转移性乳腺癌的内科治疗squip

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转移性乳腺癌的化疗中山医科大学肿瘤医院内科刘冬耕 NCCN2006 蒽环类和紫杉类是主要化疗方案蒽环类单药疗效40%左右。紫杉类单药疗效33%-50%。蒽环类与紫杉类联合疗效优于蒽环类为主的联合化疗。首选的联合治疗方案CAF/FAC/FEC/CMFAC/ECPaclitaxel+ADRDocetaxel+XelodaPaclitaxel+Gemcitabine首选的单药和其他有效的药物蒽环类、紫杉类、希罗达、NVB和健择。铂类VP-16(po)、VLB、5-FU(civ) HER2阴性转移性乳腺癌的一线治疗Anthracyclines（？）TaxanesPaclitaxel/AdriamicineXeloda/Taxotere(XT)Paclitaxel/Gemcitabine（GP）XelodaCMFOtherfitterpatientswithgoodperformancestatusandrapidlyprogressingdiseaseorvisceralmetastasesmightderivemostbenefitfrommoreintensivecombinationswhereaslessfitpatientsorthosewithmoreindolentdiseasemightderivemorebenefitfromsingle-agents. 卡培他滨Capecitabine，Xeloda长春花碱酰胺Vinorebine吉西他滨Gemcitabine铂类（Cisplatin,Carpoplatin）蒽环类与紫杉类失败后的化疗选择 希罗达和泰索帝联合与泰索帝单药对照治疗蒽环类失败的MBCalargephaseIIItrialXeloda1250mg/m2bidd1-14Taxotere75mg/m2,day1q3wTaxotere100mg/m2,day1q3wPrimaryendpoint:TTP(n=255)(n=256)O’ShaughnessyJetal.JClinOncol2002;20:2812–23随机分组 XT与Taxotere对照研究结果所有病人用过蒽环类，80%内脏转移，2/3接受过2/3线研究药物治疗。单Doce更多中粒减少性发热，联合组更多3/4级腹泻、胃炎和HFS.住院和SAE发生率相当。FDA2001.09批准泰素帝/希罗达联合治疗转移性乳腺癌XTTPvalueHazardRatioORR42%30%.006TTP6.1m4.2m.0001OS14.5m11.5m.0130.77O’ShaughnessyJetal.JClinOncol2002;20:2812–23 CapecitabineinTaxane-pretreatedMetastaticBreastCancer1.BlumJLetal.EurJCancer2001;37:S190(Abstract693)2.BlumJLetal.Cancer2001;92:1759-1768.3.ReichardtPetal.AnnOncol.2003;14:1227-1233.4.FumoleauPetal.EurJCancer.2004;40:536-542.StudyNCR+PR,%DiseaseControl(CR+PR+SD),%MedianResponseDuration,mosMedianTTP,mosMedianSurvival,mosBlumetal.116220637.93.011.6Blumetal.27426578.33.212.2Reichardtetal.313615627.43.510.1Fumoleauetal.412625545.04.615.2 GemcitabineinAnthracycline/Taxane-RefractoryMBC1.ValerioMRetal.ProcAmSocClinOncol.2001.Abstract1953.2.RhaSYetal.BreastCancerResTreat.2005;90:215-221.3.ModiSetal.ClinBreastCancer.2005;6:55-60.StudyNDose*CR+PR,%Valerioetal.1261000mg/m223Rhaetal.241800mg/m220Modietal.321850mg/m217*Days1,8,and15every21days. VinorelbineinRefractoryMBCMultiplephaseIIstudies(ORR,16%-34%)Degardinetal.1(N=100)CR+PR,16%Mediandurationofresponse,5mos(range,3-18)Livingstonetal.2(N=40)CR+PR,25%MedianTTP,13weeksMediansurvival,33weeks1.Degardinetal.,AnnOncol.1994;5:423-426.2.LivingstonRBetal.,JClinOncol.1997;15:1395-1400. 蒽环类和紫杉类方案失败后的治疗选择，XeloNVBGEM的疗效大致相当，但是毒性不同。三种药物之间没有直接对照的研究，选择时更注重避免毒性重叠。 AfterAnthracyclinesandTaxanes:MultipleOptionsCapecitabineVinorelbineGemcitabineIrinotecanVinflunineXRP9881Ixabepilonenab-paclitaxel Abraxane(ABI-007，楷素)1.IbrahimNKetal.,JClinOncol.2005;23:6019-26.2.BlumJLetal.,ProcAmSocClinOncol.2004.Abstract543.Albumin-boundpaclitaxel,nanoparticleformulationPhaseIItrial,taxane-refractoryMBC(N=106)中国注册研究已经完成II、III期临床FDA已经批准用于MBC治疗 每周凯素治疗紫杉类耐药MBC两个PhaseIITrialOShaughnessyJA凯素是纳米白蛋白紫杉醇,是第一个通过受体介导通道(gp60),使肿瘤细胞紫杉醇浓度更高。