Her阳性乳腺癌辅助治疗

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,第四级,第五级,2020/11/3,*,目前乳腺癌的治疗手段,手术,放疗,化疗,内分泌治疗,分子靶向治疗,2020/11/3,1,乳腺癌的分子分型,ER,阳性 肿瘤,luminal,A,（,HER-2,阴性）,luminal B,（,HER-2,阳性,),HER2,阳性 肿瘤,三阴性肿瘤,ER,-,阴性,PR,-,阴性,HER2-,阴性,2020/11/3,2,乳腺癌,ER+,60-70%,HER2+,20-25%,Basaloid,15%,乳腺癌是一组异质性疾病,2020/11/3,3,HER2的生物学特点,HER2是EGFR家族中的一员,约2025%的乳腺癌有HER2基因的高表达,HER2高表达提示肿瘤侵袭性强，易复发转移,预后差,HER2高表达是独立的预后不良因素,提示易对一些化疗药物和内分泌药物耐药,2020/11/3,4,HER2,高表达预示生存期缩短,Pauletti G, et al. J Clin Oncol 2000;18:365164,Time (months),Log-rank p=0.0004,Wilcoxon p=0.0009,FISH-,阴性,(n=771),FISH-,阳性,(n=189),Stage IIII breast cancer (n=900),1.0,0.9,0.8,0.7,0.6,0.5,0.4,01224364860728496108,Probability of survival,FISH = fluorescence,in situ,hybridisation,2020/11/3,5,靶向 HER2 赫赛汀 (曲妥珠单抗),人源化抗HER2单抗,亲和力高，特异性强,95%人源化,5% 鼠源,2020/11/3,6,关键临床试验,HERA,N9831,BCIRG006,2020/11/3,7,HERA研究设计,初始治疗,(手术,化疗,放疗),随机分组,赫赛汀,q3w,2年,对照组,赫赛汀,q3w 1年,肿瘤过度表达HER2（IHC检测为3+水平）,或c-erbB2基因扩增（FISH试验阳性）,的早期乳腺癌患者,2020/11/3,8,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,安全性,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,安全性,1-,年赫赛汀治,疗组,vs 2-,年赫赛汀,治疗组,2020/11/3,9,N ENJLJ MED 353;16, 2005,中位随访1年DFS,2020/11/3,10,中位随访1年OS,2020/11/3,11,100,80,60,40,20,0,患者,(%),随机分组后月,1,2,36,赫赛汀,1,年治疗组（,n=1703),事件数,218,观察组（,n=1698),事件数,321,0,1,8,6,24,30,HR=0.64,P0.0001,80.6%,74.3%,6.3%,HERA 23-month follow-up data at ASCO,on June 3rd, 2006,HERA,研究,:无病生存时间(DFS),中位随访2年,DFS,显著改善，,复发风险降低,36%,2020/11/3,12,2020/11/3,13,1703,1627,1498,1190,794,407,146,100,80,60,40,20,0,Patients(%),Months from randomisation,观察组,No. at risk,1698,1,608,1453,1097,711,366,139,总生存 (ITT分析):2-年中位随访时间,1,年赫赛汀,治疗组,Events,HR,95% CI,p value,0.66,0.47, 0.91,0.0115,2-yearOS,92.4,89.7,1,2,36,0,1,8,6,24,30,59,90,2.7%,HERA 23-month follow-up data at ASCO,on June 3rd, 2006,死亡风险降低,34%,2020/11/3,14,HERA:,不同随访时间的无病生存和总生存,死亡事件数 赫赛汀,1,年,vs,观察组,0,1,2,倾向赫赛汀,治疗,倾向非赫赛汀,治疗,HR,OS,获益,29 vs 37,p=0.26,2005,1,1,年,(0%),59 vs 90p=0.0115,182 vs 213,p=0.1087,中位随访时间,(%,选择入组后随访时间,),2006,2,2,年,(4.1%),20084,年,(30.9%),2005,1,1,年,(0%),中位随访时间,(%,选择入组后随访时间,),2006,2,2,年,(4.3%),20084,年,(33.8%),无病生存事件数赫赛汀,1,年,vs,观察组,127 