NBC三阴乳癌ppt课件.ppt

“”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“”Triplenegativeandbasal-likeBasalbut not triplenegativeTNBC:定义ER-/PgR-/HER2-15%of all breast carcinomasPoorly differentiated;express cytokeratins 5/6,17More common in younger pts,women of African descent,BRCA 1 mutcarriersTriple negativebut not basalClinicalassay(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LuminalHER2-enrichedClaudin-lowBasal-likeHER2BasalLuminalProliferationClaudin 3Claudin 4Claudin 7E-CadherinNormal Breast-likeLuminal Bluminal/HER2Basal-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BRCA 1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:TNBCBasal-likeBRCA1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Perou C,The Oncologist 2011;16(suppl 1):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-Ingram Cancer CenterUNS UnclassifiedBL1Basal-like1BL2IMMBasal-like2ImmunomodulatoryMesenchymalLAR Luminal/AndrogenreceptorTNBC的分子分型的分子分型 Cell cycle/DNAreplicationp63/cell communicationTGFb/growthfactorsmesencymalMSL Mesenchymal/Stem-likeFocal Adhesion/growthfactorsstem cellAndrogen SignalingTNBC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)“”Breakdown of TNBC by Microarray Defined Subtypes as Assigned by PAM 50 342tumorswithER,PgR,HER2andmicroarray97basal-like75/97(77%)TNBC22/97(23%)werenotTNBC97TNBC74/97(76%)basal-like23/97(24%)notbasal-likeThereissubstantialoverlapbetweenbasal-liketumorsbymicroarrayandTNBCbyIHCbutapproximately25%ofeithertypearenotconcordant8LumA,4LumB6HER2,5Normal12HER2ParkerJS,etal.JClinOnc2009;27:1160-1167.“”TNBC Shares Clinical and Pathologic Features With BRCA1-Related Breast CancersCharacteristicsHereditary BRCA1 Triple Negative/Basal-like1-3ER/PR/HER2 statusNegativeNegativeTP53 statusMutantMutantBRCA1 statusMutational inactivation*Diminished expression*Gene-expression patternBasal-likeBasal-likeTumor histologyPoorly differentiated(high grade)Poorly differentiated(high grade)Chemosensitivity to DNA-damaging agents Highly sensitiveHighly sensitive*BRCA1dysfunctionduetogermlinemutations,promotermethylation,oroverexpressionofHMGorID441.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.Heterogeneities in the Nomenclature and Classification of TNBCEGFRandcytokeratinsClaudin-lowsubtypeBasal-liketumorsTNBCER-negativePgR-negativeHER2-negativeBRCA1mutantandBRCAnessImmunesystemDifferenthistologicsubtypes“”TNBC的的预后后1BreastCancerResTreatDOI10.1007/s10549-011-1935-yAretrospectivemulti-centrecohortstudyTNBC:n=371;non-TNBC:n=3287“”TNBC的的预后后2BreastCancerResTreatDOI10.1007/s10549-011-1935-yAretrospectivemulti-centrecohortstudyTNBC:n=371;non-TNBC:n=3287“”Responsiveness to Neoadjuvant Conventional ChemotherapyTNBC often responsive to conventional NAC with good outcome similar to other subtypes pCR=poorer outcomeLiedtkeC,etal.JClinOncol.2008;26:1275-1281.1.00.90.80.70.60.50.41YrsAfterSurgery234567ProbabilityofBeingAlivepCR/non-TNBCpCR/TNBCRD/non-TNBCRD/TNBC98%94%88%68%P=.24P=.0001“”Clinical Characteristic of Metastatic TNBCNo consistent association with nodal status or stageRelapse pattern Higher risk Early timing Sites differ from luminal:CNS46%oftimenBone,%Soft Tissue,%Viscera,%TNBC79131374ER+12339754HER2+7871281LiedtkeC,etal.JClinOncol.2008;26:1275-1281.LinNU,etal.Cancer.2008;113:2638-2645.0.350.300.250.150.100.050HR0.20012345678910YrsAfterFirstSurgeryOther(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.TNBC亚型pCR率BL152%LAR10%BL20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“”USON 01062：ACT