紫杉类耐药MBC，n=106凯素100mg/m2/W3doses,1weekofrestORR15%PFS12ms13%1yrSR38%凯素125mg/m2/W3doses,1weekofrest紫杉类耐药MBC，n=75安全性：G3/4：中粒减少，感觉神经异常，血小板减少，黏膜炎 Vinflunine（长春富宁）AfterAnthracyclineandTaxaneFailureinMBCFumoleauetal.,ProcAmSocClinOncol.2004.Abstract542.Novelsemi-syntheticvincaalkaloidInhibitstubulinassemblyNostabilizingeffectonassembledmicrotubulesPhaseIIstudy(N=60)PR30.0%,diseasecontrol(PR+SD)63.3%PR36.8%,diseasecontrol57.9%intaxane-refractory(PFI<3mo)patientsGrade3/4neutropeniain63.5%ofpatients,neutropenicinfectionin5.8% Ixabepilone(BMS-247550，埃坡霉素)EpothiloneBisanaturalmacrolideproducedbythemyxobacteriumSorangiumcellulosumIxabepiloneisasemisyntheticanalogofepothiloneB(aza-epothiloneB)EpothiloneBIxabepilone AntitumorActivityinTaxane-ResistantPAT-21BreastCancerXenograftsPAT-21breastcancerxenograftsarederivedfromapatientwithMBCwhoreceived10cyclesofCMF,then4cyclesofpaclitaxel.MTD=maximumtolerateddose.Mediantumorwt.(mg)1010010004070100130160DaysposttumorimplantationControlIxabepilone(10mg/kg,MTD)Paclitaxel(36mg/kg,MTD)ControlIxabepilone(13mg/kg,MTD)Docetaxel(20mg/kg,MTD)Vinorelbine(9mg/kg,MTD)Daysposttumorimplantation101001000405060708090Mediantumorwt.(mg)Dataonfile,Bristol-MyersSquibbCompany. ClinicalResponsetoIxabepiloneNCI-0229ORRPriorTaxaneTotal37CompleteResponse1(3%)PartialResponse7(19%)StableDisease13(38%)ProgressiveDisease16(43%)Low.JClinOncol.2005;23:2726-34. PhaseIIIClinicalTrialsofIxabepilonePlusCapecitabineIxabepilone40mg/m2q3wkplusCapecitabine1000mg/m2bidx14daysCapecitabine1250mg/m2bidx14daysTrialInclusionCriteriaEndPointsCA163046Anthracycline-resistantorminimumcumulativedoseTaxane-resistantMeasurabletumorTTP(primary)OSRRCA163048Anthracycline-andtaxane-pretreatedMeasurable/nonmeasurabletumorOS(primary)TTPRRRandomized ConclusionIxabepiloneveryactiveinbreastcancerAdvantagesNosteroidpremedicationMinimalhypersensitivityreactionsandnausea/vomiting3%-5%Grade3peripheralneuropathyCombinationsinprogress 分子靶点药物临床研究HercecptininHer2+MBCBevazcizumabinMBC TargetingDysregulatedPathwaysWithNovelAgentsHERtyrosinekinaseinhibitorsApoptosisRassignalingVEGFsignalingHERsignalingTPApoptoticagentsKinaseinhibitorsAnti-HERMAbsTumor-activatedchemotherapyAnti-VEGFMAbsandothermolecules StrategiesforErbBReceptorInhibitionMonoclonalantibodies(MAbs)againsterbBreceptorsSmall-moleculetyrosinekinaseinhibitors(SMTKIs) Her2过表达的MBC的治疗 人类表皮生长因子(HER2),也称做c-erbB-2和HER2/neu,能促进细胞生长和肿瘤发生。在原发性乳腺癌患者中25%to30%有HER2蛋白过度表达，这些患者通常具有早期复发和生存期较短的临床特征。Trastuzumab是一种人源化的重组DNA单克隆抗体，能够选择性与细胞表面HER2决定簇结合。有HER2过度表达的转移性乳腺癌患者，赫赛丁单药治疗具有抗肿瘤疗效。