胡夕春：癌症三阴性的医学治疗

MedicalTreatmentfor

TripleNegativeBreastCancerXichunHuFudanUniversityShanghaiCancerCenterGoldhirschA,etal.AnnOncol2011;22:1736-1747.DefinitionofTNBCERandPR：IHC

<1%positiveHER2：IHC0/1+;if2+,noamplificationwithFISHTNBC

andbasal-likePerouC,TheOncologist2011;16(Supple1):61–70.LuminalBasal-likeHER2-enrichedClaudin-lowHER2BasalLuminalProliferationClaudin3Claudin4Claudin7E-CadherinNormalBreast-likeTNBCBasal-likeBRCA1NormallikeClaudin-lowHER2-enrichedLuminalBRCA1TNBC,80%overlappingwithbasal-likeOverlappingTNTstudy:174(82.9%)of210TNBCpatientswerebasal-likeasdeterminedbyPAM50.CALGBstudy：87%of360TNBCpatientswerebasal-likeasdeterminedbyPAM50.

ClinicalfeatureofTNBCTNBC,10-20%Mostlyinpatientsyoungerthan40yearsMorecommoninHispanicsandblacksTNBC10-20%TNBCFoulkesWD,etal.NEnglJMed2010;363:1938-1948.SchneiderBP,etal.ClinCancerRes2008;14(24):8010-8018.Morevisceraldiseases，esp.lungandbrain,lessboneECOG1199:overallsurvival10yFU:TNBC(n=1025)SparanoJA,etal.SABCS2014S3-03.0.80.60.40.20.00246810120.80.60.40.20.0024681012随机化后时间(年)随机化后时间(年)1.01.0OSDFSP365.6%(59.2-71.2)10年%95%CIP175.1%(69.4-79.9)D368.7%(62.3-74.2)D168.6%(62.1-74.1)LogrankP=0.094P358.7%(52.1-64.6)10年%95%CIP169.0%(63.0-74.3)D362.3%(55.6-68.2)D158.8%(50.0-63.1)LogrankP=0.032511.520.95(0.70,1.28)0.93(0.69,1.25)0.69(0.50,0.94)511.520.99(0.75,1.30)0.94(0.71,1.23)0.69(0.52,0.91)HR(95%CI)HR(95%CI)OS:D1/P3OS:D3/P3OS:P1/P3DFS:D1/P3DFS:D3/P3DFS:P1/P3D3/P3HR&95%CID1/P3HR&95%CIP1/P3HR&95%CITITAN:Adjuvantixabepilone<br/>fortriple-negativebreastcancerPresentedByHaroldBursteinat2015ASCOAnnualMeetingTITAN:OutcomesPresentedByHaroldBursteinat2015ASCOAnnualMeetingAdjuvantchemotherapyforTNBCIndication:T>0.5cmIntermediaterisk:ACq3kx4>wPTX

Highrisk:ACq2kx4>wPTXPatientpreferenceBRCA1-deficientcellline

PoorresponsetoDNAdamageControlCisplatinRTBRCA1wildtypeBRCA1-deficientBhattacharyyaA,etal.JBiolChem2000;275(31):23899-23903.Morefluorescences,morerepairSynergisticeffects

betweencisplatinandgemcitabineAlliE,etal.BMCPharmacol2011Jul19;11:7.AdditiveAntagonistsynergisticBCRA-deficientcelllines0.0030.0020.001000.10.20.30.40.5Gemcitabine

(um)Cisplatin

(um)Platinum-basedneoadjuvantchemotherapyfortriple-negativebreastcancerStudyPopulationRegimenNo.PatientspCRByrskietal.JCO2010BRCA1+CMF147%AC2322%FAC2821%AT258%CDDP1283%Strohetal.AnnOncol2008TNECisF17(17%)Silveretal.JCO2010TNCisplatin2821%Ryanetal.ProcASCO2009TNCisplatin+Bev5116%TNT：phaseIIItrialcomparingcarboplatinanddocetaxelintreatmentofrecurrentorlocallyadvancedtriple-negativeorBRCA1/2mutantbreastcancerTuttA,etal.2014SABCSS3-01.PFSTuttA,etal.2014SABCSS3-01.30691215180020406080100Time(m)PFS

