乳腺癌分子靶向药物治疗进展PPT课件.ppt

乳腺癌分子靶向药物治疗进展,张清媛哈尔滨医科大学附属肿瘤医院,1,Chemotherapy,Endocrinetherapy,Targetedtherapies,TreatmentofBC,HIGHLIGHTSINBREASTCANCER,DISEASEBIOLOGY,2,针对HER2受体的靶向药物针对表皮生长因子受体(EGFR)的靶向治疗针对肿瘤血管生成的分子靶向药物其他信号通路抑制剂mTOR，Ras，MEK等,乳腺癌分子靶向药物治疗,3,HER2在约20%30%的乳腺癌组织中过度表达,SlamonDJetal.Science1987;235:17782,HER2阳性与内分泌治疗及部分化疗耐药密切相关，是重要的预后指标HER2成为乳腺癌治疗的理想靶点，是预测赫赛汀疗效的重要指标,4,赫赛汀(曲妥珠单抗):人源化抗HER2单克隆抗体,高度亲和性(Kd=0.1nM)和特异性95%人源化,5%鼠抗，显著降低免疫原性(HAMA),全球第一种治疗实体瘤的单克隆抗体,5,InhibitionofHER2-mediatedsignalling,ActivationofADCC,赫赛汀的作用机制,AdditionalmechanismsPreventsformationoftruncatedHER2(p95)InhibitionofHER2-regulatedangiogenesis,ADCC,antibody-dependentcellularcytotoxicity,6,赫赛汀已成为HER2阳性乳腺癌的基础治疗,1stline,HO648gM77001USOncologyBCIRG007CHATTAnDEMRHEA,Relapse,2nd+lines,GBG-26BO17929EGF104900NumerousPhaseIIstudies,MBC,Progression,HERANSABPB-31NCCTGN9831BCIRG006,Adjuvant,NOAHMDACCGeparQuattroNumerousPhaseIIstudies,Neo,EBC,HER2,humanepidermalgrowthfactorreceptor2EBC,earlybreastcancer;MBC,metastaticbreastcancer,7,13,000患者入组的赫赛汀四大辅助临床研究,Piccart-Gebhartetal2019Romondetal2019;Slamonetal2019,NCCTGN9831(USA),HERA(ex-USA),BCIRG006(global),NSABPB-31(USA),IHC/FISH(n=5,090),Observation,1year,2years,IHC/FISH(n=3,505),1year,1year,FISH(n=3,222),1year,1year,IHC/FISH(n=2,030),1year,Doxorubicin+cyclophosphamide,IHC,immunohistochemistryFISH,fluorescenceinsituhybridisationCTx,chemotherapy,8,赫赛汀可减少三分之一的死亡风险,0,1,2,B-31/N9831ACPH,3,HERACTxH1year,2,Medianfollow-up,years,Overallsurvivalbenefit,BCIRG006ACDH,3,BCIRG006DCarboH,3,FavoursHerceptin,FavoursnoHerceptin,HR,Slamonetal2019Perezetal2019;Smithetal2019,H,Herceptin;AC,doxorubicin,cyclophosphamideP,paclitaxel;D,docetaxel;Carbo,carboplatinHR,hazardratio,Sizeofsquarerepresentssamplesize;horizontalbarsindicate95%confidenceintervals,9,无论肿瘤大小，赫赛汀均显示DFS获益,Slamonetal2019Perezetal2019;Smithetal2019,2-5cm,BCIRG006,2-5cm,5cm,0.0,0.5,2.5,1.0,1.5,2.0,0-2cm,N9831/B-31,0-2cm,5cm,ACDH,2cm,DCarboH,10+nodes,DCarboH,N-,N+,N+,BCIRG006,N-,ACDH,N-,HERA,HR,Slamonetal2019Perezetal2019;Smithetal2019,11,无论年龄大小，赫赛汀均显示DFS获益,35-49years,0.0,0.5,2.5,1.0,1.5,2.0,HERA,35years,50-59years,60years,N9831/B-31,40years,60years,40-49years,50-59years,FavoursHerceptin,FavoursnoHerceptin,HR,Perezetal2019;Smithetal2019,12,赫赛汀的新辅助治疗研究进展,1stline,HO648gM77001USOncologyBCIRG007CHATTAnDEMRHEA,Relapse,2nd+lines,GBG-26BO17929EGF104900NumerousPhaseIIstudies,MBC,Progression,HERANSABPB-31NCCTGN9831BCIRG006,Adjuvant,NOAHMDACCGeparQuattroNumerousPhaseIIstudies,Neo,EBC,13,NOAHstudy:neoadjuvantHerceptinforLABC,aHormonereceptor-positivepatientsreceiveadjuvanttamoxifenAP,doxorubicin60mg/m2,paclitaxel150mg/m2;H,Herceptin8mg/kgloadingthen6mg/kgP,paclitaxel175mg/m2;CMF,cyclophosphamide600mg/m2,methotrexate40mg/m2,5-fluorouracil600mg/m2LABC,locallyadvancedbreastcancer;q3w,every3weeks;q4w,every4weeks,HER2-positiveLABC(IHC3+and/orFISH+),n=113,H+APq3wx3,H+Pq3wx4,Hq3wx4+CMFq4wx3,Surgeryfollowedbyradiotherapya,Hcontinuedq3wtoWeek52,n=115,Pq3wx4,CMFq4wx3,Surgeryfollowedbyradiotherapya,APq3wx3,APq3wx3,Pq3wx4,CMFq4wx3,Surgeryfollowedbyradiotherapya,n=99,HER2-negativeLABC(IHC0/1+),14,p=0.002,p=0.004,pCR(%),Baselgaetal2019;Giannietal2019,HER2positive(n=228),HER2positive(n=62),NOAH研究中赫赛汀新辅助显著提高了pCR率,WithoutHerceptinWithHerceptin,90,80,70,60,50,40,30,20,10,0,HER2negative(n=99),HER2negative(n=14),23,43,17,19,55,29,Totalpopulation,IBCpopulation,pCR,pathologicalcompleteresponseinthebreastIBC,inflammatorybreastcancer,15,新辅助化疗中加入赫赛汀明显提高疗效(16个相关研究,1,226例患者入组),aXwasgiveneitherconcurrentlyorsequentiallywithD+HEC,epirubicin,cyclophosphamide;FEC,5-fluorouracil,epirubicin,cyclophosphamideMy,Myocet;X,Xeloda,0,10,20,30,40,50,60,70,80,90,100,pCR(%),16,赫赛汀已成为HER2阳性乳腺癌的基础治疗,1stline,HO648gM77001USOncologyBCIRG007CHATTAnDEMRHEA,Relapse,2nd+lines,GBG-26BO17929EGF104900NumerousPhaseIIstudies,MBC,Progression,HER2,humanepidermalgrowthfactorreceptor2EBC,earlybreastcancer;MBC,metastaticbreastcancer,EBC,HERANSABPB-31NCCTGN9831BCIRG006,Adjuvant,NOAHMDACCGeparQuattroNumerousPhaseIIstudies,Neo,17,一线赫赛汀治疗显著延长患者的生存时间,Mediansurvival(months),IHC,immunohistochemistry;P,paclitaxelH,Herceptin;D,docetaxel;Carbo,carboplatin,H0648g(IHC3+),M77001,BCIRG007,USOncology(IHC3+),Smithetal2019;Martyetal2019Robertetal2019;Pegrametal2019,18,TAnDEM-赫赛汀联合阿那曲唑治疗HER-2(+）激素敏感性转移性乳腺癌,临床研究结果（2019年圣安东尼奥）,2019年3月欧洲推荐赫赛汀联合芳香化酶抑制剂治疗HER2与激素受体阳性转移性乳癌,19,疾病进展后如何合理选择赫赛汀个体化治疗方案,1stline,HO648gM77001USOncologyBCIRG007CHATTAnDEMRHEA,Relapse,2nd+lines,GBG-26BO17929EGF104900NumerousPhaseIIstudies,MBC,Progression,EBC,HERANSABPB-31NCCTGN9831BCIRG006,Adjuvant,NOAHMDACCGeparQuattroNumerousPhaseIIstudies,Neo,20,HerceptinimprovesOSifcontinuedbeyondprogression,OS(months),ContinuedHerceptinDiscontinuedHerceptin,Extraetal2019Jackischetal2019;Menardetal2019,p1cm)brainmetastasesTreatment:Lapatinib750mgpoBIDResult2patientsPR158dand347d5patientsSD16weeksMedianTTP3.2monthsMST6.57months1patienthadresponse,butdidnotmeetRECISTLapatinib成为Trastuzumab耐药或脑转移患者新选择,LapatinibforBrainMetastasesinHer2+CancerLinetal.ASCO2019;NCI-CTEP6969trial,38,2019/12/12,39,Lapatinib+TrastuzumabforTrastuzumabprogressingonHer2+CancerASCO2019,40,Progression-FreeSurvival,41,OverallSurvivalinITTPopulation,42,0,200,Days,Gefitinib-表皮生长因子受体酪氨酸激酶抑制剂,1,30,60,90,120,150,400,600,800,1000,1200,1400,Tumourvolume(mm3),Massarwehetal.BreastCancerResTreat2019,Fulvestrant,Oestradiol,FulvestrantplusgefitinibdelaysresistanceinMCF-7/HER2tumoursinvivo,43,PhaseIITrialofGefitinibinAdvancedBreastCancer,PartialresponseStablediseaseClinicalbenefitProgressivedisease,156(66%)3,ER-positive(n=9),ER-negative(n=18),112(11%)16,Robertsonetal.ASCOProc.2019,AcquiredresistancetoTAM(n=27)orER-negativetumours(n=27)GefitinibLD1000mg(D1)Dailydose500mg/dayuntildiseaseprogressionorunacceptabletoxicity,44,Erlotinib-小分子EGFR酪氨酸激酶抑制剂,previoustherapywitheitherananthracyclineorataxaneforMBC,Erlotinib（150mgorallydaily）+gemcitabine（1000mg/m2,Days1、8,3-weekcycles）,Apartialresponse(PR)rateof17%hasbeenreported(ASCO2019),N0234：Erlotinib+Gemcitabine,45,N0234：Erlotinib+Gemcitabine,Result,TN*=ER(-)/PR(-)/HER-2(-)三阴,ASCO2019,46,西妥昔单抗(Cetuximab，erbitux，C225，爱必妥),Cetuximab是针对HER-1的特异性单克隆抗体动物试验显示，Cetuximab可有效抑制乳腺癌细胞增殖和生长，现有不少研究机构开始应用Cetuximab单药或与化疗药物联合治疗EGFR阳性乳腺癌。