与单纯化疗比较，与化疗联合应用时能提高疗效、并且能延长生存。 赫赛丁单药治疗的客观疗效StudyH0649g 赫赛丁单药一线治疗MBCStudyH0650ResponseRateN=114patients2mg/kgVs4mg/kgCompleteresponses7ptPartialresponses23ptOverallresponserate30pt(26%)Timetoresponse1.8moResponseduration11-22mo 赫赛丁与化疗联合一线治疗MBCORR(HO648g)DesignandenrolmentNoprioranthracyclinesPrioranthracyclinesPaclitaxel(n=96)Herceptin®+paclitaxel(n=92)AC(n=138)Herceptin®+AC(n=143)MetastaticbreastcancerHER2overexpressionNopriorCTforMBCMeasurablediseaseKPS60%Eligiblepatients(n=469) ComparativeStudyHO648gOverallORRP-value0.10380.0001 ComparativeStudyHO648gTime-to-DiseaseProgressionH+P(n=92)median=6.9moP(n=96)median=3.0moH+AC(n=143)median=8.1moAC(n=138)median=6.1mop=0.0003p=0.0001 OverallsurvivalCTpatientstreatedwithHerceptin®afterdisease24%62%65%progression1.00.80.60.40.200515253545H+CTCTProbabilityofsurvival25.4months(25%)20.3monthsRR=0.76p=0.025Time(months) Meancombinationindexvaluesforchemotherapeuticdrug/Herceptin®combinationsinvitro*5'-dFUrdisametaboliteofXeloda®;Herceptin®plusXeloda®demonstratesadditiveactivityinvivo31KonecnyG,etal.BreastCancerResTreat1999;57:114(Abstract467)2PegramM,etal.Oncogene1999;18:2241–513Fujimoto-OuchiK,etal.CancerChemotherPharmacol2002;49:211–16 Herceptin与每周paclitaxel(n=95)PhaseIItrialofHerceptin®plusweeklypaclitaxel(90mg/m2)RRsin70–80%rangeinHER2-positivepatients169%(DAKO)67%(PAb1)76%(CB11)81%(TAB250)75%(FISH)UsedbyIntergrouptodevelopadjuvantdesignWidelyusedintheclinicalsettingintheUSAandAustralia1SeidmanAD,etal.JClinOncol2001;19:2587–95 Herceptin联合docetaxelPhaseIItrialsHerceptin®wasadministeredasa4mg/kginitialdosefollowedby2mg/kgweeklyuntilprogression Herceptin与vinorelbine联合1BursteinH,etal.JClinOncol2001;19:2722–302JahanzebM,etal.BreastCancerResTreat2001;69:284(Abstract429) Herceptin与gemcitabine联合PhaseIIstudy(n=59)ofHerceptin®plusgemcitabine(1,200mg/m2day1and8q3-weekly)RR=33%(22/59)InpatientswithIHC3+disease,RR=45%(17/38)O’ShaughnessyJA,etal.BreastCancerResTreat2001;69:302(Abstract523) Herceptin与docetaxel和platinum联合（First-line）Herceptin®incombinationwithdocetaxelandcisplatin(BCIRG101)RR=79%(49/62)Herceptin®incombinationwithdocetaxelandcarboplatin(BCIRG102)RR=56%(31/55)ThisregimenisbeinginvestigatedinphaseIIItrialsintheadjuvant(006)andmetastatic(007)settingsNabholtzJ-M,etal.EurJCancer2001;37:S190(Abstract695) Herceptin与Xeloda联合InpatientspretreatedformetastaticbreastcancerRR=62%(8/13)whenXeloda®wasadministeredatadoseof1,125mg/m2b.i.d.1RR=53%(9/17)whenXeloda®wasadministeredatadoseof1,000mg/m2b.i.d.2ThecombinationwaswelltoleratedAdditionaltrialstofurtherexaminethiscombinationincludearandomisedphaseIItrialofHerceptin®plusdocetaxel±Xeloda®1BangemannN,etal.AnnOncol2000;11:143(Abstract653P)2BangemannN,etal.BreastCancerResTreat2000;64:123(Abstract530) M77001:trialdesignHER2-positiveMBC(IHC3+and/orFISH+)n=188Docetaxel*100mg/m2q3wx6Docetaxel100mg/m2q3wx6Herceptin®4mg/kgloading,2mg/kgweeklyuntilPD+*PatientsprogressingondocetaxelalonecouldcrossovertoreceiveHerceptin®Twopatientsdidnotreceivestudymedicationn=92n=94 