培训资料-her阳性乳腺癌辅助治疗.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,*,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,HER2,阳性早期乳腺癌辅助治疗,江西省肿瘤医院乳腺科,孙正魁,内容提要,HER2,是乳腺癌的独立预后因子,分类,中位生存期,HER-2,阳性,3,年,HER-2,阴性,6,7,年,HER2,阳性是乳腺癌的独立预后因子,1.00,0.75,0.50,0.25,0,累计生存率,0 24 48 72 96 120 144,无扩增,扩增,基因扩增,:10,拷贝数,无基因扩增,:3,拷贝数,临界值,:,不包括,死亡时间,(,月数,),Log rank p0.001,淋巴结阴性,100,80,60,40,20,0,0 12 24 36 48 60 72,死亡时间,(,月数,),HER2,基因,3,拷贝数,HER2,基因,3,拷贝数,对数秩检验,p=0.001,淋巴结阳性,Seshadri R et al.J Clin Oncol 1993;11:1936,Ross JS,Fletcher JA.Stem Cells 1998;16:413,HER2,过表达型内脏转移率显著高于其他亚型,Metzger-Filho O,Sun Z,Viale G,et alJournal of clinical oncology,2013,31(25):3083-3090内脏转移（,%,）,时间（年）,P=0.003,Pritchard et al.N Engl J Med 2006;354:2103-11.,FISH,检测,HER2,基因扩增,FISH,检测,HER2,基因不扩增,预测蒽环疗效：,MA.5 trial:CEF vs.CMF,HER2,是乳腺癌的疗效预测因子,Hayes at al.N Engl J Med 2007;357:1496-506.,FISH,检测,HER2,基因扩增,FISH,检测,HER2,基因不扩增,预测紫杉疗效：,CALGB 9344:CA-P vs.CA,HER2,是乳腺癌的疗效预测因子,预测赫赛汀疗效：,改变,HER2,+,乳腺癌的自然病程,1991-2007,Dawood S.,et al.,J Clin Oncol,.,2009;28:92.,HER2,是乳腺癌的疗效预测因子,HER2,阳性早期乳腺癌辅助治疗进展,CMF,蒽环类,紫杉类,靶向治疗,1 Weiss,R.B.,et al.(2003).J Clin Oncol 21(9):1825-1835.2 Fisher,B.,et al.(1990).J Clin Oncol 8(9):1483-1496.3 Mackey,J.R.,et al.(2013).Lancet Oncol 14(1):72-80.4 Goldhirsch A,et alESMO 2012:LBA6;SABCS 2012:S5-2,内容提要,赫赛汀显著提高早期乳腺癌,DFS,和,OS,HERA,联合,BCIRG 006,B-31/,N-9831,FinHER,0.61,（,0.43,0.86,）,0.65,（,0.47,0.90,）,0.66,（,0.57,0.77,）,0.43,（,0.17,1.04,）,0.70,（,0.57,0.85,）,0.67,（,0.54,0.82,）,0.68,（,0.58,0.79,）,0.62,（,0.56,0.68,）,0.44,（,0.24,0.82,）,0.56,（,0.48,0.65,）,研究,相对风险（,95%CI,）,相对风险（,95%CI,）,DFS,OS,Meta,分析，五项临床试验，,13,493,例早期乳腺癌患者，随访,5-10,年,HER2+EBC,使用曲妥珠单抗辅助治疗,复发风险降低,38%,，死亡率降低,34%,Dahabreh IJ,et al.The Oncologist.2008;13(6):620-630.,随访证实赫赛汀耐受性良好,De Azambuja E,et al.2013 ASCO Abstract 525;,Perez EA,et al.SABCS 2012.,;,Slamon D,et al.,2011;,.,HERAB-31/N9831,联合分析,BCIRG 006,H 1 