vs 220,p0.0001,218 vs 321,p0.0001,369 vs 458,p0.0001,0,1,2,倾向赫赛汀,治疗,倾向非赫赛汀,治疗,HR,DFS,获益,1,Piccart-Gebhart et al 2005;,2,Smith et al 2007,St.gallen 2009,2020/11/3,15,HERA研究,使用赫赛汀1年平均随访1年,得到DFS显著差异，说明：,Her2的确是乳腺癌独立的高危因子（在术后12年是复发高峰期）,使用赫赛汀1年能尽早改善无病生存,2020/11/3,16,HERA试验中显示使用赫赛汀1年平均随访2年（0-48月）， OS获益,这种现象在化疗中没有,（对于年轻女性，化疗能获得38%的长期生存优势，但在平均2年的随访中没有显示）,同样的现象在AI也没有,2020/11/3,17,瑞宁得的总生存,2004,结果,(5,年分析,),2007,结果,(100,个月分析,),2009,结果,(10,年分析,),终点,HR,(95% CI),P-VALUE,HR,(95% CI),P-VALUE,HR,(95% CI),P-VALUE,DFS,0.83,(0.73-0.94),0.0049,0.85,(0.76, 0.94),0.0027,0.86,(0.78-0.95),0.0027,TTR,0.74,(0.64-0.87),0.0002,0.76,(0.67, 0.87),0.0001,0.79,(0.70-0.89),0.0002,OS,0.97,(0.83-1.14),0.7339,0.97,(0.86, 1.11),0.6837,0.95,(0.84-1.06),0.3468,OS无获益,Cuzick J. Presented at 12th Milan Breast Cancer Conference June, 2010.,2020/11/3,18,BIG1-98,核心分析：中位随访,26,月结果,N = 8010.,来曲唑 更好,他莫昔芬更好,事件数,(LET:TAM),风险比,(LET:TAM),(CI),P,值,DFS,351,428,0.81 (0.70-0.93),0.003,总生存率,166,192,0.86 (0.70-1.06),0.16,全身,DFS*,323,383,0.83 (0.72-0.97),0.02,DFS (,不包括第二原发肿瘤,),296,369,0.79 (0.68-0.92),0.002,至远处转移时间,184,249,0.73 (0.60-0.88),0.001,至复发时间,228,310,0.72 (0.61-0.86),0.001,1.0,0.5,0.75,1.33,风险比,*从随机分组到出现以下事件的时间： 浸润性局部复发, 远处转移, 任何原因的死亡.,Thrlimann B et al.,N Engl J Med.,2005;353:2747.,总生存也无获益,2020/11/3,19,结 论,赫赛汀能降低乳腺癌早期复发和转移风险,赫赛汀能降低乳腺癌早期死亡风险,2020/11/3,20,N9831,NCCTG N9831 ：,HER2阳性的乳腺癌辅助治疗试验中,在单独化疗中序贯或同时加入,52周曲妥珠单抗的结果,Perez EA,1, Suman VJ,2,Davidson NE,3, Gralow J,4,Kaufman PA,5, Ingle JN,2, Dakhil SR,6, Zujewski JA,7,Pisansky TM,2, Jenkins RB,2,1,Mayo,Clinic, Jacksonville, FL;,2,Mayo Clinic, Rochester, MN;,3,University of Pittsburgh, Pittsburgh, PA;,4,Seattle Cancer Center Alliance,Seattle, WA ;,5,Dartmouth Hitchcock Medical Center, Lebanon, NH;,6,Cancer Center of Kansas, Wichita, KS;,7,National Cancer Institute,Bethesda, MD,NCCTG, ECOG, CALGB, SWOG,SABCS 2009,3025495-2,2020/11/3,21,N9831,N9831:研究设计,A组: AC q 3w x 4,紫杉醇 qw x 12,B组,: AC q 3w x 4,C组,: AC q 3w x 4,紫杉醇 qw x 12,紫杉醇 