TNBC三阴乳癌ppt课件

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,negativeand basal-like,Basal,but not triple negative,TNBC: 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 mut carriersTriple negative,but not basal,Clinicalassay(IHC),Gene arrays,乳腺癌的分子分型,Her2+ Her2-enriched,约占45%-60% ER和/或 PR+、Her2-、Ki6714%,Luminal A,三 阴 性,约占15%，ER-、PR 、Her-2 + IHC 3+（30%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,ProliferationClaudin 3Claudin 4Claudin 7,E-Cadherin,Normal Breast-like,Luminal Bluminal/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：CK5/6/17 50%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:,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 Center,UNS Unclassified,BL1,Basal-like1,BL2IMM,Basal-like2ImmunomodulatoryMesenchymal,LAR Luminal/Androgen receptor,TNBC的分子分型 Cell cycle/DNAreplication,p63/cell communication,TGFb/growthfactors,mesencymal MSL Mesenchymal/Stem-like,Focal Adhesion/growthfactorsstem cellAndrogen Signaling,TNBC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 and microarray,97 basal-like,75/97 (77%) TNBC,22/97 (23%) were not TNBC,97 TNBC,74/97 (76%) basal-like,23/97 (24%) not basal- like,There is substantial overlap between basal-like tumors by microarray and TNBC by IHC but approximately 25% of either type are not concordant,8 Lum A, 4 Lum B 6 HER2, 5 Normal,12 HER2,Parker JS, et al. J Clin Onc 2009;27:1160-1167.,TNBC Shares Clinical and Pathologic Features With BRCA1-Related Breast Cancers,*BRCA1 dysfunction due to germline mutations, promoter methylation, or overexpression of HMG or ID44,1. 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 TNBC,EGFR and cytokeratins,Claudin-low subtype,Basal-like tumors,TNBC ER-negative PgR-negative HER2-negative,BRCA1 mutant and BRCAness,Immune system,Different histologic subtypes,TNBC的预后1,Breast Cancer Res Treat DOI 10.1007/s10549-011-1935-y,A retrospective multi-centre cohort studyTNBC:n=371; non-TNBC:n=3287,TNBC的预后2,Breast Cancer Res Treat DOI 10.1007/s10549-011-1935-y,A retrospective multi-centre cohort studyTNBC:n=371; non-TNBC:n=3287,Responsiveness to Neoadjuvant Conventional Chemotherapy,TNBC often responsive to conventional NAC with good outcome similar to other subtypes pCR = poorer outcome,Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281.,Clinical Characteristic of Metastatic TNBC,No consistent association with nodal status or stage Relapse pattern Higher risk Early timing Sites differ from luminal: CNS 46% of time,Liedtke C, et al. J Clin Oncol. 2008;26:1275-1281. Lin NU, et al. 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,Yrs After First Surgery,Other (290 of 1421) Triple negative (61 of 180),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,Masuda H, et al. 2013 ASCO Abstract 1005.,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. ACTX,Pippen, et al. Proc ASCO 2011.,FINXX：T+XCEF亚组与RFS,Joensuu H, et al. J Clin Oncol 2011; 30:11-18.,TNBC患者卡培他滨+标准治疗：DFS的荟萃分析,Jiang Y, et al. PLoS One 2012; 7(3):e32474.,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=474,1.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),P,RR,(%),26,23,0.70,TTF (mo)OS (mo),2.88.6,4.512.8,0.0920.008,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！,CEF,CMF,BiologicSubtypeLuminal ALuminal NOSLuminal B,#623667,5 YearOS93%94%71%,#712665,5 Year pOS90%85%71%,0.0010.0001,Luminal BHeR2+/ER-Basal by IHCTNBC Non-Basal,2120359,71%55%51%65%,27233520,44%30%71%63%,Cheang M et al, ASCO 2009,TNBC对蒽环的敏感性MA.5 Revisited,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,Cortazar P, US FDA SABCS 2012.,CTNeoBC：TNBC analysis,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=0.24 P0.001,TNBC,EFS,完美模式示例,BRCA1+/TNBC:顺铂新辅助化疗BRCA1+:102 BRCA1+ patientsCDDP 75 mg/m2 x 4Byrski, JCO 2009Triple negative:, ,28 TNBC CDDP also 75 mg/m2 x 4 Prospective trial, 2/2 BRCA1+ had pCRSilver, JCO 2010,含铂新辅助化疗治疗TNBC,Burstein HJ. Presented at 2013. St. Gallen Breast Symposium.,BRCA1突变TNBC顺铂敏感性,Byrski, JCO 2009; Silver JCO 2009: Baselga ESMO 2010; Isakoff SABCS 2010,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）,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,Transcriptional ControlCellCycle,MAP Kinase Pathway,mTOR/Akt,EGFR tyrosinekinase,c-KIT tyrosine kinase,Pathway Angiogenesis,MAPK, Notch inhibitors,TNBC其他的潜在靶点dasatinib, sunitinib,cetuximab,Trabedectin, brostacillinDNA Repairpathway-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 (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),Cameron D, et al. Lancet Oncol 2013;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,Cameron D, et al. Lancet Oncol 2013;14:933-42.,次要终点：中期OS (59%的事件数),Cameron D, et al. Lancet Oncol 2013;14:933-42.,探索性分析：IDFS与VEGF-A/VEGFR-2,Cameron D, et al. Lancet Oncol 2013;14:933-42.,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),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%),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; q4w d1, d15; q4w d1, 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%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%Lobo C, et al. Breast Cancer Res Treat 2010; 123:427-435.,PFS,1.000.750.50,0.250.00,0,6,12,18,24,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 6 12 18,PFS(%)64.543.018.8,95% CI 44.0-79.1 24.7-60.16.6-35.9,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 q2wks1,R 1:1:1,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+,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=261 GC+ Iniparib,N=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,d1,8 Iniparib 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OS,ITT,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 inhibitors have demonstrated encouraging results in the treatment of TNBC.The use of antiangiogenics agents and EGFR inhibitors for treatment of TNBC has not resulted in significant improvements in outcomes.The identification of biomarkers for targeted agents and an understanding of the molecular heterogeneity of TNBC subtypes may help identify subsets of patients who may benefit from these therapies.,谢 谢,