HER2阳性乳腺癌辅助治疗临床应用

Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,赫赛汀,在,HER2,阳性早期乳腺癌辅助治疗中的临床应用,HER2的认知,赫赛汀的作用机制,关键性临床研究,平安性回忆分析,赫赛汀,研发过程,美国上市,Phase I-III,HER2cloned,1998,1992,-1995,1985,2002,中国上市,200,4,一线联合多西紫杉醇,新适应症,200,6,欧洲、美国等：辅助治疗适应症,200,7,推荐用于联合芳香化酶抑制剂治疗,HER2,与激素受体阳性的转移性乳腺癌,2021,中国：辅助治疗适应症,1987著名杂志?科学?发表HER2对乳腺癌的意义,HER2,HER2,是有别于肿瘤大小、淋巴结及激素受体外的乳腺癌,重要的,预后因子,HER2,是肿瘤复发和生存期长短的,独立,预后因子,HER2,阳性定义,IHC 3+,CISH+,FISH+,或,或,蛋白过度表达,基因扩增,中华病理学杂志,2006;35:631-623,中华病理学杂志,2006;35:580-583,HER2的认知,赫赛汀的作用机制,关键性临床研究,平安性回忆分析,赫赛汀,靶向,HER2,的人源化单抗,95%,人源化,5%,鼠抗，具有高度亲和性,(K,d,=0.1nM),和特异性，显著降低免疫原性,(,HAMA),用于治疗HER2阳性乳腺癌,MBC,：生存率提高达,45,%,EBC,：复发风险降低近,52,%,HER2的认知,赫赛汀的作用机制,关键性临床研究,平安性回忆分析,赫赛汀,辅助治疗已在全球多个国家获得批准,Chile,Columbia,Dominican Republic,Ecuador,Norway,EU,USA,Guatemala,Iceland,India,Israel,Bosnia-Herzegovina,Mexico,New Zealand,Nicaragua,Pakistan,Philippines,Russia,South Korea,Switzerland,Australia,CHINA,赫赛汀,显著提高,HER2,阳性,EBC,患者的治愈率,赫赛汀,为乳腺癌辅助治疗近年来的突破性进展,疾病相关复发风险降低百分比,0,10,20,30,40,17%,42%,46%,31%,CEF vs CMF,Levine 2005,AC,T vs AC,Henderson 2003,Piccart 2005,三苯氧胺 vs 抚慰剂,Fisher 2004,DAC vs FAC,Martin 2005,28%,HER2,+,&,HER2,-,Romond 2005,50,52%,HER2,+,化疗,+,赫赛汀,vs,化疗,化疗,赫赛汀,vs,化疗,2005 ASCO,a,Based on small subgroups of patients with HER2-positive breast cancer;,b,DDFS;CTx,chemotherapy;AC,doxorubicin,cyclophosphamide;P,paclitaxel;T,docetaxel;Carbo,carboplatin;V,vinorelbine;CEF,cyclophosphamide,epirubicin,5-fluorouracil,超过13,000例病例，证实赫赛汀治疗持续无病生存获益DFS的研究,3,4,5,4,Gianni et al 2021;Gianni et al 2021;Joensuu et al 2021;Slamon et al 2006;Perez et al 2007;Smith et al 2007;Spielmann et al 2007,3,3,中位随访时间,年,DFS,获益,B-31/N9831 AC,PH,HERA,化疗,赫赛汀,1,年,FinHer,a,VH/TH,CEF,b,BCIRG 006 AC,TH,TCH,n=231,0,1,2,倾向赫赛汀,治疗,倾向非赫赛汀,治疗,HR,1,年赫赛汀,治疗始终降低,33,的死亡风险,0,1,2,B-31/N9831,AC,P,H,3,HERA CTx,H 1 year,2,OS,获益,BCIRG 006 AC,T,H,3,TCH,3,倾向赫赛汀,治疗,倾向非赫赛汀,治疗,HR,5,FinHer VH/TH,CEF,n=231,中位随访时间,年,Gianni et al 2021;Joensuu et al 2021;Slamon et al 2006;Perez et al 2007;Smith et al 2007,P=NS,NSABP B-31NCCTG N9831,临床研究,NSABP B-31,NCCTG N9831,Arm 1,Arm 2,Arm A,Arm B,Arm C,=,阿霉素,60 mg/m,2,，环磷酰胺,600 mg/m,2,q 3 wk x 4,=,紫杉醇,175 mg/m,2,q 3 wk x 4,=,紫杉醇,80 mg/m,2,/wk x 12,=,赫赛汀,4mg/kg,首剂,+2 mg/kg/wk x 51,对照组,:AC,T,研究组,:AC,T+H,Romond et al N Engl J Med 2005;353:1673-1684,N9831/B-31,中位随访三年的无病生存期仍有显著优势,168,460,8,753,1,235,1,800,Numberat risk,N=619 events,HR*,adj,=0.48(95%CI:0.41-0.57),*Nodes,receptor status,paclitaxel schedule,protocol,73.1%,86.4%,0,20,40,60,80,100,0,1,2,3,4,5,6,7,Follow-up(yrs),Alive and