qw x 12 +,曲妥珠单抗 qw x 12,曲妥珠单抗,qw x 52,曲妥珠单抗,qw x 40,n=3,505,有适应症时，放疗和/或 激素治疗,Perez EA,曲妥珠单抗：4 mg/kg 起始剂量, 之后 2 mg/kg); A：阿霉素剂量 60 mg/m,2,;,C：环磷酰胺 600 mg/m,2,; 紫杉醇, 80 mg/m,2,; q 3w：每3周; qw：每周,3025495-3,随,机,化,2020/11/3,22,N9831:,A 组,vs,B 组,比较,根据患者特征的调整DFS,N9831,参数,入组时年龄,淋巴结阳性数目,肿瘤大小,雌激素受体,分类,40-59 岁,5cm,5cm,阴性,阳性,N,1,433,751,296,583,1,305,1,995,189,1,062,1,122,风险比,0.73,1,3.11,1.86,1,1.61,1,1.48,1,P值,0.0025,0.0001,0.0001,0.0016,0.0001,治疗组,AC T H,AC T,1,087 0.67,(0.55-0.82),5 cm,2.1-5.0 cm,2 cm,阴性,阳性,N,242,488,1,073,166,989,748,934,969,HR,2.24,1.56,1,1.84,1.57,1,1.78,P值,0.0001,0.0008,0.0019,0.0005,0.0001,治疗组,AC T+H H,AC T H,949 0.75,(0.60-0.94),954 1,0.0134,3025495-12,2020/11/3,25,N9831,序贯组 (B组),vs,联合治疗组 (C组),无病生存率,无病生存率 (%),100,AC T+H H,( 138,事件数,),90,80,70,60,Logrank p=0.0190,89.1%,85.7%,AC T H,(174,事件数,),84.2%,79.8%,50,949,954,837,830,788,766,740,705,676,641,456,418,风险患者数,40,0,1,2,3,4,5,随机化时间,3025495-13,2020/11/3,26,N9831,结果: 无病生存率,联合分析 (N9831/NSABPB31) 中位数为3年的随访,1,事件数,调整后风险比,配对比较,ACT,vs,AC T+H H,619,P 值,5年的随访,2,Log rank,调整后风险比*,配对比较,事件数,P 值,(95%CI),A,B,B,C,ACT,vs,AC T H,(n=2,184),AC T H,vs,AC T+H H,(n=1,903)*,386,312,0.0005,0.0190,0.67,(0.55-0.82),0.75,(0.60-0.94),*除外,C组,关闭后入组,B组,的,患者,1,Perez,2,Perez,EA et al: J Clin Oncol 2007;25(18S):6S; Abstr #512,EA et al: SABCS 2009; Abstr #701,3025495-14,2020/11/3,27,结果: 总生存,联合分析 (N9831/B31) 中位数为3年的随访,1,未调整 风险比,N9831,配对比较,ACT,vs,AC T+H H,事件数,258,P 值,0.0007,(95%CI),0.65,(0.51-0.84),N9831 分析 (N9831) 中位数5年的随访,2,Log rank,未调整 风险比,*,配对比较,事件数,P 值,(95%CI),A,B,B,C,ACT,vs,AC T H,(n=2,184),AC T H,vs,AC T+H H,(n=1,903)*,220,168,0.281,0.135,0.86,(0.65-1.13),0.79,(0.59-1.08),1,Perez,2,Perez,EA et al: J Clin Oncol 2007;25(18S):6S; Abstr #512,EA et al: SABCS 2009; Abstr #701,3025495-15,*除外,C组,关闭后入组,B组,的,患者,2020/11/3,28,AC T加入52周的曲妥珠单抗显著提高DFS,AC T后序贯曲妥珠单抗显著减少任意事件的发生，风险下降33%,5 年 DFS: 72% vs. 80%,与序贯治疗相比，与紫杉醇同时行曲妥珠单抗有减少任意事件的发生的明显的趋势，风险下降25%,5 年 DFS: 80% vs. 84%,结论,N9831,3025495-16,2020/11/3,29,N9831,临床实践提示,基于阳性的风险/获益比例,我们推荐在紫杉醇治疗同时加入曲妥珠单抗辅助治疗,AC T+H H,3025495-17,2020/11/3,30,BCIRG 