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1、mTOR抑制剂：依维莫司为HR+晚期乳腺癌患者治疗开启新时代,新药的不断面世为乳腺癌患者带来更多获益mBC的生存时间随着治疗进展而不断延长,Figure adapted from Chia S,et al.Cancer.2007;110(5):973-979.mBC=metastatic breast cancer.,一项来自英国的统计显示，mBC患者自诊断起的生存时间不断延长 1991-2001,N=2,150,1.0,1999-2001,1997-1998,1994-1995,1991-1992,0.8,Overall Survival,0.6,0.4,0.2,0,1,2,3,Time,y
2、ears,4,5,0,Cohorts 3&4:P.01,4 组,当前NCCN指南推荐HR+mBC患者若无明显症状内脏转移，应使用内分泌治疗,NCCN Clinical Practice Guidelines in Oncology.Breast Cancer.Version 2.2011.,不论HR+mBC患者的HER2及月经状态如何，只要无明显症状的内脏转移，均应使用内分泌治疗,常用内分泌药物汇总,内分泌治疗通过剥夺雌激素对肿瘤的影响而起作用1选择性雌激素受体调节剂通过与雌激素受体结合和减少雌激素与受体结合，从而阻碍雌激素起作用代表药物 他莫西芬(Novaldex),托瑞米芬(Faresto
3、n)芳香化酶抑制剂抑制雄激素转化为雌激素从而降低雌激素对肿瘤的作用代表药物 阿那曲唑(Arimidex),来曲唑(Femara),依西美坦(Aromasin)选择性雌激素受体下调剂通过减少有效ER数量而阻碍雌激素发挥作用代表药物 氟维司群(Faslodex),1Bilynskyj BT.ExpOncol2010;32(3):190194;2Slamon DJ,et al.N EnglJ Med 2001;344:783792;3Vogel CL,et al.J ClinOncol2002;20:719726;4Miller K,et al.N EnglJ Med 2007;357:266626
4、76;5Geyer CE,et al.N EnglJ Med2006;356:27332743.,对于HR+mBC患者，LET较TAM疗效显著,Mouridsen H,et al.J Clin Oncol.2003;21:2101-2109.,Abbreviation:MBC,metastatic breast cancer.,期待新的药物能进一步提高内分泌疗效与AI相比，氟维司群单药并不能显著改善HR+mBC患者的疗效,Trial 20&Trial 21研究N=451+400接受过内分泌治疗（主要为TAM）的绝经后晚期乳腺癌患者,EFECT研究N=693接受过非甾体类AI治疗的绝经后晚期乳腺
5、癌患者,1.Robertson JF,et al,Cancer,2003;98;2.Chia S,et al,J Clin Onco,2008;26(10);,未接受过TAM治疗的患者(n=414),治疗期间不允许接受其他类型的内分泌治疗和化疗入组时间2004.6-2009.6主要研究终点：PFS次要研究终点：OS及安全性,期待新的药物能进一步提高内分泌疗效氟维司群联合AI并不能显著改善既往未接受过TAM治疗的HR+mBC患者的疗效,内分泌作用通路与其他通路之间的CROSS-TALKPI3K/Akt/mTOR通路的激活与内分泌耐药相关,Yue W,et al.J Steroid Biochem
6、 Mol Biol.2007;106:102-110.,Abbreviations:E,estrogen;EGFR,epidermal growth factor receptor;ER,estrogen receptor;IGF-1R,insulin-like growth factor-1 receptor;mTOR,mammalian target of rapamycin.,芳香化酶抑制剂：ER+乳腺癌,内分泌治疗耐药与肿瘤细胞信号传导通路的改变有关,在雌激素剥夺后的ER+乳腺癌细胞中观察到PI3K/AKT mTOR通路活化1,1.Santen RJ,et al.Endocr Rela
7、t Cancer.2005;12 suppl 1:S61-S73;2.Boulay A,et al.Clin Cancer Res.2005;11:5319-5328.,ER+的肿瘤细胞中观察到依维莫司和来曲唑具有协同作用2,*P.001,2-way ANOVA using Tukeys test for pairwise comparisons(synergistic drug interaction),临床前数据支持mTOR抑制剂与内分泌治疗联用,*,*,*,*,Abbreviations:ANOVA,analysis of variance;ER,estrogen receptor;mT
