乳腺癌新辅助治疗临床思路课件

乳腺癌新辅助治疗临床思路乳腺癌新辅助治疗临床思路1NeoadjuvantoftreatmentforbreastcancerNeoadjuvantoftreatmentforb2Thefirstgeneration

ofneoadjuvantclinicaltrials

-

NSABP18Thefirstgeneration

ofneoad3Thesecondgenerationof

neoadjuvantclinicaltrials-NSABP27Thesecondgenerationof

neo4NSABP-B18/27

Neoadjuvantvsadjuvant“AC”RastogietalJCO20081,Neo-adjuvant=Adjuvant2,pCRisagoodsurrogatemarkerforlong-termoutcome3,NSABP-27showedthattheadditionofpreoperativetaxanestoACimprovetheresponseNSABP-B18/27

Neoadjuvantvsad5QuestionInthesecondgenerationofneoadjuvantclinical,althoughadditionoftaxanesgenerallyledtohigherpCRrates,aclinicallymeaningfulimprovementinlong-termoutcomeswasnotshownconsistentlyearlyimprovementsinpCRratescannotyetactassurrogateendpointsmostneoadjuvanttrialsundertakensofarhaveenrolledunselectedpopulationsofpatients.QuestionInthesecondgenerati6PartⅠ:Proposalforthestandard

characterisationofthepopulationtotreatGianniLEW,SemiglazovV,etal.SABC2008(abstract31/LeoneJPetal.JClinOncol27:15s,2009(suppl;abstr625)ChangHRetal.JClinOncol26:2008(May20suppl;abstr604)thegenomiccomplexityofbreastcancerhasstartedtobeappreciated,withseveralsubtypeswithspecificmolecularprofilesPartⅠ:Proposalforthestanda7SubtypesbyIHC

-ASCO/CAPguidelinesSubtypesbyIHC

-ASCO/CA8ShanghaiBreastCancerSurvivalStudydatasSuetal.BMCCancer2011,11:292/1471-2407/11/292ShanghaiBreastCancerSurviva9HER2positive4cyclesNeoTHLuminalB4cyclesNeoXTTripenegative4cyclesNeoTPPathology,IHCsubtypesLuminalAsubtype：ER+orPR+，HER2-,Ki67<14%LuminalBsubtype：ER+orPR+，HER2-,Ki67>16%LuminalBsubtype,Her2+:HER2+subtype：ER-PR-，HER2+TNBC：ER-、PR-、HER2-NeoadjuvantinBC-phaseⅡtrialHER2positiveLuminalBTripeneg10SubtypesLuminalBHER2+veTNBCregimesCapecitabine+DocetaxelPaclitaxel+TrastuzumabPaclitaxel+DDPnumbers90(42%)90(42%)33(16%)Medianage45

(26-69)47

(26-76)46

(29-66)绝经前64(71.1%)59(65.6%)22(66.7%)绝经后26(28.9%)31(34.4%)11(33.3%)Grade117(18.9%)0(0%)0(0%)

261(67.8%)69(76.7%)19(57.6%)

312(13.3%)21(23.3%)14(42.2%)TumorsizeT19(10%)7(7.8%)4(12.1%)T266(73.3%)58(64.4%)21(63.6%)T39(10%)16(17.8%)4(12.1%)T46(6.7%)9(10.0%)4(12.2%)NodeN045(50%)39(43.3%)18(54.5%)N136(40%)40(44.4%)12(36.4%)N25(5.6%)8(8.9%)1(3.0%)N34(4.4%)3(3.3%)2(6.1%)Stage

