乳腺癌新輔助治療臨床思路

Neoadjuvantoftreatmentforbreastcancer當(dāng)前1頁，總共33頁。Thefirstgeneration

ofneoadjuvantclinicaltrials

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NSABP18當(dāng)前2頁，總共33頁。Thesecondgenerationof

neoadjuvantclinicaltrials-NSABP27當(dāng)前3頁，總共33頁。NSABP-B18/27

Neoadjuvantvsadjuvant“AC”RastogietalJCO20081,Neo-adjuvant=Adjuvant2,pCRisagoodsurrogatemarkerforlong-termoutcome3,NSABP-27showedthattheadditionofpreoperativetaxanestoACimprovetheresponse當(dāng)前4頁，總共33頁。QuestionInthesecondgenerationofneoadjuvantclinical,althoughadditionoftaxanesgenerallyledtohigherpCRrates,aclinicallymeaningfulimprovementinlong-termoutcomeswasnotshownconsistentlyearlyimprovementsinpCRratescannotyetactassurrogateendpointsmostneoadjuvanttrialsundertakensofarhaveenrolledunselectedpopulationsofpatients.當(dāng)前5頁，總共33頁。PartⅠ:Proposalforthestandard

characterisationofthepopulationtotreatGianniLEW,SemiglazovV,etal.SABC2008(abstract31/LeoneJPetal.JClinOncol27:15s,2009(suppl;abstr625)ChangHRetal.JClinOncol26:2008(May20suppl;abstr604)thegenomiccomplexityofbreastcancerhasstartedtobeappreciated,withseveralsubtypeswithspecificmolecularprofiles當(dāng)前6頁，總共33頁。SubtypesbyIHC

-ASCO/CAPguidelines當(dāng)前7頁，總共33頁。ShanghaiBreastCancerSurvivalStudydatasSuetal.BMCCancer2011,11:292biomedcentral/1471-2407/11/292當(dāng)前8頁，總共33頁。HER2positive4cyclesNeoTHLuminalB4cyclesNeoXTTripenegative4cyclesNeoTPPathology,IHCsubtypesLuminalAsubtype：ER+orPR+，HER2-,Ki67<14%LuminalBsubtype：ER+orPR+，HER2-,Ki67>16%LuminalBsubtype,Her2+:HER2+subtype：ER-PR-，HER2+TNBC：ER-、PR-、HER2-NeoadjuvantinBC-phaseⅡtrial當(dāng)前9頁，總共33頁。SubtypesLuminalBHER2+veTNBCregimesCapecitabine+DocetaxelPaclitaxel+TrastuzumabPaclitaxel+DDPnumbers90(42%)90(42%)33(16%)Medianage45

(26-69)47

(26-76)46

(29-66)絕經(jīng)前64(71.1%)59(65.6%)22(66.7%)絕經(jīng)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)當(dāng)前10頁，總共33頁。SubtypesLuminalBHER2+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)Results當(dāng)前11頁，總共33頁。Allpatients6377EligiblewithknownHER2-status4387HER2negative3060HER2positivew/otrastuzumab665HER2positivewithtrastuzumab662pCR454pCR119pCR181nopCR2606nopCR546nopCR481pCR-Rate*14.8%pCR-Rate*17.9%pCR-Rate*27.3%*ypT0ypN0AGO當(dāng)前12頁，總共33頁。OSanalysisbypCRArmNEventspositivewtrast48135positivew/otrast54675negative 2606310NopCRArmNEventspositivewtrast

1811positivew/otrast1199negative 45414pCR

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

vsp=0.295vsp=0.384

當(dāng)前13頁，總共33頁。ClinicalT網(wǎng)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(biāo)志物的指導(dǎo)意義的試驗，1項研究雙膦酸鹽療效的試驗已經(jīng)沒有正在進行中的非基于分子分型的標(biāo)準(zhǔn)化療的乳腺癌新輔助化療臨床試驗當(dāng)前14頁，總共33頁。PartⅡ:ProposalforUseofthefunctionalandmolecularimagineasendpoint?MRI-Ultrasonography-Mammography-

PET-CT-

MammographyIscontroversialwithrespecttobothassessmentofdiseaseextentandresponsetotreatment.False-positivefindingsonbreastMRIcanariseafterneoadjuvantchemotherapy.Itcouldoverestimatetheextentofresidualdisease.FindingssuggestthatthevalueofMRIcouldbeofparticularimportanceforsomeBCsubtype.MRItobethemostpromisingresearchimagingmethodtoinvestigateintheneoadjuvantsettingatpresent

tendstooverestimateresidualtumourvolumeand,comparedwithmammographyandMRI,ithasthehighestrateoffalse-positivefindingsandlowspecificityspecificityofmammographyislowandpredictionofpathologicaloutcomeispoor,especiallywhencalcificationsarepresent.Resultsavailableonuseof(FDG)PET-CTintheneoadjuvantsettingarecontradictory當(dāng)前15頁，總共33頁。PartⅡ: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.當(dāng)前16頁，總共33頁。StudyN=71patientsN=71evaluablePETCTstudy71patientsbeforeneochemothearpy4cyclesneoOurPETimagingstudy