006,：,III期试验比较ACT 、 ACTH和 TCH辅助治疗 HER2扩增的早期乳腺癌患者,第3次的中期疗效分析,Slamon D, Eiermann W, Robert N, Pienkowski T, Martin,M, Rolski J, Chan A, Mackey J, Liu M, , Pinter T, Valero,V, Falkson C, Fornander T, Shiftan T, Olsen S, Buyse,M, Kiskartalyi T, Landreau V, Wilson V, Press M, Crown,J, on behalf of the BCIRG 006 Investigators.,Study sponsored by sanofi-aventis,Support from Genentech,2020/11/3,31,BCIRG 006 试验设计,AC,T,4 x AC,60/600 mg/m,2,4 x 多西他赛,100 mg/m,2,Her 2+,(中心FISH),4 x AC,60/600 mg/m,2,4 x 多西他赛,100 mg/m,2,淋巴结阳性,或高危淋巴结阴性,N=3,222,按淋巴结和激素受体状态分层,ACTH,TCH,1 年曲妥珠单抗,6 x 多西他赛 和卡铂,75 mg/m,2,AUC 6,1 年曲妥珠单抗,2020/11/3,32,BCIRG 006 研究终点,主要研究终点,无病生存率,次要研究终点,总生存率,毒性,病理和分子标记物,2020/11/3,33,BCIRG 006当前数据：,无病生存率 第3次中期分析,1,0.9,84%,0.8,0.7,0.6,81%,75%,0.5,0.4,患者 数 事件数 HR (95% C.I.),AC-T 1073 257 1,(基准),AC-TH 1074 185 0.64 (0.53 - 0.78),TCH 1075 214 0.75 (0.63 - 0.90),P, 0.001,0.04,0,12,24,36,48,60,72,时间（月）,无病生存概率,2020/11/3,34,BCIRG 006 分组事件,ACT,n=1,073,ACTH,n=1,074,TCH,n=1,075,DFS事件总数,147/,192,/,257,77/,128,/,185,98/,142,/,214,第1次分析,第2次分析,第3次分析,P,0.001,P=,0.002,P=,0.21,转移事件,113/,143,/,188,52/,93,/,124,67/,98,/,144,2020/11/3,35,BCIRG 006,总生存 第3次中期分析,1,92%,0.9,0.8,0.7,91%,87%,0.6,0.5,0.4,患者数 事件数 HR (95% C.I.),AC-T 1073 141 1,(基准),AC-TH 1074 94 0.63 (0.48 - 0.81),TCH 1075 113 0.77 (0.60 - 0.99),P, 0.001,0.038,0,12,24,36,48,60,72,时间（月）,总生存概率,2020/11/3,36,BCIRG 006 死亡,ACT,n=1,073,ACTH,n=1,074,TCH,n=1,075,任何原因死亡总数,36/,80,/,141,20,/49,/,94,28/,56,/,113,P,0.001,P=,0.038,P=,0.14,乳腺癌死亡,33/,69,/,122,19/,44,/,83,21/,47,/,97,第1次分析,第2次分析,第3次分析,2020/11/3,37,BCIRG 006,淋巴结阴性:DFS,1,93%,0.9,90%,0.8,0.7,85%,0.6,0.5,0.4,患者数 事件数 HR (95% C.I.),AC-T 309 46 1,(基准),AC-TH 310 23 0.47 (0.28 - 0.77),TCH 309 32 0.64 (0.41 - 1.01),P,0.003,0.057,0,12,24,36,48,60,72,时间（月),无病生存概率,2020/11/3,38,BCIRG 006,淋巴结阴性:OS,1,0.9,0.8,0.7,97%,96%,93%,0.6,0.5,0.4,AC-T,AC-TH,TCH,患者 事件数 HR (95% C.I.),309 22 1,(基准),310 8 0.38 (0.17 - 0.87),309 12 0.56 (0.27 - 1.13),P,0.02,0.11,0,12,24,36,48,60,72,时间（月),总生存概率,2020/11/3,39,BCIRG 006,淋巴结阳性:DFS,1,0.9,0.8,0.7,80%,78%,71%,0.6,0.5,0.4,AC-T,AC-TH,TCH,患者数 