TNBC三阴乳癌

TNBC的治疗,TNBC的治疗,生物学：TNBC的分子分型TNBC的预后临床：TNBC的化疗TNBC的靶向治疗,Triple,negativeandbasal-like,Basal,butnottriplenegative,TNBC:定义ER-/PgR-/HER2-15%ofallbreastcarcinomasPoorlydifferentiated;expresscytokeratins5/6,17Morecommoninyoungerpts,womenofAfricandescent,BRCA1mutcarriersTriplenegative,butnotbasal,Clinicalassay(IHC),Genearrays,乳腺癌的分子分型,Her2+Her2-enriched,约占45%-60%ER和/或PR+、Her2-、Ki6730%的浸润性癌细胞的胞膜呈现完整的强着色）FISH显示HER2扩增约占15%，ER-/PR/Her2，与,Luminal,HER2-enriched,Claudin-,lowBasal-like,HER2Basal,Luminal,ProliferationClaudin3Claudin4Claudin7,E-Cadherin,NormalBreast-like,LuminalBluminal/HER2,Basal-like相关联c-kit、层粘连蛋白、CK5/6高表达，p53及BRCAI突变率高均为TN型紧密连接蛋白低表达具有干细胞特征和上皮间质转化(EMT)的特征,约占5-10%，ER+/PR+、Her2-、Ki6714%ER+/PR+、Her2+、Ki67任何水平,Basal-likeClaudin-low,TN中的-75%基底细胞样：CK5/6/1750%P53突变,高增殖：Ki-67，RB和P53缺失,BRCA1突变,Claudin-low:均为TN型,紧密连接蛋白低表达具有干细胞特征和上皮间质转化(EMT)的特征,TNBC的分子分型Basal-like:,TNBC,Basal-like,BRCA1,上皮间叶转化是癌症发生转移中的一个普遍现象,波形蛋白(Vimentin)蛋白表达上调为其中的一个主要特点PerouC,TheOncologist2011;16(suppl1):6170.,Claudin水平减少细胞极性失调与肿瘤发生相关细胞黏附缺失与癌症转移相关,乳腺癌的5-10%,终生患病风险50-90%,Vanderbilt-IngramCancerCenter,UNSUnclassified,BL1,Basal-like1,BL2IMM,Basal-like2ImmunomodulatoryMesenchymal,LARLuminal/Androgenreceptor,TNBC的分子分型Cellcycle/DNAreplication,p63/cellcommunication,TGFb/growthfactors,mesencymalMSLMesenchymal/Stem-like,FocalAdhesion/growthfactorsstemcellAndrogenSignaling,TNBC可分为以下6类和1类不稳定型(UNS)基底样1(BL1)基底样2(BL2)免疫调制(IM)间质性(M)间质干细胞样(MSL)Luminal雄激素受体(LAR),BreakdownofTNBCbyMicroarrayDefinedSubtypesasAssignedbyPAM50,342tumorswithER,PgR,HER2andmicroarray,97basal-like,75/97(77%)TNBC,22/97(23%)werenotTNBC,97TNBC,74/97(76%)basal-like,23/97(24%)notbasal-like,Thereissubstantialoverlapbetweenbasal-liketumorsbymicroarrayandTNBCbyIHCbutapproximately25%ofeithertypearenotconcordant,8LumA,4LumB6HER2,5Normal,12HER2,ParkerJS,etal.JClinOnc2009;27:1160-1167.,TNBCSharesClinicalandPathologicFeaturesWithBRCA1-RelatedBreastCancers,*BRCA1dysfunctionduetogermlinemutations,promotermethylation,oroverexpressionofHMGorID44,1.PerouCM,etal.Nature.2000;406:747-752.2.CleatorS,etal.LancetOncol.2007;8:235-44.3.SorlieT,etal.ProcNatlAcadSciUSA.2001;98:10869-10874.4.MiyoshiY,etal.IntJClinOncol.2008;13:395-400.,Metzger-FilhoO,etal.JClinOncol.2012;30:1879-1887.Reprintedwithpermission.