Thechangesintheglucoseuptakevalueshouldbeassociatedwiththetumor’srespondtoNAC,weconductedthisretrospectivestudytoinvestigatethevalueofPETimagingintheevaluationofrespondtoNACinbreastcancer.histologicaldiagnosisandsubtypebyIHCofbreastcancerbycoreneedlebiopsy當(dāng)前17頁，總共33頁。

Characteristicsofpatients當(dāng)前18頁，總共33頁。Primaryresult-ForallcasesAUCFigure.1.Thereceiveroperatingcharacteristiccurveoftheoverallpredictivevalueofallthecasesinthestudy.Theareaundercurveis0.697,thesensitivityis0.72,whilethespecificityis0.674.95%CI:0.568-0.826,,negativepredictivevalueis95.1%,positivepredictivevalueis32.4%.

當(dāng)前19頁，總共33頁。TheSUVdecreaserateandtumorresponse

ReceiveroperatingcharacteristiccurvebetweenSUVdecreaserateandpathologiccompleteresponse.TheAUCis0.797andrevealsasensitivityof0.852andspecificityof0.453.當(dāng)前20頁，總共33頁。ROCcurvesofdifferentsubtypesAHER2:Areaundercurve:0.679BLuminalA:Areaundercurve:0.188CLuminalB:Areaundercurve:0.889DTriplenegative:Areaundercurve:0.875;Sensitivity:1.00;Specificity:0.750;95%CI:0.00-1.00ABCD當(dāng)前21頁，總共33頁。PartⅡ:ProposalforUseofthefunctionalandmolecularimagineasendpoint?

Inourstudy-conclusionsForPETCT,themetabolicresponseobtainedontheendofneoadjuvantchemotherapymaybeusefulindetermininghistopathologicnon-responderswithhighnegativepredictivevalueof95.1%DifferentmolecularphenotypesbasedonIHCreflectdifferentmetabolicproperties.Asourresult,theluminalBsubtypeobtainabestpredictivevalue,thelessproliferationsubgroupluminalAweretheworst.3.PETCTmaybeagoodfunctionalandmolecularimagineasthepredicitiveresponseforLuminalB/TNBCsubtypes當(dāng)前22頁，總共33頁。PartⅢ:Proposalforthestandardevaluation

oftheresponsetotreatment

1,PCRAnintermediateendpointforbreastcancerrelapseandsurvival-ToassessthepathologicalresponsetoneoadjuvanttreatmentandtodefinePCRvariesbetweenclinicaltrials當(dāng)前23頁，總共33頁。PartⅢ:Evaluationoftheresponsetotreatment

1,PCRNode-negativestatusaftertreatmenthaveexcellementsurvival-Retrospectiveanalysisofadatabaseincluding2302patientswithneoadjuvantchemotherapyatMDAndersonCancerCenterindicatednosignificantdifferenceinDFSandOSbetweenPCRandresidualDCIS當(dāng)前24頁，總共33頁。III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(jīng)狀態(tài)激素受體狀態(tài)組織學(xué)分級

HER2受體狀態(tài)

研究點6x表柔比星多西他賽手術(shù)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.當(dāng)前25頁，總共33頁。253005101520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(xué)類型：導(dǎo)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(jīng)logist回歸模型分析無關(guān)臨床淋巴結(jié)狀態(tài)、停經(jīng)狀態(tài)以及HER2受體狀態(tài)均可從EDC方案中獲得一致的pCR當(dāng)前26頁，總共33頁。PartⅢ:Evaluationoftheresponsetotreatment

2,

Ki-67ThestandardcutoffforthevalueofKi67asaresponseendpoint?MeasurementofKi67當(dāng)前27頁，總共33頁。PartⅢ:Evaluationoftheresponsetotreatment

3,PreoperativeEndocrinePrognosticIndex(PEPI)Predictlong-termoutcome(relapse-free/OS)inpatientstreatedwithneoadjuvantEndocrinetherapy:Ki67indexPathologicaltumorsizeNodalstatusERstatus當(dāng)前28頁，總共33頁。PartⅢ:Standardevaluationofthe

responsetothetreatment

conclusion當(dāng)前29頁，總共33頁。Part