2010年乳腺癌治疗研究进展.ppt

1,2010年乳腺癌治疗研究进展,2,乳腺癌的治疗方法,手术,放疗,乳腺癌,化疗,分子靶向治疗,内分泌治疗,3,乳腺癌化疗进展,术后辅助化疗转移性乳腺癌的化疗,4,FinXX5年分析：中高危早期乳腺癌中随机、开放的III期研究结果,JoensuuH,Kellokompu-LehtinenP-L,HuovinenR,Jukkola-VuorinenA,TannerM,KokkoR,AhlgrenJ,AuvinenP,BonoP,LindmanHOnBehalfoftheFinXXStudyInvestigators,5,FinXX研究:设计,LN(+)LN(-)andT2cmandPR(-),6,中位随访5年,7,中位随访5年,8,中位随访5年,9,10,11,USON01062：AC序贯T（多西他赛）卡培他滨辅助治疗高危早期乳腺癌的随机开放III期临床研究,OShaughnessyJ,PaulD,StokoeC,PippenJ,BlumJL,KrekowL,HolmesFA,VukeljaS,LindquistD,SedlacekS,RiveraR,BrooksR,McIntyreK,PluennekeR,SchwartzJ,JonesS,BrownsteinC,GilbergF,12,USON01062：研究设计,13,14,15,16,乳腺癌化疗进展,术后辅助化疗转移性乳腺癌的化疗,17,eribulin对既往治疗过的MBC的II期临床研究,1Vahdat,etal.JClinOncol2009;2Vahdat,etal.ASCO2008(Abst1084),18,StudyDesign,19,Results,N=762patientsAtleasttwopriormetastaticchemoregimensEribulinPhysicianchoiceOS13.1m10.6mHR0.81p=0.04PFS3.7m2.2.mHR0.87p=0.14RR12.2%4.7%ToxicityMaintoxicityassociatedwiththisagentFN3.0%GradeNeuropathy8.2%,20,乳腺癌的治疗方法,手术,放疗,分子靶向治疗,乳腺癌,化疗,内分泌治疗,21,乳腺癌内分泌治疗进展,术后辅助内分泌治疗转移性乳腺癌的内分泌治疗,22,在绝经后受体阳性乳腺癌中辅助Exemestane和Anastrozole的III期随机临床研究,P.E.GossJ.N.Ingle,J.W.Chapman,M.J.Ellis,G.W.Sledge,G.T.Budd,M.Rabaglio,K.Gelmon,L.Shepherd,K.I.Pritchard.,NCICCTGMA.27,23,NCICCTGMA.27研究设计,primaryobjective:EFSSecondaryobjectives:OS、DDFS、CBC、safety,24,Percentage,#AtRisk,AnastrozoleExemestane,Anastrozole,Exemestane,0,604020,MA.27主要研究终点(EFS)10080,时间(年)#AtRisk(Anastrozole)#AtRisk(Exemestane),037873789,136743655,234873461,331823190,421902230,5723734,65652,中位随访4.1年分层HR:1.02(0.87-1.18)p=0.85,25,Exemestane比Anastrozole,分层,事件(%)事件(%),HR(95%CI),P-value,EFSOSDDFSDSS,350(9.2)208(5.5)157(4.1)89(2.4),343(9.1)224(5.9)164(4.3)98(2.6),1.02(0.87,1.18)0.93(0.77,1.13)0.95(0.76,1.18)0.93(0.70,1.24),0.850.640.460.62,MA.27研究结果,26,MA.27:不良反应-各级别(70%1/2级),Exemestanen(%)Anastrozolen(%)P-value潮热关节炎/关节痛肌肉痛阴道出血ALTAST胆红素痤疮雄性化心梗中风/一过性脑缺血/TIA房颤高甘油三酯a高胆固醇骨质疏松任何临床骨折脆性骨折,2051(55)253(7)649(17)40(1)53(1)47(1)59(2)12(0)36(1)38(1)32(1)72(2)80(2)577(15)1171(31)358(10)136(4),2101(56)231(6)606(16)61(2)23(1)19(1)24(1)3(0)11(0)32(1)38(1)46(1)124(3)665(18)1304(35)354(9)136(4),3761(100),3759(100),0.240.320.190.040.0010.0010.00010.040.00010.550.470.020.0020.010.0010.910.98,较好,27,乳腺癌内分泌治疗进展,术后辅助内分泌治疗转移性乳腺癌的内分泌治疗,28,氟维司琼对比阿那曲唑一线治疗转移性乳腺癌：FIRST研究,RobertsonJF,LindemannJP,Llombart-CussacA,RolskiJ,FeltiD,DewarJ,EmersonL,DeanA,EllisMJ,29,30,31,32,依维莫司联合三苯氧胺对比三苯氧胺用于HR+,HER2-既往AI治疗的转移性乳腺癌II期随机临床试验,BachelotT,BourgierC,CropetC,GuastallaJ-P,FerreroJ-M,Leger-FalandryC,SoulieP,EymardJ-C,DebledM,SpaethD,LegouffeE,DelozierT,ElKouriC,ChidiacJ,TAMRAD:,33,33,PI3K/AKt/mTOR信号传导通路,mTOR（mammaliantargetofrapamycin）细胞内丝氨酸/苏氨酸激酶，PI3K/Akt传导途经中的一员mTOR是细胞内中枢调控器，可感知如下细胞因子的变化生长因子信号1,2营养和能量信号1-3mTOR活化可促进细胞生长和增殖3血管生成4通过加强的营养物质摄取和利用，可加快肿瘤细胞代谢3,5,血管生成,mTOR,AMPK,TSC1,TSC2,LKB1,细胞生长(212):re15.Huangetal.CancerBiolTher.2003;2:222-232.Wullschlegeretal.Cell.2006;124:471-484.Humaretal.FASEBJ.2002;16:771-780.EdingerandThompson.MolBiolCell.2002;13:2276-2288.,34,抑制血管生成,mTOR,AMPK,TSC1,TSC2,LKB1,细胞生长106;102.-110,36,TAMRAD研究试验设计,随机II期临床试验先前使用过AI的转移性乳腺癌患者A:三苯氧胺20mg/day(TAM)B:三苯氧胺20mg/day+RAD00110mg/day(TAM+RAD)分层:原发或继发的内分泌耐药原发:辅助AI复发;在MBC开始AI治疗后6个月内复发继发:开始AI治疗6月后复发或AI初始有效继而进展无换药计划BachelotT,etal.CancerRes.2010;70(24Suppl):AbstractS1-6.,R,主要终点：CBR次要终点：TTP、OS、ORR、安全性,37,主要研究终点:CBR,CBR=临床获益率;RAD=RAD001;TAM=三苯氧胺BachelotT,etal.CancerRes.2010;70(24Suppl):AbstractS1-6.,(29.1-55.9),(46.9-74.1),P=.045(探索分析),N=57,N=54,38,至疾病进展时间-TTP,39,OS(2010年10月),40,不同内分泌耐药的TTP,原发内分泌耐药(n=54)TAM:3.9月TAM+RAD:5.4月HR=0.74(0.42-1.3)继发内分泌耐药(n=56)TAM:5.0月TAM+RAD:17.4月HR=0.38(0.21-0.71)HR=危险比;RAD=RAD001;TAM=三苯氧胺BachelotT,etal.CancerRes.2010;70(24Suppl):AbstractS1-6.,41,不良反应,发生率,n(%)TAM(n=57)TAM+RAD(n=54)等级Any3/4Any3/4常见不良事件(AE)疲劳30(52.6)6(10.5)40(74.1)3(5.6)口腔炎4(7.0)028(51.9)6(11.1)皮疹3(5.3)1(1.8)21(38.9)3(5.6)食欲减退10(17.5)2(3.5)24(44.4)5(9.3)腹泻5(8.8)021(38.9)1(1.9)恶心19(33.3)018(33.3)2(3.7)呕吐7(12.3)2(3.5)9(16.7)0肺炎2(3.5)2(3.5)9(16.7)1(1.9)血栓4(7.0)4(7.0)7(13.0)3(5.6)疼痛48(84.2)11(19.3)42(77.8)5(9.3)因不良事件减轻剂量015(28.0)因不良事件出组4(7.0)3(5.6)BachelotT,etal.CancerRes.2010;70(24Suppl):AbstractS1-6.,42,乳腺癌进展后激素受体和HER2状态变化,LindstromL,KarlssonE,WilkingU,BerghJ*,43,TheKarolinskaHRandHER2研究方法,receptorTheKarolinskacohort(1997-2007)1051局部或全身复发乳腺癌患者ReportedtoStockholm-GotlandBreastCancerRegistry,459例患者原发和复发灶的ER437例患者原发和复发灶的PR118例患者原发和复发灶的HER2,多部位复发患者ER信息101例患者多个复发部ER,74例患者2个复发部位ER13例患者3个复发部位ER10例患者4个复发部位ER2例患者5个复发部位ER2例患者6个复发部位ER,BC=乳腺癌;ER=雌激素受体LindstromL,etal.CancerRes.2010;70(24Suppl):AbstractS3-5.,44,原发和复发肿瘤中ER,PR和HER2状态,45,受体的改变对生存的影响,46,乳腺癌的治疗方法,手术,放疗,分子靶向治疗,乳腺癌,化疗,内分泌治疗,47,CellGrowth,Proliferation,Survival,Metastasis,Angiogenesis,乳腺癌的靶向治疗药物,RAD001PhaseIII,EGFR,HER2,4E-BP1,elF-4E,ProteinSynthesis,VEGFR,SunitinibPhaseII,BevacizumabPhaseIII,VEGF,48,乳腺癌分子靶向治疗进展,转移性乳腺癌新辅助治疗,49,1.Miller,etal.NEJM20072.Miles,etal.ASCO2008;3.Robert,etal.ASCO2009,贝伐珠单抗联合化疗一线治疗LR/MBC临床研究,LR=locallyrecurrentmBC=metastaticbreastcancer;q2w=every2weeksq3w=every3weeks;PFS=progression-freesurvival,*Stratifiedandcensoredfornon-protocoltherapybeforediseaseprogressionThesecombinationsarenotincludedwithinthecurrentSmPCpvalueisexploratory;HR=hazardratio;IRF=independentreviewfacility,贝伐珠单抗联合化疗显著提高PFS,1.00.20,PFSestimate,0612182430,Time(months),9.2,8.0,AVADO3,4,HR=0.67*(0.540.83)p=0.0002,1.00.20,PFSestimate,061218243036,Time(months),8.1,10.0,Placebo+docetaxel(n=241)Bevacizumab15mg/kgq3w+docetaxel(n=247),Placebo+docetaxel(n=207)Bevacizumab+taxane/anthracycline(n=415),1.00.20,0612182430,Time(months),HR=0.64*(0.520.80)p0.0001,HR=0.69*(0.560.84)p=0.0002,Placebo+capecitabine(n=206)Bevacizumab+capecitabine(n=409),8.6,5.7,RIBBON-1:taxane/anthracyclinecohort2,HR=0.48*(0.390.61)p0.0001,PFSestimate,1.00.20,PFSestimate,061218243036,Time(months),Paclitaxel(n=354)Bevacizumab+paclitaxel(n=368),5.8,11.3,E2100(IRFassessment)1,RIBBON-1:capecitabinecohort2,1.GrayR,etal.JCO2009.Reprintedwithpermission2009AmericanSocietyofClinicalOncology;2.Robert,etal.ASCO20093.Miles,etal.SABCS2009;4.AvastinSmPC,51,贝伐珠单抗联合化疗显著提高ORR,*pvalueisexploratory;inpatientswithmeasurablediseaseatbaselinemg/kgq3w;ThesecombinationsarenotincludedwithinthecurrentSmPCORR=overallresponserate;Pl=placebo;P=paclitaxelD=docetaxel;T=taxaneBev=bevacizumab;Cap=capecitabineanthr=anthracycline-basedtherapy,E2100(IRF)1,2,AVADO3,1.Klencke,etal.ASCO2008;2.AvastinSmPC3.Miles,etal.SABCS20094.Robert,etal.ASCO2009,ORR(%),50%p0.0001,22%,PBev+P(n=243)(n=229),RIBBON-14,100806040200,ORR(%),64%p=0.0003*,46%,PI+DBev15+D(n=207)(n=206),100806040200,ORR(%),35%p=0.0097,24%,PI+Bev+PI+Bev+capcapT/anthrT/anthr(n=161)(n=325)(n=177)(n=345),100806040200,38%,51%p=0.0054,52,1.Cameron.EJCSuppl20082.Miles,etal.SABCS2009;3.Robert,etal.ASCO2009,贝伐珠单抗联合化疗:未延长总生存,*15mg/kgq3w;ExploratorypvaluesThesecombinationsarenotincludedwithinthecurrentSmPC,Patients,%,NR,Miles.EJCSuppl2008Miles,etal.SABCS2009Robert,etal.ASCO2009,NR=dataforATEsnotreportedforRIBBON-1studyGI=gastrointestinalLVEF=leftventricularejectionfraction;ATE=arterialthromboemboliceventsVTE=venousthromboembolicevents;*ThesecombinationsarenotincludedwithinthecurrentSmPC,Grade3events,贝伐珠单抗一线治疗MBC临床研究不良反应,其它抗血管生成剂一线治疗MBC临床研究,1.Barrios,etal.SABCS2009;2.Mackey,etal.SABCS20093.Martin,etal.ECCO/ESMO2009;4.Baselga,etal.SABCS2009;5.Gradishar,etal.SABCS2009,Patientsmusthaveprogressedduringoraftertreatmentwithbevacizumab,*Trialperformedinmixedfirst-/second-linepopulation,55,拉帕替尼,口服的双重酪氨酸激酶抑制剂，对ErbB1（EFGR）和ErbB2受体都有特异性与胞浆中激酶的ATP结合部位发生可逆性结合，从而防止受体磷酸化和受体激活,N-3-氯-4-(3-氟苯基)氧基苯基-6-5-(2(甲磺酰基)乙基氨基甲基)-2-呋喃基-4-喹唑啉胺,拉帕替尼,56,ErbB3,ErbB4,PI3K/AKTRas/MEK/MAPK(STAT),TF,CoA,CoR,增殖游走分化凋亡,TK,X,TK,TK,ErbB2,ErbB2,ErbB1/EGFR,拉帕替尼,拉帕替尼阻断ErbB家族的信号传导途径,57,EGF104535：拉帕替尼+紫杉醇一线治疗HER2阳性MBC的III期临床研究,随机分组,N=444,紫杉醇80mg/m2IV每周1次+拉帕替尼1500mgpoQD,紫杉醇80mg/m2IV每周1次+安慰剂,MBC一线FISH+*,*中心实验室进行FISH检测,开放性延长期研究拉帕替尼单药治疗,终点临床受益*OSPFS,中国(302)泰国香港巴西秘鲁,分层激素受体(阳性/阴性)和病灶部位(内脏/非内脏),主要研究终点：OS次要研究终点：PFS、ORR、CBR、安全性,58,疗效,L+P(n=222)P(n=222)OS27.8m20.5mHR0.64p=0.0005PFS9.7m6.5mHR0.52p=0.0001ORR69%50%OR2.3P0.001CBR75%56%OR2.34P0.001,59,不良反应,TheincidenceofwithdrawalfromtreatmentduetoAEs(13%vs10%)wasasimilar.,60,乳腺癌分子靶向治疗进展,转移性乳腺癌新辅助治疗,61,拉帕替尼对比曲妥珠单抗联合蒽环+紫杉的新辅助化疗：GEPARQUINTO(GBG44)研究疗效分析,UntchM,LoiblS,BischoffJ,EidtmannH,KaufmannM,BlohmerJU,HilfrichJ,StrumbergD,FaschingP,KreienbergR,TeschH,HanuschC,GerberB,RezaiM,JackischC,HuoberJ,KhnT,NekljudovaV,vonMinckwitzGOnBehalfoftheGermanBreastGroup,62,63,64,65,66,Neo-ALTTO研究：拉帕替尼、曲妥珠单抗或两者联合+紫杉醇新辅助治疗HER2阳性原发性乳腺癌的随机开放的III期临床研究,BaselgaJ,BradburyI,EidtmannH,DiCosimoS,AuraC,deAzambujaE,GomezH,DinhP,FauriaK,VanDoorenV,PaolettiP,GoldhirschA,ChangT-W,LangI,UntchM,GelberRD,Piccart-GebhartMOnBehalfoftheNeo-ALTTOStudyTeam,67,68,NSABPguidelines,breastANDlymphnodes,69,70,71,72,新辅助帕妥珠单抗联合曲妥珠单抗：一项随机II期临床研究疗效及安全性分析(NeoSphere),GianniL,PienkowskiT,ImY-H,RomanL,TsengL-M,LiuM-C,Lluch-HernandezA,SemiglazovV,SzadoT,RossG,73,帕妥珠单抗（Pertuzumab）:第一个HER2二聚体形成的抑制剂,Hubbard2005,曲妥珠单抗,帕妥珠单抗,74,HER2:HER3二聚体形成产生对曲妥珠单抗的逃避,+,+,+,+,+,+,+,+,+,+,+,Signallingactivity,+,+,+,+,Homodimers,Heterodimers,HER1:HER1,HER2:HER2,HER3:HER3,HER4:HER4,HER1:HER2,HER1:HER3,HER1:HER4,HER2:HER3,HER2:HER4,HER3:HER4,Tzaharetal.MolCellBiol1996;Serginaetal.Nature2007,帕妥珠单抗和曲妥珠单抗与HER2的不同区域结合产生协同作用,HER2receptor,Trastuzumab,Pertuzumab,SubdomainIVofHER2,DimerisationdomainofHER2,Juntilaetal.CancerCell2009,激活抗体依赖的细胞毒作用增强ErbB2的内化抑制细胞胞外结构域脱落抑制血管发生,激活抗体依赖的细胞毒作用防止受体二聚体形成是ErbB介导的信号传导途径的强效抑制剂,76,临床前研究:帕妥珠单抗和曲妥珠单抗具有协同作用,Pertuzumabtreatmentafterprogressionfollowingtrastuzumabtreatment,Meantumourvolume(mm3)SEM,6/10animalscured,6005004003002001000,01020304050607080,Treatmentperiod(days),Pertuzumab+trastuzumabinitialcombination,Vehiclecontrol,Pertuzumab(30/15mg/kg/wip),Trastuzumab(30/15mg/kg/wip),Pertuzumab(30/15mg/kg/wip)+trastuzumab(30/15mg/kg/wip),0102030405060708090,Treatmentperiod(days),Vehiclecontrol,Trastuzumab(30/15mg