TNBC三阴乳癌.ppt

TNBC的治疗的治疗TNBC的治疗的治疗n n生物学：n nTNBCTNBC的分子分型的分子分型n n TNBCTNBC的预后的预后n n临床：n nTNBCTNBC的化疗的化疗n nTNBCTNBC的靶向治疗的靶向治疗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-lowTN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(BL 1)基底样2(BL 2)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 50 342 tumors with ER,PgR,HER2 andmicroarray97 basal-like75/97(77%)TNBC22/97(23%)were notTNBC97 TNBC74/97(76%)basal-like23/97(24%)not basal-likeThere is substantial overlap between basal-like tumors by microarray and TNBC by IHC but approximately 25%of either type are not concordant8 Lum A,4 Lum B6 HER2,5 Normal12 HER2Parker JS,et al.J Clin Onc 2009;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*BRCA1 dysfunction due to germline mutations,promoter methylation,or overexpression of HMG or ID441.Perou CM,et al.Nature.2000;406:747-752.2.Cleator S,et al.Lancet Oncol.2007;8:235-44.3.Sorlie T,et al.Proc Natl Acad Sci U S A.2001;98:10869-10874.4.Miyoshi Y,et al.Int J Clin Oncol.2008;13:395-400.Metzger-Filho O,et al.J Clin Oncol.2012;30:1879-1887.Reprinted with permission.(2012)American Society of Clinical Oncology.All rights reserved.Heterogeneities in the Nomenclature and Classification of TNBCEGFR andcytokeratinsClaudin-lowsubtypeBasal-liketumorsTNBCER-negativePgR-negativeHER2-negativeBRCA1 mutantand BRCAnessImmune systemDifferent histologicsubtypesTNBC的的预后后1Breast Cancer Res Treat DOI 10.1007/s10549-011-1935-yA retrospective multi-centre cohort study TNBC:n=371;non-TNBC:n=3287TNBC的的预后后2Breast Cancer Res Treat DOI 10.1007/s10549-011-1935-yA retrospective multi-centre cohort study TNBC:n=371;non-TNBC:n=3287Responsiveness to Neoadjuvant Conventional Chemotherapyn nTNBC often responsive to conventional NAC with good outcome similar to other subtypesTNBC often responsive to conventional NAC with good outcome similar to other subtypesn n pCR=poorer outcome pCR=poorer outcomeLiedtke C,et al.J Clin Oncol.2008;26:1275-1281.1.00.90.80.70.60.50.41Yrs After Surgery234567Probability of Being AlivepCR/non-TNBCpCR/TNBCRD/non-TNBCRD/TNBC98%94%88%68%P=.24P=.0001Clinical Characteristic of Metastatic TNBCn nNo consistent association with nodal status or stagen nRelapse patternn nHigher riskHigher riskn nEarly timingEarly timingn nSites differ from Sites differ from luminal:luminal:n nCNS 46%of timeCNS 46%of timenBone,%Soft Tissue,%Viscera,%TNBC79131374ER+12339754HER2+7871281Liedtke C,et al.J Clin Oncol.2008;26:1275-1281.Lin NU,et al.Cancer.2008;113:2638-2645.0.350.300.250.150.100.050HR0.20012345678910Yrs After First SurgeryOther(290 of 1421)Triple negative(61 of 180)三阴性乳腺癌三阴性乳腺癌(TNBC)不同分子不同分子亚型患者亚型患者新辅助治疗后病理完全缓解率不新辅助治疗后病理完全缓解率不同同n nTNBCTNBC亚型与亚型与pCRpCR状态显著相关状态显著相关 (p=0.044)(p=0.044)n nTNBCTNBC亚型为亚型为pCRpCR状态的独立预测因素状态的独立预测因素 (p=0.022)(p=0.022)n nLehmannLehmann亚型分类较亚型分类较PAM50PAM50内在亚型内在亚型 (基底样基底样 vs.vs.非基底样非基底样)能更好地预测能更好地预测pCRpCR状态状态Masuda H,et al.2013 ASCO Abstract 1005.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的治疗的治疗n n生物学：n nTNBCTNBC的定义的定义n nTNBCTNBC的分子分型的分子分型n n TNBCTNBC的预后的预后n n临床：n nTNBCTNBC的化疗的化疗n nTNBCTNBC的靶向治疗的靶向治疗USON 01062：ACT vs.ACTXPippen,et al.Proc ASCO 2011.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亚组与亚组与RFSJoensuu H,et al.J Clin Oncol 2011;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=202TNBC患者卡培他滨患者卡培他滨+标准治疗：标准治疗：DFS的荟萃分析的荟萃分析Jiang Y,et al.PLoS One 2012;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DFSCortazar P,US FDA SABCS 2012.