(2012)AmericanSocietyofClinicalOncology.Allrightsreserved.,HeterogeneitiesintheNomenclatureandClassificationofTNBC,EGFRandcytokeratins,Claudin-lowsubtype,Basal-liketumors,TNBCER-negativePgR-negativeHER2-negative,BRCA1mutantandBRCAness,Immunesystem,Differenthistologicsubtypes,TNBC的预后1,BreastCancerResTreatDOI10.1007/s10549-011-1935-y,Aretrospectivemulti-centrecohortstudyTNBC:n=371;non-TNBC:n=3287,TNBC的预后2,BreastCancerResTreatDOI10.1007/s10549-011-1935-y,Aretrospectivemulti-centrecohortstudyTNBC:n=371;non-TNBC:n=3287,ResponsivenesstoNeoadjuvantConventionalChemotherapy,TNBCoftenresponsivetoconventionalNACwithgoodoutcomesimilartoothersubtypespCR=pooreroutcome,LiedtkeC,etal.JClinOncol.2008;26:1275-1281.,ClinicalCharacteristicofMetastaticTNBC,NoconsistentassociationwithnodalstatusorstageRelapsepatternHigherriskEarlytimingSitesdifferfromluminal:CNS46%oftime,LiedtkeC,etal.JClinOncol.2008;26:1275-1281.LinNU,etal.Cancer.2008;113:2638-2645.,0.35,0.30,0.25,0.15,0.10,0.05,0,HR,0.20,0,1,2,3,4,5,6,7,8,9,10,YrsAfterFirstSurgery,Other(290of1421)Triplenegative(61of180),三阴性乳腺癌(TNBC)不同分子亚型患者新辅助治疗后病理完全缓解率不同,TNBC亚型与pCR状态显著相关(p=0.044)TNBC亚型为pCR状态的独立预测因素(p=0.022)Lehmann亚型分类较PAM50内在亚型(基底样vs.非基底样)能更好地预测pCR状态,MasudaH,etal.2013ASCOAbstract1005.,结论：将TNBC分为7个亚型可预测较高和较低的pCR率需要对这些结果所产生的假设进行前瞻性的验证,TNBC的治疗,生物学：TNBC的定义TNBC的分子分型TNBC的预后临床：TNBC的化疗TNBC的靶向治疗,USON01062：ACTvs.ACTX,Pippen,etal.ProcASCO2011.,FINXX：T+XCEF亚组与RFS,JoensuuH,etal.JClinOncol2011;30:11-18.,TNBC患者卡培他滨+标准治疗：DFS的荟萃分析,JiangY,etal.PLoSOne2012;7(3):e32474.,CALGB9342亚组分析:紫杉醇治疗晚期TNBCCALGB93421：三种剂量紫杉醇单药治疗MBC，期，n=474,1.WinnerEPetal.,JClinOncol22:2061-2068.2.HarrisLNetal.,BreastCancerRes.2006;8(6):R66.,TNBC(n=44),Non-TNBC(n=92),P,RR,(%),26,23,0.70,TTF(mo)OS(mo),2.88.6,4.512.8,0.0920.008,高剂量组(210mg/m2、250mg/m2)未提高患者获益OS明显低于其他亚型！