M77001:efficacysummary*Kaplan-MeierestimateIntent-to-treatpopulation,12-monthcut-off HerceptininmetastaticbreastcancerEvidencesupportsHerceptintherapyinHER-2overexpressingmetastaticbreastcancer1.Herceptinwithchemotherapyinfirstlineimprovedtimetotreatmentfailureincreasedresponseratesimprovedsurvival2.Herceptinmonotherapyactiveinfirstlineandinsecond/thirdlinefavourablesafetyprofilesurvivaldatainfirstlinenotinferiortocombinationtherapy 3药联合治疗Her2OverexpressMBCWeeklyVS3weekly---NCCTGChemotherapy+Trastuzumabx6mo®Trastuzumabq3wCarboplatinAUC6Paclitaxel200mg/m2q3w+TrastuzumabqweekCarboplatinAUC2Paclitaxel80mg/m2qweek(3of4)+Trastuzumabqweek1stLineHER2+MBCPI:PerezEA ResponsetoTherapy(InterimAnalysis)50%OverallResponse56%27%1-yearPFS13.4mo8.8moMedianPFS61%39%PartialResponse78%11%CompleteResponseweekly(n=18)q3w(n=18) Survival(InterimAnalysis)81%50%2-yearOS100%89%1-yearOSweekly(n=18)q3w(n=18) AdverseEvents:Hematologic(70EvaluablePatients)--3%15%FebrileNeutropenia-6%-29%RBCTransfusion-3%-18%Anemia-3%-35%Thrombocytopenia11%44%71%18%Neutropenia4343NCIGradeweekly(n=36)q3w(n=34)p*0.0030.010.0050.050.01*p-valuefromFisher’sExacttest;post-hocanalysis AdverseEvents:Non-Hematologic(70EvaluablePatients)---9%-3%-24%-47%-68%Alopecia(grade2)Neuropathy-3%-18%Myalgia-8%6%6%Hypersensitivity-11%-12%Fatigue-8%-15%Arthralgia4343NCIGradeweekly(n=36)q3w(n=34)p*0.471.00.710.050.110.0120.10*p-valuefromFisher’sExacttest;post-hocanalysisMotorSensory ConclusionsBothq3wandweeklyregimenofcarboplatin,paclitaxel,andtrastuzumabarehighlyactiveinHER2+MBCWeeklyregimenisbettertoleratedTherapeuticratioofcarboplatin,paclitaxel,andtrastuzumabinHER2+MBCisimprovedwithweeklyregimen ForbesJF,etal.ASCO2006.Abstract516.THarmDocetaxel100mg/m2q3wks+Trastuzumab4mg/kgloadingdosethen2mg/kgq3wks(n=131)PatientswithuntreatedHER2+(byFISH)metastaticbreastcancer(N=263)TCHarmDocetaxel75mg/m2q3wks+Trastuzumab4mg/kgloadingdosethen2mg/kgq3wks+CarboplatinAUC6q3wks(n=132)8cyclesStratificationbasedonprioradjuvantand/orneoadjuvantchemotherapyandstudycenterTrastuzumab(6mg/kgq3wksuntilprogression)BCIRG007:First-LineTrastuzumab+Docetaxel±CarboplatinHER2+MBC