II71(78.9%)66(73.3%)25(75.8%)III19(21.1%)24(26.7%)8(24.2%)213patients(medianfollowup24months)SubtypesLuminalBHER2+veTNBCre11SubtypesLuminalBHER2+veTNBCRegimesXTTHTPnumber90(42%)90(42%)33(16%)clinicalCR19(21.1%)47(52.2%)14(42.4%)PR52(57.8%)36(40.0%)14(42.4%)SD18(20%)7(7.8%)5(15.2%)PD1(1.1%)0(0%)0(0%)pathologypCR13(14.4%)39(43.3%)11(33.3%)non-pCR77(85.6%)51(56.7%)22(66.7%)BreastpCR20(22.2%)40(44.4%)20(60.6%)TotalpCR29.6%(61/213)ORR85.4%(182/213)ResultsSubtypesLuminalBHER2+veTNBCR12Allpatients6377EligiblewithknownHER2-status4387HER2negative3060HER2positivew/otrastuzumab665HER2positivewithtrastuzumab662pCR454pCR119pCR181nopCR2606nopCR546nopCR481pCR-Rate*14.8%pCR-Rate*17.9%pCR-Rate*27.3%*ypT0ypN0AGOAllpatientsEligiblewithknow13OSanalysisbypCRArmNEventspositivewtrast48135positivew/otrast54675negative 2606310NopCRArmNEventspositivewtrast

1811positivew/otrast1199negative 45414pCR

n=662HER2+withtrastuzumabn=3060HER2negativen=665HER2+;notrastuzumabLog-rankvsp=0.058vsp=0.134

vsp=0.295vsp=0.384

OSanalysisbypCRArmNEventspo14ClinicalT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ClinicalT网站显示全球目前正在进行中15PartⅡ:ProposalforUseofthefunctionalandmolecularimagineasendpoint?MRI-Ultrasonography-Mammography-

PET-CT-

MammographyIscontroversialwithrespecttobothassessmentofdiseaseextentandresponsetotreatment.False-positivefindingsonbreastMRIcanariseafterneoadjuvantchemotherapy.Itcouldoverestimatetheextentofresidualdisease.FindingssuggestthatthevalueofMRIcouldbeofparticularimportanceforsomeBCsubtype.MRItobethemostpromisingresearchimagingmethodtoinvestigateintheneoadjuvantsettingatpresent

tendstooverestimateresidualtumourvolumeand,comparedwithmammographyandMRI,ithasthehighestrateoffalse-positivefindingsandlowspecificityspecificityofmammographyislowandpredictionofpathologicaloutcomeispoor,especiallywhencalcificationsarepresent.Resultsavailableonuseof(FDG)PET-CTintheneoadjuvantsettingarecontradictoryPartⅡ:ProposalforUseofth16PartⅡ:ProposalforUseofthefunctional

andmolecularimagineasendpoint?PETCT-haveshownthatmetabolicinformationobtainedfromFDG-PETprovidesareliablemarkeroftumourviabilityandtreatmentresponse,beingassociatedwithresponsetoneoadjuvantchemotherapyatanearlystage,

andaccuratelyvisualisinglymph-nodemetastases2CurrentguidelinesdonotsupportuseofFDG-PETorFDG-PETwithCTforstagingofbreastcancerbecauseofthehighfalse-negativeratefordetectionoflesionsthataresmall(<1cm)orlowgrade,therelativelylowsensitivityfordetectionofaxillarynodalmetastases1,NationalCancerInstitute.Breastcancertreatment(PDQ).Nov21,20112,

DuchJ,etal..EurJNuclMedMolImaging2009;36:1551–57.3,

StraverME,etal.EurJNuclMedMolImaging2010;37:1069–76.PartⅡ:ProposalforUseofth17StudyN=71patientsN=71evaluablePETCTstudy71patientsbeforeneochemothearpy4cyclesneoOurPETimagingstudy

Thechangesintheglucoseuptakevalueshouldbeassociatedwiththetumor’srespondtoNAC,weconductedthisretrospectivestudytoinvestigatethevalueofPETimagingintheevaluationofrespondtoNACinbreastcancer.histologicaldiagnosisandsubtypebyIHCofbreastcancerbycoreneedlebiopsyStudyN=71evaluablePETCTst18

CharacteristicsofpatientsCharacteristicsofpatients19Primaryresult-ForallcasesAUCFigure.1.Thereceiveroperatingcharacteristiccurveoftheoverallpredictivevalueofallthecasesinthestudy.Theareaundercurveis0.697,thesensitivityis0.72,whilethespecificityis0.674.95%CI:0.568-0.826,,negativepredictivevalueis95.1%,positivepredictivevalueis32.4%.