vs.ACTXPippen,etal.ProcASCO2011.DFSOSACTACTXACTACTXTNBC N=384N=396N=384N=396 事件数(%)66(17.2)57(14.4)55(14.3)37(9.3)HR(95%CI)0.81(0.57-1.15)0.62(0.41-0.94)ER+N=837N=831N=837N=831 事件数(%)84(10.0)75(9.0)46(5.5)32(3.9)HR(95%CI)0.90(0.66-1.23)0.71(0.45-1.11)“”FINXX：T+XCEF亚组与RFSJoensuuH,etal.JClinOncol2011;30:11-18.ER+HER2-ER+HER2+ER-HER2-ER-HER2-1008060402001234567100806040201008060402010080604020时间(年)RFS(%)RFS(%)RFS(%)RFS(%)0123456701234567时间(年)TX-CEXT+CEFHR=0.9095%CI=0.44-1.86P=0.786;N=122TX-CEXT+CEFHR=0.9195%CI=0.63-1.30P=0.591;N=1009TX-CEXT+CEFHR=1.1195%CI=0.40-3.06P=0.845;N=16301234567TX-CEXT+CEFHR=0.4895%CI=0.26-0.88P=0.18;N=202“”TNBC患者卡培他滨+标准治疗：DFS的荟萃分析JiangY,etal.PLoSOne2012;7(3):e32474.研究USOFINXX总体P=0.764RR(95%CI)0.69(0.52,0.92)0.74(0.53,1.03)0.71(0.57,0.88)0.52111.92卡培他滨更好对照组更好“”CALGB9342 亚组分析:紫杉醇治疗晚期TNBCCALGB9342 1：三种剂量紫杉醇单药治疗MBC，期，n=4741.Winner EP et al.,J Clin Oncol 22:2061-2068.2.Harris LN et al.,Breast Cancer Res.2006;8(6):R66.TNBC(n=44)Non-TNBC(n=92)PRR(%)26230.70TTF(mo)OS (mo)2.88.64.512.80.0920.008高剂量组(210 mg/m2、250 mg/m2)未提高患者获益OS明显低于其他亚型！“”CEFCMFBiologicSubtypeLuminal ALuminal NOSLuminal B#6236675 YearOS93%94%71%#7126655 Year pOS90%85%71%0.0010.0001Luminal BHeR2+/ER-Basal by IHCTNBC Non-Basal212035971%55%51%65%2723352044%30%71%63%CheangMetal,ASCO2009TNBC对蒽环的敏感性MA.5 Revisited“”临床试验试验分期治疗方案三阴性患者结局Pivot(2009)III对蒽环或紫杉类耐药的转移性乳腺癌伊沙匹隆+卡培他滨vs卡培他滨ORR改善(27%vs9%)PFS延长（4.1vs2.1月)Baselga(2009)II新辅助治疗伊沙匹隆pCR=26%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：TNBC analysis1.00.80.60.40.20.0020406080100120pCR(n=389)无PCR(n=768)HR=0.24P0.001TNBCEFS完美模式示例TNBC1.41.20.60.40.811.41.80000pCROREFSHR1.00.8EFSHRpCRORR2=0.01R2=0.0031.41.20.60.41.00.8“”RegimenNpCRCMF141(7%)AC235(22%)FAC286(21%)AT252(8%)Cisplatin1210(83%)pCRtoCisplatin6(22%)ClinicalCR4(14%)ClinicalPR10(36%)Stabledisease5(17%)BRCA1+/TNBC:顺铂新辅助化疗BRCA1+:102 BRCA1+patientsCDDP 75 mg/m2 x 4Byrski,JCO2009Triple negative:28 TNBCCDDP also 75 mg/m2 x 4Prospective trial 2/2 BRCA1+had pCRSilver,JCO2010“”含铂新辅助化疗治疗TNBCBursteinHJ.Presentedat2013.St.GallenBreastSymposium.研究人群方案No.pCRByrski et al.JCO 2010BRCA1+CMF147%AC2322%FAC2821%AT258%CDDP1283%Stroh et al.Ann Oncol 2008ECisF17(17%)Silver et al.JCO 2010顺铂2821%Ryan et al.Proc ASCO 2009顺铂+BEV5116%“”TrialCharacteristicsRegimennpRCByrskiBRCA1+mutcarriersNot-platinum-based9014(16%)/BRCA1+mutcarriers2CDDP75mg/mx41210(83%)SilversporadicsTNBCs(notBRCA1+mutcarriers)2CDDP75mg/mx4264(15%)/BRCA1mutcarriers2CDDP75mg/mx422(100%)RyansporadicsTNBCs(notBRCA1+mutcarriers)CDDP75mg/m2x4+bevacizumab15mg/kgq3wkx3518(16%)BRCA1突变TNBC顺铂敏感性Byrski,JCO 2009;Silver JCO 2009:Baselga ESMO 2010;Isakoff SABCS 2010“”GoodplatinumresponseYoungage.001lowBRCA1mRNAexpression.03BRCA1promotermethylation.04p53mutation.01geneexpressionprofileofE2F3activation.03TNBC 顺铂治疗敏感人群“”三阴性非三阴性P值No.(%)265(23)863(77)pCR,%22110.034PFS(3-y),%63760.0001OS(3-y),%74890.0001三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）Liedtke et al.J Clin Oncol.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“”TranscriptionalControlCellCycleMAP Kinase PathwaymTOR/AktEGFRtyrosinekinasec-KITtyrosinekinasePathwayAngiogenesisMAPK,Notch inhibitorsTNBC其他的潜在靶点dasatinib,sunitinibcetuximabTrabedectin,brostacillinDNA Repairpathway-platinumagents,PARPinhibitorsbevacizumabMicrotubulestabilizationixabepilone“”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(0 vs.1-3 vs.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.