乳腺癌新輔助治療臨床思路課件

乳腺癌新輔助治療臨床思路乳腺癌新輔助治療臨床思路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)絕經前64(71.1%)59(65.6%)22(66.7%)絕經后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網站顯示全球目前正在進行中的總共有15項乳腺癌新輔助化療的III期臨床試驗其中有7項是基于分子分型的試驗，受試對象為三陰性乳腺癌或HER2陽性乳腺癌未進行分子分型的試驗8項，其中5項新藥試驗，3項尋求驗證新的分子標志物的指導意義的試驗，1項研究雙膦酸鹽療效的試驗已經沒有正在進行中的非基于分子分型的標準化療的乳腺癌新輔助化療臨床試驗ClinicalT網站顯示全球目前正在進行中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、隨機、對照試驗，新輔助治療樣本量：512主要研究終點：pCR率ABCSG-24試驗：主要研究終點的亞組分析N=512分層因素：月經狀態(tài)激素受體狀態(tài)組織學分級

HER2受體狀態(tài)

研究點6x表柔比星多西他賽手術HER2(-)HER2(+)HER2(-)HER2(+)曲妥珠單抗安慰劑6x表柔比星多西他賽卡培他濱N=89隨機化隨機化活檢StegerGG,etal.ASCO2010Abst530.1.2.2III期、隨機、對照試驗，新輔助治療ABCSG-24試驗：26253005101520患者(%)EDEDCpCR16.024.3p=0.02EDC方案對于特定患者可以顯著提高pCR率StegerGG,etal.ASCO2010Abst530.OR95%CIP值腫瘤較小0.610.44-0.84<0.003組織學類型：導管0.390.16-0.930.03HR(-)0.210.14-0.34<0.0001病理分化級別G33.672.3-5.9<0.0001經logist回歸模型分析無關臨床淋巴結狀態(tài)、停經狀態(tài)以及HER2受體狀態(tài)均可從EDC方案中獲得一致的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