNuclMedMolImaging2010;37:106976.,17,StudyN=71patients,N=71evaluable,PETCTstudy71patientsbeforeneochemothearpy,4cyclesneo,OurPETimagingstudy,ThechangesintheglucoseuptakevalueshouldbeassociatedwiththetumorsrespondtoNAC,weconductedthisretrospectivestudytoinvestigatethevalueofPETimagingintheevaluationofrespondtoNACinbreastcancer.,histologicaldiagnosisandsubtypebyIHCofbreastcancerbycoreneedlebiopsy,18,Characteristicsofpatients,19,Primaryresult-ForallcasesAUC,Figure.1.Thereceiveroperatingcharacteristiccurveoftheoverallpredictivevalueofallthecasesinthestudy.Theareaundercurveis0.697,thesensitivityis0.72,whilethespecificityis0.674.95%CI:0.568-0.826,negativepredictivevalueis95.1%,positivepredictivevalueis32.4%.,20,TheSUVdecreaserateandtumorresponse,ReceiveroperatingcharacteristiccurvebetweenSUVdecreaserateandpathologiccompleteresponse.TheAUCis0.797andrevealsasensitivityof0.852andspecificityof0.453.,21,ROCcurvesofdifferentsubtypes,AHER2:Areaundercurve:0.679;Sensitivity:0.500;Specificity:0.857;95%CI:0.370-0.987BLuminalA:Areaundercurve:0.188;Sensitivity:0.00;Specificity:0.375;95%CI:0.00-1.00CLuminalB:Areaundercurve:0.889;Sensitivity:1.00;Specificity:0.778;95%CI:0.353-0.916DTriplenegative:Areaundercurve:0.875;Sensitivity:1.00;Specificity:0.750;95%CI:0.00-1.00,A,B,C,D,22,Part:ProposalforUseofthefunctionalandmolecularimagineasendpoint?Inourstudy-conclusions,ForPETCT,themetabolicresponseobtainedontheendofneoadjuvantchemotherapymaybeusefulindetermininghistopathologicnon-responderswithhighnegativepredictivevalueof95.1%DifferentmolecularphenotypesbasedonIHCreflectdifferentmetabolicproperties.Asourresult,theluminalBsubtypeobtainabestpredictivevalue,thelessproliferationsubgroupluminalAweretheworst.3.PETCTmaybeagoodfunctionalandmolecularimagineasthepredicitiveresponseforLuminalB/TNBCsubtypes,23,Part:Proposalforthestandardevaluationoftheresponsetotreatment1,PCR,Anintermediateendpointforbreastcancerrelapseandsurvival-ToassessthepathologicalresponsetoneoadjuvanttreatmentandtodefinePCRvariesbetweenclinicaltrials,24,Part:Evaluationoftheresponsetotreatment1,PCR,Node-negativestatusaftertreatmenthaveexcellementsurvival-Retrospectiveanalysisofadatabaseincluding2302patientswithneoadjuvantchemotherapyatMDAndersonCancerCenterindicatednosignificantdifferenceinDFSandOSbetweenPCRandresidualDCIS,25,III期、随机、对照试验，新辅助治疗样本量：512主要研究终点：pCR率,ABCSG-24试验：主要研究终点的亚组分析,N=512分层因素：月经状态激素受体状态组织学分级HER2受体状态研究点,6x表柔比星多西他赛,手术,HER2(-),HER2(+),HER2(-),HER2(+),曲妥珠单抗,安慰剂,6x表柔比星多西他赛卡培他滨,N=89,随机化,随机化,活检,StegerGG,etal.ASCO2010Abst530.,1.2.2,26,患者(%),EDEDCpCR,16.0,24.3,p=0.02,EDC方案对于特定患者可以显著提高pCR率,StegerGG,etal.ASCO2010Abst530.,经logist回归模型分析,无关临床淋巴结状态、停经状态以及HER2受体状态均可从EDC方案中获得一致的pCR,27,Part:Evaluationoftheresponsetotreatment2,Ki-67,ThestandardcutoffforthevalueofKi67asaresponseendpoint?,MeasurementofKi67,28,Part:Evaluationoftheresponsetotreatment3,PreoperativeEndocrinePrognosticIndex(PEPI),Predictlong-termoutcome(relapse-free/OS)inpatientstreatedwithneoadjuvantEndocrinetherapy:Ki67indexPathologicaltumorsizeNodalstatusERstatus,29,Part:Standardevaluationoftheresponsetothetreatmentconclusion,30,Part:Standarddefinitionofsurvivalendpoint?-islacking,STEEPsystem-standardiseddefinitionforefficacyendpointIssue:howtodefinethestartingpointforassessmentoftime-to-ev