(%)MedianPFSCBP：3.1m

(95%CI:2.5-4.2)DOC：4.5m

(95%CI:4.1-5.2)CBP

(181/188)DOC

(182/188)OSTuttA,etal.2014SABCSS3-01.30691215180020406080100Time(m)OS

(%)CBP

(152/188)DOC

(151/188)ORR

–BRCA1/2

statusTuttA,etal.2014SABCSS3-01.0102030405060708017/25(68.0%)6/18(33.3%)36/128(28.1%)53/145(36.6%)CBPDOCBRCA1/2Mutation(N=43)Difference34.7%(95%CI:6.3-63.1)P=0.03PFS：BCRA1/2status随机治疗与BCRA1/2状态交互检验(限制平均生存)：P=0.03TuttA,etal.2014SABCSS3-01.1008060402000183691215随机化后时间(月)PFS(%)CBP+BRCA1/2

mutationmPFS=6.8m

(95%CI:4.4-8.1)CBP+BRCA1/2

nomutationmPFS=3.1m

(95%CI:2.4-4.2)DOC+BRCA1/2

mutationmPFS=4.8m

(95%CI:2.2-7.2)DOC+BRCA1/2

nomutationmPFS=4.6m

(95%CI:4.2-5.5)GemcitabinewithCisplatinorPaclitaxelasFirst-lineTreatmentforTNBCHuXetal.360PD.ClinicalT:NCT01287624.q21dMaincriteria:18-70yearsfemaleTNBCbylocalassessmentNopriorCTforMBCRECIST1.1measurablediseaseECOGPS≤1PD,8cycles,orunacceptabletoxicityGTGEM1250mg/m2D1,8PTX175mg/m2(3hr)D1GPGEM1250mg/m2D1,8DDP75mg/m2(2hr)D1Primaryendpoint：PFSSecondaryendpoint：ORR，OS,SafetyRCBCSG006

PFSandOSintheGPandGTarmsORRs:67.9%(76/112)vs.50.4%(58/115),P=0.008mPFS,201events,7.73vs.6.47m,P=0.009;HR0.692,95%CI0.523-0.915mOS,97events,22.40vs.18.53m,P=0.611;HR=0.902,95%CI0.605-1.344HuXetal.360PD.ClinicalT:NCT01287624.1.00.80.60.40.20.002004006008001000PFS(days)1.00.80.60.40.20.0020040060080010001200OS(days)SurvivalFunctionsCumSurvivalGTGPGT-censoredGP-censoredGTGPGT-censoredGP-censoredSurvivalFunctionsCumSurvivalConclusionsGPregimenisbetterthanGTregimenintermsofobjectiveresponseandPFS,whichmetourprimaryendpoint.Thetoxicityprofileofthetworegimenswasdifferentwithoutanyunexpectedfindings.First-lineGPvsGCforTNBCGCGPBSI201CBCSG006DoseGEM1000d1,8CBPAUC2d1,8GEM1250d1,8DDP75d1Patients149118ORR30.2%(1stor2nd)67.2%mPFS4.6m7.73m

O’ShaughnessyJetal.JCO2014,PlatinumsformTNBCCisplatinbetterthancarboplatinSynergisticeffectsbetweenGEMandDDPNCCNguidelinerecommendsGEM+CBPGemcitabinewithcisplatinisastandardregimenforChineseTNBCpatients,andpossiblyinotherethnicpopulations.ToimprovechemotherapyefficacyGCABX+CBPABX+GEMGCIXGPABX+DDPGCvsABX/CBPvsABX/GEM复发或转移性乳腺癌三阴性乳腺癌N=790Nab-PTX125mg/m2吉西他滨1000mg/m2D1,8Nab-PTX125mg/m2卡铂AUC2D1,8R吉西他滨1000mg/m2卡铂AUC2D1,8选择的方案Nab-PTX+G或者Nab-PTX+CII期III期一项国际多中心、随机、开放标签、对照的II／III期研究主要终点：PFS次要终点：ORR、OS、安全性等ClinicalT:NCT01881230GPvsABX/DDP(GAP)TNBCfirst-lineABX125mg/m2D1,8DDP75mg/m2D1RGEM1250mg/m2D1,8DDP75mg/m2D1CBCSG018RandomizedphaseIIPFSORR、OS、safetyHottopicsforplatinumsinTNBCpCRincreasecantranslatesurvivalbenefit?BRCA1/2statuscanpredictplatinumbenefit?PresentedByGunterVonMinckwitzat2015SABCSS2-04CarboplatininTNBC:PCRtoDFSSikovWMetal.SABCS2013abstrS5-01.CALGB40603Allianc