yearAC,PH,AC,DH,TCH,4.1,NR,18.08.6,严重,CHF,%,心源性死亡,%,LVEF,下降,%,a,分组,EBC,研究,LVEF,：左室射血分数,a,：由于不同的评估标准，数据不具可比性,16822028,1068,1056,n,0.8,1.9,1.90.4,0,0,.1,00,赫赛汀在,EBC,多个大型临床研究中心血管耐受性情况,随访年数,8,8.4,5,HER2,阳性乳腺癌治疗指南推荐,St.Gallen,共识,NCCN,指南,中国抗癌协会指南,HR,*,+/HER2+,化疗,+,抗,HER2,治疗,+,内分泌治疗,HR,*,-/HER2+,化疗,抗,HER2,治疗,内容提要,曲妥珠单抗在,HER2,阳性早期乳腺癌辅助治疗的研究,研究,方案,DFS,OS,HR(95%CI),P,值,HR(95%CI),P,值,HERA 8,年随访,1,CT RT,CT RT,H,0.76,0.0001,0.76,0.0005,NCCTG N9831/NSABP B-31,10,年随访,2,ACT,H,ACT,0.60,(0.530.68),0.0001,0.63,(0.540.73),0.0001,BCIRG 006 5,年随访,3,ACT,H,ACT,0.64,(0.530.78),0.001,0.63,(0.480.81),0.001,TC,HACT,0.75,(0.630.90),0.04,0.77,(0.600.99),0.038,1.Goldhirsch A,et al.ESMO 2012;2.Perez EA,et al.SABCS 2012.;3.Slamon D,et al.,2011,曲妥珠与化疗（,NCCTG N9831,）,：序贯,vs.,联合,多中心、随机,III,期研究,主要终点：,DFS,A,多柔比星,C,环磷酰胺,T,紫杉醇,H,曲妥珠单抗,浸润性乳腺癌,HER2,阳性,I-III,期,N=3505,术后随机,1,年,1,年,Perez EA,et al.J Clin Oncol 2011;29:44914497,.,曲妥珠单抗与化疗,(NCCTG N9831):,序贯,vs.,联合,100,80,60,40,20,0,1,0,3,2,5,4,7,6,0,1,0,3,2,5,4,7,6,OS(%),DFS(%),100,80,60,40,20,时间,(,年,),时间,(,年,),AC,THH(n=949),5,年,84.5%,ACTH(n=954),5,年,80.1%,AC,THH(n=949),5,年,91.9%,ACTH(n=954),5,年,89.7%,DFS,HR=0.77,95%CI:0.53-1.11,P=0.022,OS,HR=0.78,95%CI:0.58-1.05,P=0.102,曲妥珠单抗序贯比联合化疗可降低复发风险达,23%(P=0.022)*,曲妥珠单抗序贯比联合化疗未能显著降低死亡风险,(P=0.102,),分组,CHF,发生率,AC-TH(570),3.3%,AC-T-H(710),2.8%,APHINITY,：曲妥珠,+,帕妥珠辅助,主要终点：浸润性,DFS,次要终点：浸润性,DFS,包括继发非乳腺癌；,DFS,、,OS,、,RFS,、无远处复发间期、心脏安全性、总安全性、,QOL,2011,2012,20132023,2024,2011,年,11,月：首例患者,预计完成：,2024,年,8,月,抗,HER2,治疗,1,年,(52,周,),术后,7,周内随机,第,2,组,手术,第,1,组,R,中心确认,HER2,状态,曲妥珠单抗,帕妥珠单抗,AT,或,TC,6-8,个周期,曲妥珠单抗,安慰剂,10,年,随访,1,周内开始治疗,6-8,个周期,AT,或,TC,www.clinicaltrials.gov/ct2/show/NCT01358877.,辅助,/,新辅助化疗方案,优选方案：,AC-THP,或,TCHP,NCCN,指南解释：,T2,或,N1,的早期病人可使用帕妥珠单抗,新辅助未使用过帕妥珠单抗的病人可在辅助阶段使用,其他方案：,AC-,多西他赛,+,曲妥珠单抗,帕妥珠单抗*,FEC-,多西他赛,+,曲妥珠单抗,+,帕妥珠单抗*,FEC-,紫杉醇,+,曲妥珠单抗,+,帕妥珠单抗*,紫杉醇,+,曲妥珠单抗,帕妥珠单抗,+,曲妥珠单抗,+,多西他赛,-FEC*,帕妥珠单抗,+,曲妥珠单抗,+,紫杉醇,-FEC*,延迟用药是否获益：,HERA,研究,HER2-,阳性可手术乳腺癌,(IHC 