,47,泰欣生是一个针对EGFR的单抗药物，通过与EGFR胞外区3A表位结合，竞争性抑制配体与EGFR的结合，使受体失去活性：IgG1型单克隆抗体，分子量为150KD95人源化激发ADCC和CDC效应抑制肿瘤细胞比内源性配体亲合力更高（Kd=10-9）,泰欣生（尼妥珠单抗,Nimotuzumab）,48,古巴：泰欣生联合新辅助化疗治疗乳腺癌,研究终点评估尼妥珠单抗联合化疗药物治疗局部晚期乳腺癌患者新辅助化疗的安全性、药代动力学及疗效。,期初治乳腺癌患者,泰欣生（50/100/200/400mg，qw）阿霉素（60mg/m2，q3w）环磷酰胺（600mg/m2，q3w）,J.Soriano,N.Batista,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page116,49,1781522282936434950576470,RANDOMIZATION,SURGERY,Nimotuzumab,AC,用药方案,J.Soriano,N.Batista,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page116,50,疾病控制情况,疾病控制情况共有13例患者入组，12例患者可评估：9例PR，3例SD。,J.Soriano,N.Batista,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page116,51,安全性：在50、100、200和400mg中，未见剂量限制性毒性临床未见心脏毒性；联合治疗安全性高，患者耐受性良好常见不良反应为：皮疹、皮肤反应、恶心、呕吐；红斑,丘疹及色素沉着较常见，通常发生在面部及上肢上部，能自行缓解初步结论：泰欣生治疗乳腺癌有效，联合治疗在50，100，200和400mg剂量下是安全的，有很好的耐受性,结论,J.Soriano,N.Batista,etal.EuropeanJournalofCancerSupplements,Vol5No4,Page116,52,苏尼替尼（Sunitinib）-小分子多靶点酪氨酸激酶抑制剂,Selectiveinhibitorof:PDGFRVEGFR2(KDR)KITFLT3,2019年1月美国FDA批准上市,用于治疗晚期肾细胞癌和胃肠道间质瘤。,53,SunitinibinBreastCancerPatientsmulticentricphaseIIstudywith64patients,*OnePRnotyetconfirmed.,patientshadreceived3.5differentchemotherapies（anthracyclineortaxane）85%ofpatientshadreceivedadjuvantchemotherapy,sunitinib50mg/d,54,多激酶抑制剂：丝氨酸/苏氨酸：C-Raf(Raf-1)和B-Raf1酪氨酸激酶受体：VEGFR-2、VEGFR-3、PDGFR-b、FLT-3和c-KIT,WilhelmSetal.ClinCancerRes.2019;64:7099-7109.,索拉非尼(sorafenib)：口服信号转导抑制剂,在Raf激酶水平和受体酪氨酸激酶VEGFR-2和PDGFR-阻断Raf/MEK/ERK途径,抗肿瘤血管生成及肿瘤细胞增殖,55,SofitinibphaseIIinMBC,56,针对HER2受体的靶向药物针对表皮生长因子受体(EGFR)的靶向治疗针对肿瘤血管生成的分子靶向药物其他信号通路抑制剂mTOR，Ras，MEK等,57,Angiogenesisisinvolvedthroughouttumourformation,growthandmetastasis,AdaptedfromPoonRT,etal.JClinOncol2019;19:120725,Stagesatwhichangiogenesisplaysaroleintumourprogression,Premalignantstage,Malignanttumour,Tumourgrowth,Vascularinvasion,Dormantmicrometastasis,Overtmetastasis,(Avasculartumour),(Angiogenicswitch),(Vascularisedtumour),(Tumourcellintravasation),(Seedingindistantorgans),(Secondaryangiogenesis),58,血管生成的双向调节机制,AngiostatinEndostatinThrombospondin-1,VEGFbFGFPDGF,59,Bevacizumab(MonoclonalAntibodytoVEGF),Humanizedtoavoidimmunogenicity(93%human,7%murine)Recognizesallisoformsofvascularendothelialgrowthfactor,Kd=8x10-10MTerminalhalflife17-21days,60,715casesStratify:DFI24os.3metastaticsitesAdjuvantchemotherapyyesvs.noER+vs.ER-vs.ERunknownage,RANDOMIZE,Paclitaxel+Bevacizumab,Paclitaxel,E2100:StudyDesign-线治疗晚期乳腺癌的期临床研究,28-DayCycle:Paclitaxel90mg/m2D1,8and15Bevacizumab10mg/kgD1and15,61,Allpatients,MeasurableDisease,0,10,20,30,40,Paclitaxel,OverallResponseRate,Pac+B