BCIRG007:First-LineTrastuzumab+Docetaxel±CarboplatinHER2+MBCMedianfollow-up:27.6monthsTimetoprogressionequivalentbetweenarms(P=.57)TH:11.07monthsTCH:10.35monthsSimilaroverallresponseTH:72.5%TCH:72.7%Mediansurvival:>40monthsYearsFromRandomizationProgression-FreeSurvival0.20.40.60.81.0004123THTCHForbesJF,etal.ASCO2006.Abstract516. BCIRG007:First-LineTrastuzumab+Docetaxel±CarboplatinHER2+MBCToxicity,n(%)Docetaxel+Trastuzumab(n=131)Docetaxel+Trastuzumab+Carboplatin(n=132)PValueSensoryneuropathy76(57.3)58(44.3).048Motorneuropathy12(9.2)4(3.1).07Myalgia58(44.3)41(31.3).04Desquamatousrash42(32.1)20(15.3).002Nailchanges72(55.0)43(32.8)<.001Grade3-4neutropenicinfection22(16.8)12(9.2).097Grade3-4thrombocytopenia3(2.3)20(15.3)<.001Nausea70(53.4)96(73.3)NRVomiting37(28.2)58(44.3)NRDifferenttoxicityprofilesnotedwitheachtreatmentTH:neuropathy,myalgia,rash,nailchanges,neutropeniaTCH:thrombocytopenia,nausea,vomitingForbesJF,etal.ASCO2006.Abstract516. CerbB2Over-expressedMBCHerceptin联合化疗的首选方案Paclitaxel+/-CarboplatinDocetaxel+/-CarboplatinVinorebineNCCN2004 Tykerb(lapatinib)—ADualReceptorTyrosineKinaseInhibitorPotent,oral,reversibledualtyrosinekinaseinhibitorBindstoATPsiteoferbB-1anderbB-2receptorkinases,blockingkinaseactivityanddownstreamsignaling StrategiesforErbBReceptorInhibitionMonoclonalantibodies(MAbs)againsterbBreceptorsSmall-moleculetyrosinekinaseinhibitors(SMTKIs) Lapatinib:TargetingEGFRandHER2LapatiniboraltyrosinekinaseinhibitorofErbB1andErbB2BlockssignalingthroughEGFRandHER2homodimersandheterodimersMayalsopreventsignalingbetweenErbB1/ErbB2andotherErbBfamilymembersRusnakDW,etal.MolCancerTher.2001;1:85-94.XiaW,etal.Oncogene.2002;21:6255-6263.PTENLapatinibP13KpAktRasRafpErkShcGrb2So8Phospholipidcellmembrane EGF100151:Lapatinib+CapecitabineinAdvancedBreastCancerRefractory,progressivemetastaticorlocallyadvancedHER2+breastcancerpreviouslytreatedwithanthracycline,taxane,ortrastuzumab(N=528planned*)Lapatinib1250mgdaily+Capecitabine2000mg/m2dailyforDays1-14,3-weekcycles(n=160)Capecitabine2500mg/m2dailyforDays1-14,3-weekcycles(n=161)Follow-up:untilprogressionorunacceptabletoxicity*StudyenrollmentterminatedearlybyIDMCduetosuperiorityofcombinationarminprimaryendpoint.GeyerCE,etal.ASCO2006.ClinicalScienceSymposium. EGF100151:Lapatinib+CapecitabineinAdvancedBreastCancer(cont’d)Additionoflapatinibtocapecitabineinwomenwithtreatment-refractory,advancedmetastaticbreastcancerassociatedwithLongertimetoprogression36.9vs19.7wks(P=.00016)Longerprogression-freesurvival36.9vs17.9wks(P=.000045)Fewerprogressionsordeaths38%vs48%Response(independentreview)Overall:22.5%vs14.3%(P=.113)Progression-FreeSurvival(%)Time(Wks)2040608001001020304050CapecitabineLapatinibcapecitabineITTpopulationGeyerCE,etal.ASCO2006.ClinicalScienceSymposium. EGF100151:Lapatinib+CapecitabineinAdvancedBreastCancer(cont’d)Gr3Gr2SeverityGr4Gr1DiarrheaPatients(%)PPESL+CRashand/orSkinReaction20406080100026131512928201913CAloneL+CCAloneL+CCAlone19116951171000001203GeyerCE,etal.ASCO2006.ClinicalScienceSymposium. EGF103009:LapatinibMonotherapyinRelapsed/RefractoryIBC58womenwithrelapsedorrefractoryinflammatorybreastcancergivenlapatinib1500mg/dayinphaseIIstudyMedianpriorchemotherapyregimens:4.5(range:0-21)ResponseratesinErbB2overexpressers:62%AllclinicalrespondersErbB2(IHC3+/FISH+)p-ErbB2+ResponseratesinErbB1overexpressers:8.3%SpectorNL,etal.ASCO2006.Abstract502.Patients(%)62.021.017.08.317.058.00204060ErbB2+(n=24)ErbB1+/ErbB2-(n=12)*PartialresponseStablediseaseProgressivedisease80100*Statusof17%stillpending. TargetingHER2viaHSP-90Heatshockprotein-90(HSP-90)isachaperoneproteinforavarietyofoncogenicproteins,includingHER2,ER/PR,AKT,MET,andRafkinase17-AAG(KOS-953),aninhibitorofHSP-90,suppressestumorgrowthinmousexenograftmodelsofHER2+humanbreastcancersPTENPIP3PIP2PDKAKT17-AAGBAD,Caspase9,FKHD,etcCyclinDp85HER217-AAGHER3p110ModiS,etal.ASCO2006.Abstract501. 17-AAG+TrastuzumabPartialresponse:159%↓inlungmetastasisTumorregression:4AllHER2+MBCwhoprogressedontrastuzumabDecreasesinlung,nodal,breastmetastasesnotedStabledisease:4(≥4months)PhaseIItrialof17-AAG(450mg/m2)+trastuzumabinHER2+metastaticbreastcancerongoingDatafromphaseItrialof17-AAG+trastuzumabreportedWeekly17-AAG(variousdoses)+standardweeklytrastuzumab25patientswithvarioussolidtumortypesevaluatedLargestproportionhadHER2+overexpressingbreastcancerMaximum450mg/m2dosewelltolerated1grade2thrombocytopeniaModiS,etal.ASCO2006.Abstract501. 单药紫杉醇vslapatinib+紫杉醇一线治疗Her2过表达MBCPhaseIII首次复发的转移性乳腺癌有可测量病灶Her2过渡表达（IHC+++orFISH+） 抗血管生成因子治疗 TargetingDysregulatedPathwaysWithNovelAgentsHERtyrosinekinaseinhibitorsApoptosisRassignalingVEGFsignalingHERsignalingTPApoptoticagentsKinaseinhibitorsAnti-HERMAbsTumor-activatedchemotherapyAnti-VEGFMAbsandothermolecules AgentsTargetingtheVEGFPathwayPodarandAnderson.Blood.2005;105:1383VEGFR-2VEGFR-1PPPPPPPPEndothelialcellSmall-moleculeVEGFRinhibitors(PTK787,SU11248,ZD6474,BAY43-9006)Anti-VEGFRantibodies(IMC-1121b)VEGFAnti-VEGFantibodies(bevacizumab)SolubleVEGFRs(VEGF-TRAP) Capecitabine±BevacizumabforMBCSignificantlyincreasedresponseincombinationarm19.8%vs9.1%;P=.001NosignificantdifferenceinPFSorOS,combinationvssingleagentPFS,4.86vs4.17mos,HR=0.98;OS15.1vs14.5mosMillerKDetal.JClinOncol.2005;23:792-799.Capecitabine(n=230)Capecitabine+Bevacizumab(n=232)PatientswithMBCPreviouslytreatedwithA/T Capecitabine±BevacizumabforMBCMillerKDetal.JClinOncol.2005;23:792-799.Eligiblepatientshadreceivedanthracyclineandtaxanetreatment1or2priorchemotherapyregimensforMBC,orRelapsewithin12monthsofcompletinganthracycline-andtaxane-containingadjuvanttherapyStudyregimenincludedbevacizumab15mg/kgIVq3w,capecitabine1250mg/m2poBIDx14dq3w Bevacizumab的其他研究Millerandcolleagues[2]比较capecitabinewithandwithoutbevacizumabIn462patients一线MBCcapecitabine2500mg/m2/day×14dq21dayalonecapecitabine2500mg/m2/day+bevacizumab15mg/kgd1虽然RR在XB组较高（19.8%)vsXalone(9.1%)，但是PFS(XB4.86mvs4.17msXalone)或OS(XB15.1msvsX14.5ms)都没有改善。