3+,和,/,或,FISH+),（,n=5102,）,手术,+(,新,),辅助化疗,+,放疗,赫赛汀,q3w x 1,年,（,n=1703,）,观察组,（,n=1701,）,赫赛汀,q3w x 2,年,（,n=1698,）,2005,年中期分析,885,例交叉接受赫赛汀治疗,469,继续留在观察组,最终,1698,例患者初始分配至观察组,1354,例患者,无病生存,延迟使用赫赛汀一年辅助治疗仍有显著,DFS,获益,100,80,60,40,20,0,0,无病生存患者,(%),6,12,18,24,30,36,42,48,观察组,:2005,年,5,月,16,日时无病生存患者,随机分组后,（,月,）,1354,1353,1339,1316,1278,1239,1180,992,712,885,885,884,878,870,851,822,690,480,选择赫赛汀,治疗患者,469,468,455,438,408,388,358,302,232,未选择赫赛汀,治疗患者,交叉入组患者开始治疗中位时间：,22.8,个月,选择交叉治疗,vs.,无交叉治疗：校正后,HR=0.68,，,P=0.0077,Gianni L,et al.St.Gallen 2009.Abstr S25,内容提要,Outcomes for T1a/bN0 HER2+Tumors,HER2,状态,n,5,年,RFS,阳性,98,77.1%,阴性,867,93.7%,J Clin Oncol.2014;32(20):2142-50,HER2,状态,n,5,年,DFS,阳性,255,83.3%,阴性,3127,89.1%,J Clin Oncol 27:5700-5706.,J Clin Oncol.2010 Oct 1;28(28):e541-2,AERIO retrospectively reviewed 20022008,APT,：研究设计,HER2+,ER+,或,ER-,淋巴结阴性,肿瘤小于等于,3cm,入组,406,例,入组,P 80mg/m2,T 2mg/kg,12,周期 单周方案,T 6mg/kg*,13,周期 三周方案,Ruddy KJ,et al.2013 SABCS P3-08-05.,*剂量可调整为,2mg/kg IV,单周 持续,40,周,*完成紫杉醇化疗后可开始放疗及内分泌治疗,患者特征,N,%,年龄,70,41,10,原发肿瘤大小,T1a 0.5cm,77,19,T1b 0.5-1.0cm,124,31,T1c 1.02.0cm,169,42,T2 2.0-3.0cm,36,9,患者特征,N,%,组织学分级,I,高分化,44,11,II,中分化,131,32,III,低分化,228,56,HR,状态（,ER,和,/,或,PR,）,阳性,272,67,阴性,134,33,50%,50%,Tolaney SM,et al.SABC2013 Abstract S1-04.,APT trial,：,DFS,曲妥珠单抗用于,HER2,阳性小肿瘤,NCCN,指南及,St Gallen,共识,NCCN guidelines for breast cancer 2014 v2,治疗阈值为,T1b,也有部分专家认为,HER2,阳性肿瘤不论大小均应适用曲妥珠单抗,辅助,/,新辅助化疗方案,优选方案：,AC-THP,或,TCHP,NCCN,指南解释：,T2,或,N1,的早期病人可使用帕妥珠单抗,新辅助未使用过帕妥珠单抗的病人可在辅助阶段使用,其他方案：,AC-,多西他赛,+,曲妥珠单抗,帕妥珠单抗*,FEC-,多西他赛,+,曲妥珠单抗,+,帕妥珠单抗*,FEC-,紫杉醇,+,曲妥珠单抗,+,帕妥珠单抗*,紫杉醇,+,曲妥珠单抗,帕妥珠单抗,+,曲妥珠单抗,+,多西他赛,-FEC*,帕妥珠单抗,+,曲妥珠单抗,+,紫杉醇,-FEC*,内容提要,Her2+,型,-pCR,的意义,J Clin Oncol 30:17961804,荟萃分析,DFS in HER2+tumor,FDA,：,CTNeoBC Meta-analysis,，,pCR,率,1TRIALS Patients(n),GBG/AGO:7,：,6377,NSABP:2,：,3171,EORTC/BIG:1,：,1856,ITA:2,：,1589,Total#patients,：,12993,Study