disease-free(%),AC,T(n=1,979;397 events),P 0.00001,77.6%,202,522,4,868,1,347,1,854,85.9%,92.3%,AC,T+H(n=1,989;222 events),87.9%,*,Intent to treat events:recurrent disease,contralateral bc,2nd primary,death,Perez et al,ASCO 2007,B-31/N9831,生存期中位随访三年,Numberat risk,258(36%)of the 710 events neededfor final analysis have occurredunadjusted HR=0.65(95%CI:0.51-0.84),P=0.0007,0,20,40,60,80,100,0,1,2,3,4,5,Follow-up(yrs),Alive(%),AC,T,211,562,898,1,376,1,863,89.4%,95.9%,*,Intent to treat,92.7%,AC,T+H,217,570,938,1,419,1,886,92.6%,97.5%,94.6%,Small difference to date,but virtually,all patients on control,arm went on to received,trastuzumab at relapse.,Perez et al,ASCO 2007,0,1,2,3,4,0,20,40,60,80,100,120,Rate per 1000 Women/Yr,Years From Randomization,AC,TH,AC,T,B31/N9831,B-31/N9831,研究远处转移风险分析,随机分组后年,Romond et al N Engl J Med 2005;353:1673-1684,6,4,2,0,0.0,0.5,1.0,1.5,2.0,2.5,3.0,4.1%,0.8%,开始,赫赛汀,治疗后时间,(年,),AC PHn=850,31 CHFs,0,心源性死亡,AC Pn=814,4 CHFs,1,心源性死亡,Tan-Chiu et al 2005,NSABP B-31:,心脏不良事件的累积发生率,差异,3.3%,患者,(%),平均,LVEF,的变化,-95%,可信区间,64,62,60,58,Baseline,Post-AC,6 Month,9 Month,18 Month,LVEF,N=654,N=793,AC,T,(N=903),AC,T+H,(N=947),Perez et al,ASCO 2007,NSABP B-31NCCTG N9831,结论,赫赛汀联合化疗可以降低52的复发风险，降低35的死亡风险,赫赛汀联合化疗平缓了复发顶峰,赫赛汀有良好的心脏耐受性和平安性。赫赛汀引起的LVEF下降是可逆的随着使用赫赛汀时间的延长，LVEF可以恢复到基线水平。,HERA,临床研究,HERA,研究设计,初始治疗,(,手术,化疗,放疗),随机分组,赫赛汀,q3w,二年,对照组,赫赛汀,q3w,一年,肿瘤过度表达HER2IHC检测为3+水平,或HER2基因扩增FISH试验阳性,的早期乳腺癌患者,HERA,研究终点,首要终点,无病生存期,1-年赫赛汀治疗组 vs 观察组,2-年赫赛汀治疗组 vs 观察组,次要终点,总生存,无复发生存,远处转移无病生存,平安性,1-年赫赛汀治疗组 vs 观察组,2-年赫赛汀治疗组 vs 观察组,比较无病生存,总生存,无复发生存,远处转移无病生存,平安性,1-年赫赛汀治疗组 vs 2-年赫赛汀治疗组,DFS,disease-free survival;OS,overall survival;RFS,relapse-free survival,1703,1,591,1434,1127,742,383,140,1698,1,535,1330,984,639,334,127,No.at risk,无病生存期,(ITT,分析,):2-,年中位随访时间,100,80,60,40,20,0,Patients(%),随机分组后月,1,2,36,赫赛汀1年治疗组n=1703),观察组n=1698),0,1,8,6,24,30,Events,HR,95%CI,p value,0.64,0.54,0.76,T,1074,128,AC-TH,1075,142,TCH,81%,87%,86%,77%,83%,82%,87%,93%,92%,HR(AC-TH vs AC-T)=,0.61 0.48;0.76,PT)=,0.67 0.54;0.83,P=0.0003,Year from randomization,DFS,分析,Slamon,et al.,SABCS 2005,OS,分析,HR(AC-TH vs AC-T)=,0.59 0.42;0.85,P=0.004,HR(TCH vs AC-T)=,0.66 0.47;0.93,P=0.017,%Survival,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,Patients,Events,1073,80,AC-T,1074,49,AC-TH,1075,56,TCH,97%,99%,98%,93%,97%,95%,92%,91%,86%,Year from randomization,Slamon,et al.,SABCS 2006,DFS,亚组分析,1.0,0.0,2.0,AC-TH,better,AC-T,better,Subgroup,Node neg,Node pos,HR-,HR+,Tsize2cm,Tsize,2cm,AC-TH vs AC-T,1.0,0.0,2.0,Subgroup,Node