Primaryresult-Forallcases20TheSUVdecreaserateandtumorresponse

ReceiveroperatingcharacteristiccurvebetweenSUVdecreaserateandpathologiccompleteresponse.TheAUCis0.797andrevealsasensitivityof0.852andspecificityof0.453.TheSUVdecreaserateandtumo21ROCcurvesofdifferentsubtypesAHER2: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:0.00-1.00ABCDROCcurvesofdifferentsubtyp22PartⅡ:ProposalforUseofthefunctionalandmolecularimagineasendpoint?

Inourstudy-conclusionsForPETCT,themetabolicresponseobtainedontheendofneoadjuvantchemotherapymaybeusefulindetermininghistopathologicnon-responderswithhighnegativepredictivevalueof95.1%DifferentmolecularphenotypesbasedonIHCreflectdifferentmetabolicproperties.Asourresult,theluminalBsubtypeobtainabestpredictivevalue,thelessproliferationsubgroupluminalAweretheworst.3.PETCTmaybeagoodfunctionalandmolecularimagineasthepredicitiveresponseforLuminalB/TNBCsubtypesPartⅡ:ProposalforUseofth23PartⅢ:Proposalforthestandardevaluation

oftheresponsetotreatment

1,PCRAnintermediateendpointforbreastcancerrelapseandsurvival-ToassessthepathologicalresponsetoneoadjuvanttreatmentandtodefinePCRvariesbetweenclinicaltrialsPartⅢ:Proposalforthestan24PartⅢ:Evaluationoftheresponsetotreatment

1,PCRNode-negativestatusaftertreatmenthaveexcellementsurvival-Retrospectiveanalysisofadatabaseincluding2302patientswithneoadjuvantchemotherapyatMDAndersonCancerCenterindicatednosignificantdifferenceinDFSandOSbetweenPCRandresidualDCISPartⅢ:Evaluationoftheresp25III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.ASCO2010Abst530.1.2.2III期、随机、对照试验，新辅助治疗ABCSG-24试验：26253005101520患者(%)EDEDCpCR16.024.3p=0.02EDC方案对于特定患者可以显著提高pCR率StegerGG,etal.ASCO2010Abst530.OR95%CIP值肿瘤较小0.610.44-0.84<0.003组织学类型：导管0.390.16-0.930.03HR(-)0.210.14-0.34<0.0001病理分化级别G33.672.3-5.9<0.0001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pCR253005101520患者(%)E27PartⅢ:Evaluationoftheresponsetotreatment

2,

Ki-67ThestandardcutoffforthevalueofKi67asaresponseendpoint?MeasurementofKi67PartⅢ:Evaluationoftheresp28PartⅢ:Evaluationoftheresponsetotreatment

3,PreoperativeEndocrinePrognosticIndex(PEPI)Predictlong-termoutcome(relapse-free/OS)inpatientstreatedwithneoadjuvantEndocrinetherapy:Ki67indexPathologicaltumorsizeNodalstatusERstatusPartⅢ:Evaluationoftheresp29PartⅢ:Standardevaluationofthe

responsetothetreatment

conclusionPartⅢ:Standardevaluationof30PartⅣ:Standarddefinitionofsurvivalendpoint?

-islackingSTEEPsystem-standardiseddefinitionforefficacyendpointIssue:howtodefinethestartingpointforassessmentoftime-to-eventdata-DFShasbeendefinedinconsistentlyeitherfromthedateofstudyentryorfromthedateofsurgery-STEEPsysteminadjuvantsetting,thest