三阴性乳腺癌的治疗进展--吴新红.ppt

三阴性乳腺癌的治疗现状,2011年StGallen共识乳腺癌亚型,亚型定义LuminalA型ER和（或）PR阳性，HER2阴性，Ki67低表达（14%）LuminalB型LuminalB（HER2阴性），ER和（或）PR阳性，HER2阴性，Ki67高表达（14%）LuminalB（HER2阳性），ER和（或）PR阳性，HER2过表达或增殖，Ki67任何水平HER-2过表达型HER2阳性（非Luminal），ER和PR缺失，HER2过表达或增殖基底样型三阴性（导管），ER和PR缺失，HER2阴性,一、三阴性乳腺癌（TNBC）:概念,Triplenegativeandbasal-like,Basalbutnottriplenegative15-40%areER+,PR+orHER2+,Triplenegativebutnotbasal,Clinicalassay(IHC),Genearrays,ER-/PgR-/HER2-,BRCA1、Basal-Like、TNBC乳腺癌的关系,LeslieK.etal.Adv.Anat.Pathol.2007;14:419-430,Basal-like,TripleNegative,BRCA1,二、TNBC的风险因素(排除BRCA状态),YoungerageatmenarcheHigherparityYoungerageatfulltermpregnancyShorterdurationofbreastfeedingHighbodymassindex(BMI)HighwaisttohipratioLackofexercise,Fulfordetal,Histopathology2006;Livasyetal,ModPathol,2006,BauerKRCancer2007CareyJAMA2006,三、TNBC预后因素,LargetumorsizePresenceofnodalmetastasisPresenceofdistantmetastasisPresenceofcentralnecrosisAbsenceofandrogenreceptorBasalphenotypeEGFRAge40?(Liedtkeetal.ASCO2010),占所有乳腺癌病理类型的10.0%20.8%；具有特殊的生物学行为和临床病理特征；预后较其他类型差；多发生于绝经前年轻女性；尤其是非洲裔美国妇女：50岁以下非洲裔美国妇女的发病率甚达39%；白种人则仅为16%。,四、TNBC流行病学,组织学分级多为级,细胞增殖比例较高,c-kit、p53、EGFR表达多为阳性,基底细胞标志物细胞角蛋白(CK)5/6、17也多为阳性。,五、TNBC分子病理特征,临床表现为侵袭性病程；远处转移风险较高,内脏转移几率较骨转移高,脑转移几率也较高。预后较差,死亡风险较高。,六、TNBC临床特征,TNBC:ShorterMedianTimefromDistantRelapsetoDeath,22months,9months,DentR,TrudeauM,PritchardK,HanaW,NarodS.etal.ClinicalCancerRes2007,“TripleNegative”,OtherBreastCancer,TNBC与Non-TNBC的生存比较,TNBC:RecurrenceandSurvival,IncreasedlikelihoodofdistantrecurrenceVisceralmetastasestobrain,lung,anddistantnodalsitescommonMetastasestoboneandliverlesscommonRelapsemostlikelyduringthefirst3yaftertherapyMajorityofdeathswithinfirst5yBy10years,OSdifferencesbetweenTNBC26:1275-1281.,(4)AdjuvantAnthracycline+TaxaneforTNBC,Hughetal.JClinOncol.2009;27:1168-1176.,DFS(BCIRG001):TACvsFAC(n=192),OS:ACTvsATT(N=378),Loeschetal.JClinOncol.2010;28:2958-2965,(5)sequentialchemotherapyforTNBC,PACS01试验（期随机临床试验）针对淋巴结阳性乳腺癌患者FEC6VSFEC3序贯D3，序贯治疗组中,基底样乳腺癌患者的无病生存(DFS)率(P=0.05)和总生存(OS)率(P=0.005)较好。因此,虽然基底样乳腺癌的预后较差,但对FEC序贯多西他赛化疗有较好的反应。,高危乳腺癌术后辅助化疗的期临床试验(2007年ASCO报告)A组：AC4序贯P(175mg/m2,Q3W)4B组：AP4序贯P(80mg/m2,QW)12结论:对于三阴性乳腺癌,AP序贯P组五年OS优势更加明显(87%对79%,P=0.037)。紫杉类药物对TNBC有一定的疗效,序贯方式也可能是其获得较好疗效的方式之一。研究结果均来自试验的亚组分析或回顾性分析,尚需前瞻性研究的证实。