已切除的TNBC(中心确认)浸润性乳腺癌(N=2591)研究者选择标准化疗(4-8周期)+贝伐珠单抗5mg/kg/w(n=1301)研究者选择标准化疗(4-8周期)(n=1290)R观察贝伐珠单抗单药持续共1年治疗主要终点：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DFS1.00.80.60.40.21.0661218243036424854时间(月)IDFS贝伐珠单抗+CT(n=1301)：3年IDFS83.7%；中位随访32.0个月CT(n=1290)：3年IDFS82.7%；中位随访31.5个月HR=0.8795%CI=0.72-1.07P=0.1810CameronD,etal.LancetOncol2013;14:933-42.“”次要终点：中期OS(59%的事件数)1.00.80.60.40.21.061218243036424854时间(月)OS贝伐珠单抗+CT(n=1301)CT(n=1290)HR=0.8495%CI=0.64-1.12P=0.2318CameronD,etal.LancetOncol2013;14:933-42.“”探索性分析：IDFS与VEGF-A/VEGFR-2CameronD,etal.LancetOncol2013;14:933-42.100608040200061218243036424854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)1006080402000121824303642 4854DFS(%)时间(月)6低VEGFR-2化疗(n=291)高VEGFR-2化疗(n=278)低VEGFR-2BEV+化疗(n=295)高VEGFR-2BEV+化疗(n=308)0.20.5125低高低高42/27545/28562/42125/13946/30940/28665/44621/1490.89(0.58-1.36)0.81(0.53-1.26)0.92(0.65-1.31)0.64(0.35-1.16)0.74150.3551中位(77.0pg/mL)第三个四分位数(133.6pg/mL)支持BEV+化疗支持化疗0.20.5125低高低高52/29534/30868/44818/15542/29145/27864/43123/1380.02910.0776中位(10.2pg/mL)第三个四分位数(12.7pg/mL)1.24(0.82-1.89)0.61(0.39-0.97)1.03(0.73-1.46)0.51(0.26-0.98)支持BEV+化疗支持化疗“”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/m2 d1,8,15 q4w；175 mg/m2 d1,8,q3w；多西他赛75-100 mg/m2 d1,8 q3w吉西他滨1250 mg/m2 d1,8 q3w卡培他滨1000 mg/m2 bid d1-14 q3w长春瑞滨30 mg/m2 d1,8,15q3w贝伐单抗或安慰剂(15 mg/kg q3w或10mg/kg q2w)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Brufsky A.,et al.Breast Cancer Res Treat 2012 Mar 14(Epub ahead of print)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Brufsky A.,et al.Breast Cancer Res Treat 2012 Mar 14(Epub ahead of print)“”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1500 mg/m2150 mg/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Lobo C,et al.Breast Cancer Res Treat 2010;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%CI8(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%Lobo C,et al.Breast Cancer Res Treat 2010;123:427-435.“”PFS1.000.750.500.250.0006121824时间(月)Lobo C,et al.Breast Cancer Res Treat 2010;123:427-435.三阴性ER阳性P=0.707月61218PFS(%)64.543.018.895%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/kg q2wks2对照组：紫杉醇 90mg/m2/周+贝伐单抗 10mg/kg q2wks1R1:1:1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/kg q2wks3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CALGB 40502-NCCTG N063H-CTSU 40502一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+TNBCHRP值95%CI纳米紫杉醇vs紫杉醇伊沙匹隆vs紫杉醇1.381.600.01940.00061.05-1.811.22-2.08HRP值95%CI纳米紫杉醇vs紫杉醇伊沙匹隆vs紫杉醇0.931.460.73540.06470.62-1.400.98-2.18“”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TNBCPARP1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RN=261GC+IniparibN=258吉西他滨+卡铂(GC*)q3w IV期三阴性乳腺癌 ECOG PS 0-1 允许稳定的CNS 转移灶存在 之前接受过0-2次化疗 根据之前接受化疗情况进行分层一线二/三线主要终点：OS,PFS两者之一达到即为阳性次要终点：ORR，安全性，耐受性,GCI组药代动力学疾病进展后允许交叉至GCI组(GCI)q3w吉西他滨1000 mg/m2,IV,d1,8;卡铂 AUC 2,IV,d1,8Iniparib 5.6 mg/kg,IV,d1,4,8,11在初步分析时有96%(n=152)的患者交叉至GCI组OShaughnessy,et al.2011 ASCO.Abstract#1007“”结果：PFS和OSITT“”探索性分析：二/三线ITT人群GCI组有潜在获益OS“”引发思考期研究结果令人振奋，为何期研究结果却是阴性？“”研究启示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入组患者BRCA1相关乳腺癌具体情况？两组患者的其他相关分子标记物分析？“”PARP抑制剂对晚期TNBC的临床研究汇总“”“”总结TNBC is a complex disease with distinct subtypes.DNA damaging agents such as platinum salts and PARP inhibitorshave demonstrated encouraging results in the treatment of TNBC.The use of antiangiogenics agents and EGFR inhibitors for treatmentof TNBC has not resulted in significant improvements in outcomes.The identification of biomarkers for targeted agents and anunderstanding of the molecular heterogeneity of TNBC subtypes may help identify subsets of patients who may benefit from these therapies.“”谢谢