与Herceptin+Paclitaxel在改善PFSvsOS的疗效十分相似，是以往细胞毒方案所不能比拟的，显示十分重要的前景。有可能成为Her2阴性乳癌的一线治疗。 Milleretal.ASCO2005.Oralpresentationduringsymposium,AdvancesinMonoclonalAntibodyTherapyforBreastCancer.Bevacizumab10mg/kgDays1,15+Paclitaxel90mg/m2Days1,8,15(n=365)Paclitaxel90mg/m2Days1,8,15(n=350)Patientswithlocallyrecurrentormetastaticbreastcancer,ECOGperformancestatusscore0-1(N=715)Stratifiedbydisease-freeinterval,numberofmetastaticsites,adjuvantchemotherapy,andestrogenreceptorstatusBevacizumab±Paclitaxel1stlineforLocallyRecurrentorMetastaticDiseaseEasternCooperativeOncologyGroup(ECOG)2100trialFirstplannedinterimanalysisofrandomized,first-line,phase3trial Milleretal.ASCO2005.Oralpresentationduringsymposium,AdvancesinMonoclonalAntibodyTherapyforBreastCancer.Bevacizumab±PaclitaxelforLocallyRecurrentorMetastaticDiseasePFSsignificantlylongerwithcombinationtherapy10.97monthsvs6.11monthsHR=0.498(95%CI,0.401-0.618),P<.001Overallsurvivalsignificantlyhigherforpatientsreceivingbevacizumab+paclitaxelvspaclitaxelaloneHR=0.674(95%CI,0.495-0.917),P=.01Overallresponsesignificantlybetterforpatientstreatedwithbevacizumab+paclitaxel28.2%vs14.2%forpaclitaxelalonecohort(P<.0001) Grade3/4EventBevacizumab+Paclitaxel,%(n=342)Paclitaxel,%(n=330)PValueHypertension13.30<.0001Thromboembolism1.21.2NSBleeding0.90NSProteinuria2.40.0004Neuropathy20.514.2.01Fatigue5.02.7NSNeutropenia5.33.0NSDecreasedLVEF0.30.0NSMilleretal.ASCO2005.Oralpresentationduringsymposium,AdvancesinMonoclonalAntibodyTherapyforBreastCancer.Bevacizumab±PaclitaxelforLocallyRecurrentorMetastaticDiseaseBevacizumab+paclitaxelregimenassociatedwithmoregrade3/4adverseeventsvspaclitaxelalone 结论Millerandcolleagues比较XBvsx一线MBCRR在XB组较高（19.8%)vsXalone(9.1%)，但是PFS(XB4.86mvs4.17msXalone)或OS(XB15.1msvsX14.5ms)都没有改善。BevacizumabimprovesPFSwhenaddedtopaclitaxelfortreatmentoflocallyrecurrentormetastaticdiseaseImprovedoverallsurvivalandoverallresponseIncreasedhypertension,proteinuria,neuropathywithbevacizumab与Herceptin+Paclitaxel在改善PFSvsOS的疗效十分相似，是以往细胞毒方案所不能比拟的，显示十分重要的前景。有可能成为Her2阴性乳癌的一线治疗。 影响治疗MBC选择的因素肿瘤的特征：肿瘤负荷，肿瘤部位，进展速度，肿瘤相关并发症，以及肿瘤特殊标志。病人的考虑：患者的年龄，身体条件，患者对治疗方案的主观看法。病史：过去治疗，无病间隔，合并疾病：心、肝、肾功能，糖尿病等。治疗药物和方案的效果和毒性，以及费用。 小结细胞毒药物仍然是主要治疗方法.Herceptin是HER2过表达MBC一线治疗选择。激素受体阳性,同时又适合内分泌治疗,应给予内分泌治疗.根据病人的肿瘤情况和身体状况，选择和制定合理的治疗方案，控制肿瘤同时，尽量避免治疗的不良反应。