事件数 HR (95% C.I.),764 211 1,(基准),764 162 0.68 (0.56 - 0.84),766 182 0.78 (0.64 - 0.95),P,0.0003,0.013,0,12,24,36,48,60,72,时间（月),无病生存概率,2020/11/3,40,BCIRG 006,阳性淋巴结 4：DFS,1,0.9,0.8,73%,0.7,72%,0.6,0.5,0.4,AC-T,AC-TH,TCH,患者数 事件数 HR (95% C.I.),350 133 1,(基准),350 99 0.66 (0.51 - 0.86),352 101 0.66 (0.51 - 0.86),61%,P,0.002,0.002,0,12,24,36,48,60,72,时间（月),无病生存概率,2020/11/3,41,安全性结果,2020/11/3,42,BCIRG 006,3/4级非血液学毒性,AC,T,n=1,050,%,AC,TH,n=1,068,%,TCH,n=1,056,%,关节痛,肌痛,疲劳,手足综合征,口炎,腹泻,恶心,呕吐,月经失调,3.2,5.2,7,1.9,3.5,3.0,5.9,6.1,27,3.3,5.2,7.2,1.4,2.9,5.6,5.7,6.7,24.3,1.4*,1.8*,7.2,0.0*,1.4*,5.4,4.8,3.5*,26.5,黄色=*统计学事件数显着减少,2020/11/3,43,BCIRG 006,特定的非血液学毒性 (所有分级),AC,T,n=1,050,%,AC,TH,n=1,068,%,TCH,n=1,056,%,感觉神经病变,运动神经病变,指甲病变,肌痛,肾衰,3/4级肌酐下降,48.6,5.2,49.3,52.8,0.0,0.6,49.7,6.3,43.6,55.5,0.0,0.3,36.1*,4.2*,28.7*,38.6*,0.1,0.1,黄色=*统计学事件数显着减少,2020/11/3,44,BCIRG 006,3/4 级血液学毒性,AC,T,n=1,050,(%),AC,TH,n=1,068,(%),TCH,n=1,056,(%),中性粒细胞减少,白细胞减少,发热性中性粒细胞减少,中性粒细胞减少伴感染,贫血,血小板减少,急性白血病: #(%),63.5,51.9,9.3,11.5,2.4,1.6,6 (0.6),71.6,60.4,10.9,12.1,3.1*,2.1*,1 (0.1),66.2*,48.4*,9.6,11.2,5.8,6.1,1 (0.1*),黄色=*统计学事件数显着减少,*此例患者在TCH治疗后24个月进展为B细胞淋巴瘤，表示为ITT DFS事件,此例患者在B细胞淋巴瘤CHOP治疗后20个月后发生急性白血病,2020/11/3,45,经独立的评估委员会,心源性死亡和CHF结果,ACT,n=1,050,ACTH,n=1,068,TCH,n=1,056,心源性死亡,0/,0,/,0,0/,0,/,0,0/,0,/,0,心脏左心室功能 (CHF),3 / 4级,3/,4,/,7,17/,20,/,21,4/,4,/,4,第1次分析,第2次分析,第3次分析,P =,0.0121,P 10%的患者,ACT,n = 1,018,ACTH,n = 1,042,TCH,n = 1,031,患者,%,91/,102,/,114,9/,10,/,11,180/,189,/,194,17/,18,/,19,82/,89/,97,8/,9,/,9,第1次中期分析,第2次分析,第3次分析,P,0.001,P,1 cm or node-positive tumours,ESMO,Treat HER2-positive node-negative tumours 1 cm or node-positive tumours with Herceptin,St Gallen,Treat HER2-positive tumours 1 cm and HER2-positive, node-positive tumours with Herceptin,MBC,Both NCCN and ESMO recommend,1st line: Herceptin + chemotherapy,Beyond progression: maintain HER2 suppression with Herceptin or lapatinib,Cardoso et al 2009; Goldhirsch et al 2009;Kataja et al 2009; NCCN 2010,2020/11/3,51,2020/11/3,52,2020/11/3,53,2020/11/3,54,