,CEF,CMF,BiologicSubtypeLuminalALuminalNOSLuminalB,#623667,5YearOS93%94%71%,#712665,5YearpOS90%85%71%,0.0010.0001,LuminalBHeR2+/ER-BasalbyIHCTNBCNon-Basal,2120359,71%55%51%65%,27233520,44%30%71%63%,CheangMetal,ASCO2009,TNBC对蒽环的敏感性MA.5Revisited,伊沙匹隆对三阴性乳腺癌的作用,最常见的毒副反应为神经毒性,新辅助化疗pCR与分型,TNBC：pCR与DFS,CortazarP,USFDASABCS2012.,CTNeoBC：TNBCanalysis,1.0,0.8,0.6,0.4,0.2,0.0,0,20,40,60,80,100,120,pCR(n=389)无PCR(n=768),HR=0.24P0.001,TNBC,EFS,完美模式示例,BRCA1+/TNBC:顺铂新辅助化疗BRCA1+:102BRCA1+patientsCDDP75mg/m2x4Byrski,JCO2009Triplenegative:,28TNBCCDDPalso75mg/m2x4Prospectivetrial,2/2BRCA1+hadpCRSilver,JCO2010,含铂新辅助化疗治疗TNBC,BursteinHJ.Presentedat2013.St.GallenBreastSymposium.,BRCA1突变TNBC顺铂敏感性,Byrski,JCO2009;SilverJCO2009:BaselgaESMO2010;IsakoffSABCS2010,TNBC顺铂治疗敏感人群,三阴性乳腺癌新辅助化疗,1118例患者接受T-FAC方案,除pCR增加外，三阴性患者的预后更差（总生存率）,Liedtkeetal.JClinOncol.2008;26:1275-1281.,TNBC的治疗,生物学：TNBC的定义TNBC的分子分型TNBC的预后临床：TNBC的化疗TNBC的靶向治疗,TNBC：靶向治疗,TranscriptionalControlCellCycle,MAPKinasePathway,mTOR/Akt,EGFRtyrosinekinase,c-KITtyrosinekinase,PathwayAngiogenesis,MAPK,Notchinhibitors,TNBC其他的潜在靶点dasatinib,sunitinib,cetuximab,Trabedectin,brostacillinDNARepairpathway-platinumagents,PARPinhibitors,bevacizumabMicrotubulestabilizationixabepilone,BEATRICE：含贝伐珠单抗方案辅助治疗TNBC的随机III期研究结果,分层因素：腋窝淋巴结状态(0vs.1-3vs.4)辅助化疗(蒽环类vs.紫杉类vs.蒽环类+紫杉类)激素受体状态(阴性vs.低）手术类型(保乳vs.乳房切除),化疗：紫杉类(4周期)蒽环类(4周期)蒽环类+紫杉类(各3-4周期),CameronD,etal.LancetOncol2013;14:933-42.,主要终点：浸润性DFS(IDFS)次要终点：OS、无乳腺癌间期、DFS、DDFS、安全性、生物标志物,主要终点：IDFS,各临床亚组中，贝伐珠单抗联合化疗的IDFS均无获益,IDFS-浸润性DFS,CameronD,etal.LancetOncol2013;14:933-42.,次要终点：中期OS(59%的事件数),CameronD,etal.LancetOncol2013;14:933-42.,探索性分析：IDFS与VEGF-A/VEGFR-2,CameronD,etal.LancetOncol2013;14:933-42.,低VEGF-A化疗(n=421)高VEGF-A化疗(n=139)低VEGF-ABEV+化疗(n=446)高VEGF-ABEV+化疗(n=149),DFS(%),时间(月),安全性,贝伐珠单抗vs.