ref.,n,Stage,Neoadjuvant therapy,pCR rate%,(definition),MDAndersonBuzdar et al.,42,II-IIIA,P/3 weeks(4C)FEC(4C),concomitant weekly trastuzumab,65%versus 26%(ypT0/is ypN0),NOAH,Gianni et al.2010,235,Only LABC,(26%cT4d),A+P/3 weeks(3C)P/3 weeks(4C)CMF(3C),concomitant 3 weeks trastuzumab,38%versus 19%(ypT0/is ypN0),GeparQuattroUntch et al.2010,445,II-III,(10%cT4d),EC 4 D X,+concomitant trastuzumab/3 weeks,40%(ypT0/is ypN0),HannaH,Ismael et al.2012,596,II-III,D(4C)FEC-75(4C)+concomitant 3 weeks trastuzumab intravenously or subcutaneously,34%versus 39%(ypT0/is ypN0),Randomized phase III trials of chemotherapy and trastuzumab in the neoadjuvant setting,ACOSGO Z1041,：,HER2+,可手术,BC(N=282),FECP+T,(n=140*),P+TFEC+T,(n=142)R,5-FU 500 mg/m2,表柔比星,75mg/m2,环磷酰胺,500 mg/m2,d1,，,21d4,紫杉醇,80mg/m2/w12,曲妥珠单抗,4mg/kg-2 mg/kg,每周,11,术后,q3w40w,主要入组标准：,肿瘤大小,2cm,、淋巴结阳性、左心室射血分数,55%,主要终点：,pBCR,(,乳腺,),次要终点：,pBNCR,(,乳腺,+,淋巴结,),、安全性,两组患者在年龄，肿瘤分期和,HR,状态,(HR,阴性：,40%),方面均衡,Buzdar A,et al.2013 ASCO Abstract 502,.,*,其中,2,例患者未接受治疗而提前退出,ACOSGO Z1041,：,pCR,乳腺的病理学缓解率,组,1,N=138,组,2,N=142,p,值,乳腺,pCR,56.5%,54.2%,0.72,95%CI,47.8-64.9%,45.7-62.6%,cN1-3,患者中乳腺和腋下的病理学缓解率,组,1,N=89,组,2,N=90,p,值,乳腺和腋下,pCR,48.3%,46.7%,0.88,95%CI,37.6-59.2%,36.4-56.9%,Buzdar A,et al.2013 ASCO Abstract 502,.,双靶向用于新辅助,/,辅助治疗,联合帕妥珠单抗组患者获得显著更高的,pCR,率；心脏毒性可耐受,Gianni L,et al.Lancet Oncol 2012;13:25-32.,Schneeweiss A,et al.Ann Oncol 2013;24(9):2278-2284,.,pCR,病理完全缓解,H,曲妥珠单抗,P,帕妥珠单抗,T,多西他赛,患者获得,pCR(%,95%CI,),p=0.0141,0,10,20,30,40,50,60,HP,(,组,C),16.8,THP,(,组,B),45.8,TH,(,组,A),29.0,TP,(,组,D),24.0,p=0.003,p=0.0198,NeoSPHERE,TRYPHENA,辅助,/,新辅助化疗方案,优选方案：,AC-THP,或,TCHP,NCCN,指南解释：,T2,或,N1,的早期病人可使用帕妥珠单抗,新辅助未使用过帕妥珠单抗的病人可在辅助阶段使用,其他方案：,AC-,多西他赛,+,曲妥珠单抗,帕妥珠单抗*,FEC-,多西他赛,+,曲妥珠单抗,+,帕妥珠单抗*,FEC-,紫杉醇,+,曲妥珠单抗,+,帕妥珠单抗*,紫杉醇,+,曲妥珠单抗,帕妥珠单抗,+,曲妥珠单抗,+,多西他赛,-FEC*,帕妥珠单抗,+,曲妥珠单抗,+,紫杉醇,-FEC*,总结,Thank you!,