,(6)PlatinumAgentsforTNBC,Carbo=carboplatin;Cis=cisplatin;D=docetaxel;E=epirubicin;F=5-FU;H=trastuzumab;P=paclitaxel;retro=retrospective.,(7)Highdosechemotherapy(HDC)forTNBC,WSGAM01试验9个以上淋巴结阳性的乳腺癌患者分为两组A组：密集EC2序贯HDC2(EPI90mg/m2,CTX3g/m2,塞替派400mg/m2)B组：密集EC4序贯密集CMF3结果表明,年轻的三阴性乳腺癌患者从HDC中获益最多。,(8)MoleculartargetedtherapiesforTNBC,CellCycle,TranscriptionalControl,MAPKinasePathway,AktPathway,EGFRtyrosinekinase,c-KITtyrosinekinase,DNARepairpathway-platinumagents,PARPinhibitors,Angiogenesis,Microtubulestabilization,MAPK,Notchinhibitors,dasatinib,sunitinib,cetuximab,ixabepilone,Trabedectin,brostacillin,bevacizumab,BevacizumabforTNBC,*MedianPFSvsnon-TNBCsubgroup.,Thomssen,etal.SABCS2009.Abstract6093.OShaughnessyJ,etal.SABCS2009.Abstract207.,OSinTNBCpopulationshowednodifferencebetweenbevandnon-bevtreatedgroups(HR=0.96;95%CI:0.79-1.16)OShaughnessyetal.ASCO2010,EGFRInhibitionforTNBC,TNBCstronglyassociatedwithEGFRexpressionEGFRinhibitorscombinedwithplatinumCurrentdataconflicting,EfficacydatafromphaseIItrials,NR=notreported;PFS=progression-freesurvival;RR=responserate;TBCRC=TranslationalBreastCancerResearchConsortium,Careyetal.ASCO2008;abstr1009;OShaughnessyetal.SABCS2007;abstr308.,OtherTargetsforTNBC,AdaptedfromTanandSwain.CancerJournal.2008;14.,PARP1inBreastCancer,*definedbypercentageofsamplesexceedingthe95%UCLofnormaltissuedistribution,Infiltratingductalcarcinoma(IDC)isahighlyinvasivetumor,accountingfor70-80%ofallbreastmalignanciesIDCshowsstatisticallysignificantPARP1upregulationincomparisonwithnormalbreasttissues:p=2x10-27PARP1isupregulatedinTNBC,Therateofclinicalbenefitfrom34%to56%(P=0.01)Therateofoverallresponsefrom32%to52%(P=0.02).PFS：3.6Mto5.9M(hazardratioforprogression,0.59;P=0.01)OS：7.7Mto12.3M(hazardratiofordeath,0.57;P=0.01).,(9）RadiotherapyforTNBC,Haffty等对442（100TNBC)例保乳手术乳腺癌进行了分析,比较局部复发和远处转移TNBC的OS(67%对75%,P=0.096)、无远处转移生存率(61%对75%,P=0.002)、特异性生存率(67%对78%,P=0.03)和无淋巴结转移生存率(93%对99%,P=0.021)局部控制率方面没有差异(均为83%),证明了其对放射线的敏感性,（10）TNBC:OngoingClinicalTrials,NumerousprospectivetrialsongoingtoevaluatevarioustherapeuticoptionsspecificallyinTNBCMostincludeTNBCpopulationsonlyStudiesincludetargetedagents,vaccinesAcrossstagesofdisease,（11）TNBC:Conclusions,TNBCisadistinctsubtypeofBCandisassociatedwithtreatmentchallengesduetoitsaggressivenatureTNBChasnospecifictargetyetAntracyclineandtaxanework(butnotverywell)MolecularpathwaysthatcontroltumordevelopmentcoulddeterminetreatmentPlatinum-basedchemotherapyisemergingasbackboneofnewtreatmentsIntrod