单纯化疗显著增加下述不良事件3级高血压(12%vs.1%)严重心脏事件(1%vs.0.5%)停药(20%vs.2%),CameronD,etal.LancetOncol2013;14:933-42.,结论：不建议贝伐珠单抗辅助治疗未经选择的TNBC患者需要进一步随访以评估贝伐珠单抗对OS的潜在影响,紫杉醇90mg/m2d1,8,15q4w；175mg/m2d1,8,q3w；,多西他赛75-100mg/m2d1,8q3w吉西他滨1250mg/m2d1,8q3w卡培他滨1000mg/m2bidd1-14q3w长春瑞滨30mg/m2d1,8,15q3w贝伐单抗或安慰剂(15mg/kgq3w或10mg/kgq2w),化疗+安慰剂,化疗+贝伐单抗,HER2阴性局部复发/转移乳腺癌接受过一次化疗,未接受过抗VEGF治疗N=684,紫杉类或吉西他滨或,卡培他滨或长春瑞滨,2:1R,分层因素：,化疗方案从诊断到第1次进展时间ER/PR状态,BrufskyA.,etal.BreastCancerResTreat2012Mar14(Epubaheadofprint),贝伐单抗联合二线化疗治疗TNBC的疗效RIBBON-2研究亚组分析研究者决定化疗方案,治疗直至疾病进展；进展后允许,两组交叉,二线化疗联合贝伐单抗治疗TNBC人群,PFS显著获益，OS有延长趋势,BrufskyA.,etal.BreastCancerResTreat2012Mar14(Epubaheadofprint),n=30，其中TNBC13例(44.8%)给药方式,主要终点：PFS次要终点：ORR、OS、安全性,药物吉西他滨nab紫杉醇贝伐单抗,剂量1500mg/m2150mg/m210mg/kg,途径静脉静脉静脉,给药时间d1,d15;q4wd1,d15;q4wd1,d15;q4w,吉西他滨/nab紫杉醇联合贝伐单抗：一线治疗单中心、开放标签的II期研究,1例患者不符合入组标准，未纳入分析LoboC,etal.BreastCancerResTreat2010;123:427-435.,吉西他滨/nab紫杉醇联合贝伐单抗：结果,总患者(n=29),TNBC(n=13),完全缓解(CR)部分缓解(PR)疾病稳定(SD)a疾病进展临床获益率(CR+PR+SD)18个月PFS率95%CI18个月OS率95%CI,8(27.6%)14(48.3%)5(17.2%)2(6.9%)27(93.1%)18.86.6-35.877.2%51.1-90.5%,5(38.4%)4(30.7%)2(13.4%)2(13.4%)11(84.6%)10.6%0.6-36.882.5%46.1-95.3%,a根据RECIST，病灶缩小30%LoboC,etal.BreastCancerResTreat2010;123:427-435.,PFS,1.000.750.50,0.250.00,0,6,12,18,24,时间(月)LoboC,etal.BreastCancerResTreat2010;123:427-435.,三阴性ER阳性P=0.707,月61218,PFS(%)64.543.018.8,95%CI44.0-79.124.7-60.16.6-35.9,吉西他滨/nab紫杉醇联合贝伐单抗：结果中位PFS：10.4个月(95%CI：5.6-15.2),N=900(计划),分层紫杉类辅助ER/PR状态,贝伐单抗10mg/kgq2wks2,对照组：紫杉醇90mg/m2/周+贝伐单抗10mg/kgq2wks1,R1:1:1,每2个周期后重新分期直至PD,试验组2：伊沙匹隆16mg/m2/周+贝伐单抗10mg/kgq2wks3所有化疗方案使用3周，停1周6个周期后如果CR/PR/SD,患者可以停止化疗，继续贝伐单抗单药治疗,CALGB40502-NCCTGN063H-CTSU40502一线治疗局部复发或转移性乳腺癌III期研究试验组1：纳米紫杉醇150mg/m2/周+,PFS分析,ER+,TNBC,HR,P值,95%CI,纳米紫杉醇vs紫杉醇伊沙匹隆vs紫杉醇,1.381.60,0.01940.0006,1.05-1.811.22-2.08,HR,P值,95%CI,纳米紫杉醇vs紫杉醇伊沙匹隆vs紫杉醇,0.931.46,0.73540.0647,0.62-1.400.98-2.18,3度以上不良事件,纳米紫杉醇(n=258),紫杉醇(n=262),伊沙匹隆(n=237),血液毒性非血液毒性任何不良事件(血液或非血液),51%P0.000160%P=0.000279%,21%44%55%,12%P=0.00456%P=0.00559%,贝伐单抗对晚期TNBC的临床研究汇总,其他VEGF-TKI对晚期TNBC的临床研究汇总,PRAP1治疗TNBC,PARP1抑制剂能阻止,BRCA1和BRCA2修复受损的双链DNA,而导致细胞死亡或细胞调亡,吉西他滨/卡铂联合Iniparib治疗TNBC,吉西他滨/卡铂联合Iniparib治疗TNBC,吉西他滨/卡铂联合Iniparib治疗TNBC多中心随机化期研究,R,N=261GC+Iniparib,N=258吉西他滨+卡铂(GC*)q3w,IV