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TNBC1.41.20.60.40.811.41.80000pCR OREFS HR1.00.8EFS HRpCR ORR2=0.01R2=0.0031.41.20.60.41.00.8RegimenNpCRCMF141(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含铂新辅助化疗治疗TNBCBurstein HJ.Presented at 2013.St.Gallen Breast Symposium.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 2010GoodplatinumresponseYoungage.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的治疗的治疗n n生物学：n nTNBCTNBC的定义的定义n nTNBCTNBC的分子分型的分子分型n n TNBCTNBC的预后的预后n n临床：n nTNBCTNBC的化疗的化疗n nTNBCTNBC的靶向治疗的靶向治疗TNBC：靶向治疗TranscriptionalControlCellCycleMAP Kinase PathwaymTOR/AktEGFRtyrosinekinasec-KITtyrosinekinasePathwayAngiogenesisMAPK,Notch inhibitorsTNBC其他的潜在靶点dasatinib,sunitinibcetuximabTrabedectin,brostacillinDNA Repairpathway-platinumagents,PARPinhibitorsbevacizumabMicrotubulestabilizationixabepiloneBEATRICE：含贝伐珠单抗方案：含贝伐珠单抗方案辅助治疗辅助治疗TNBC的随机的随机III期研究期研究结果结果n n分层因素：分层因素：n n腋窝淋巴结状态腋窝淋巴结状态 (0 vs.1-3 vs.(0 vs.1-3 vs.4)4)n n辅助化疗辅助化疗 (蒽环类蒽环类 vs.vs.紫杉类紫杉类 vs.vs.蒽环类蒽环类+紫杉类紫杉类)n n激素受体状态激素受体状态 (阴性阴性 vs.vs.低）低）n n手术类型手术类型 (保乳保乳 vs.vs.乳房切除乳房切除)n n化疗：化疗：n n紫杉类紫杉类 (4 4周期周期)n n蒽环类蒽环类 (4 4周期周期)n n蒽环类蒽环类+紫杉类紫杉类 (各各3-43-4周期周期)Cameron D,et al.Lancet Oncol 2013;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：主要终点：IDFSn n各临床亚组中，贝伐珠单抗联合化疗的各临床亚组中，贝伐珠单抗联合化疗的IDFSIDFS均无获益均无获益IDFS-浸润性DFS 1.00.80.60.40.21.0661218243036424854时间(月)IDFS贝伐珠单抗+CT(n=1301)：3年IDFS 83.7%；中位随访32.0个月CT(n=1290)：3年IDFS 82.7%；中位随访31.5个月HR=0.8795%CI=0.72-1.07P=0.1810Cameron D,et al.Lancet Oncol 2013;14:933-42.次要终点：中期次要终点：中期OS(59%的事件的事件数数)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=0.2318Cameron D,et al.Lancet Oncol 2013;14:933-42.探索性分析：探索性分析：IDFS与与VEGF-A/VEGFR-2Cameron D,et al.Lancet Oncol 2013;14:933-42.100608040200061218243036424854低VEGF-A 化疗(n=421)高VEGF-A 化疗(n=139)低VEGF-A BEV+化疗(n=446)高VEGF-A BEV+化疗(n=149)DFS(%)时间(月)10060804020001218243036424854DFS(%)时间(月)6低VEGFR-2 化疗(n=291)高VEGFR-2 化疗(n=278)低VEGFR-2 BEV+化疗(n=295)高VEGFR-2 BEV+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(77.0 pg/mL)第三个四分位数(133.6 pg/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(10.2 pg/mL)第三个四分位数(12.7 pg/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安全性n n贝伐珠单抗 vs.单纯化疗显著增加下述不良事件n n 3 3级高血压级高血压 (12%vs.1%)(12%vs.1%)n n严重心脏事件严重心脏事件 (1%vs.0.5%)(1%vs.0.5%)n n停药停药 (20%vs.2%)(20%vs.2%)Cameron D,et al.Lancet Oncol 2013;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0.931.460.73540.06470.62-1.400.98-2.183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%贝伐单抗对晚期贝伐单抗对晚期TNBC的临床的临床研究汇总研究汇总其他其他VEGF-TKI对晚期对晚期TNBC的临床研究汇总的临床研究汇总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抑制剂对晚期抑制剂对晚期TNBC的临的临床研究汇总床研究汇总总结总结n nTNBC is a complex disease with distinct subtypes.TNBC is a complex disease with distinct subtypes.n n DNA damaging agents such as platinum salts and PARP inhibitors DNA damaging agents such as platinum salts and PARP inhibitorshave demonstrated encouraging results in the treatment of TNBC.have demonstrated encouraging results in the treatment of TNBC.n n The use of antiangiogenics agents and EGFR inhibitors for treatment The use of antiangiogenics agents and EGFR inhibitors for treatmentof TNBC has not resulted in significant improvements in outcomes.of TNBC has not resulted in significant improvements in outcomes.n n The identification of biomarkers for targeted agents and an The identification of biomarkers for targeted agents and anunderstanding of the molecular heterogeneity of TNBC subtypes may help identify understanding of the molecular heterogeneity of TNBC subtypes may help identify subsets of patients who may benefit from these therapies.subsets of patients who may benefit from these therapies.谢谢谢谢