8、OR,mammalian target of rapamycin;PFS,progression-free survival.,依维莫司(Everolimus),口服mTOR抑制剂已获批用于转移性肾细胞癌，神经内分泌肿瘤及室管膜下巨细胞星状细胞瘤体外试验肯定了其对于内分泌抵抗的乳腺癌细胞有效1 早期临床试验肯定了其疗效2,3新辅助治疗试验（2222试验）更证实了LET+EVE的疗效4,1.Boulay A,et al.Clin Cancer Res.2005;11:5319-5328;2.Ellard SL,et al.J Clin Oncol.2009;27:4536-4541;3.Awad
9、a A,et al.Eur J Cancer.2008;44:84-91;4.Baselga J,et al.J Clin Oncol.2009;27:2630-2637.,Abbreviation:mTOR,mammalian target of rapamycin.,n=138,n=132,Tumor biopsies(surgery),16 wk,Surgery,Tumor biopsies(pretreatment),Tumor biopsies(2 wk),Baselga J,et al.J Clin Oncol.2009;27:2630-2637.,新辅助 Letrozole Ev
10、erolimus的II期临床研究,新诊断,未治疗的ER+乳腺癌触诊肿瘤大小:2 cm,RANDOMIZE,Letrozole 2.5 mg/dayEverolimus 10 mg/day,Letrozole 2.5 mg/dayPlacebo,SCREEN,Abbreviation:ER,estrogen receptor.,依维莫司组的患者中57%Ki67表达降低(一种细胞增殖的标记物)，而对照组仅30%,Baselga J,et al.J Clin Oncol.2009;27:2630-2637.,Abbreviations:CR,complete response;PR,partial
11、response.,新辅助 Letrozole Everolimus的II期临床研究,TAMRAD 方案,随机，II期临床研究接受过AI治疗的HR+,HER2-的转移性乳腺癌患者分层因素:原发/继发内分泌耐药原发:AI治疗时发生复发转移，或AI治疗后6个月内继发:复发转移(6 mo)或针对转移性病灶应用AI后出现进一步的疾病进展不允许交叉换药,Bachelot T,et al.Breast Cancer Res Treat.2010;100 suppl 1;SABCS 2010,abstract S1-6.,Abbreviation:TAM,tamoxifen.,14,患者人群特征,Bourg
12、ier，Abstract,ESMO,2011,临床获益率及至疾病进展时间(TTP),15,临床获益率P=0.045(exploratory analysis),0,10,20,30,40,50,60,70,TAM,TAM+EVE,CBR,%of Patients(95%CI),42.1%(29.1-55.9),61.1%(46.9-74.1),至疾病进展时间TAM:4.5 monthsTAM+EVE:8.6 monthsHR(95%CI)=0.54(0.36-0.81)P=0.0021(exploratory analysis),0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,
13、0.8,0.9,1.0,0,2,4,6,8,10,12,14,16,18,20,22,24,26,28,30,32,34,随访时间，月,TTP Probability,TAM,At risk,57,54,45,39,34,28,26,25,20,19,17,14,10,3,3,2,1,44,30,24,22,16,13,11,7,6,4,2,2,1,0,0,TAM+EVE,Bourgier，Abstract,ESMO,2011,16,总生存,TAM,TAM+EVE,Bourgier，Abstract,ESMO,2011,根据内分泌耐药情况分析至疾病进展时间,17,原发性耐药TAM:3.8 mo
14、nthsTAM+EVE:5.4 monthsHR=0.70(0.40-1.21)P=NS(exploratory analysis),继发性耐药TAM:5.5 monthsTAM+EVE:14.8 months HR=0.46(0.26-0.83)P=0.0087(exploratory analysis),Bourgier，Abstract,ESMO,2011,TAM,TAM+EVE,18,根据内分泌耐药情况分析总生存,原发性耐药N(%)of eventsTAM:15(54%)TAM+EVE:12(46%)HR=0.73(0.34-1.55)P=0.41(exploratory analys
15、is),继发性耐药N(%)of eventsTAM:16(55%)TAM+EVE:4(15%)HR=0.21(0.07-0.63)P=0.002(exploratory analysis),Bourgier，Abstract,ESMO,2011,副反应分析,Bourgier，Abstract,ESMO,2011,20,TAMRAD 小结,在这项mTOR抑制剂和抗雌激素药物联合应用的随机II期临床研究中：与他莫西芬单药治疗相比，他莫西芬联合依维莫司能有效提高患者CBR,TTP及总生存CBR:61 vs 42%TTP:HR=0.54;95%CI,0.36-0.81总生存:HR=0.45;95%CI
16、,0.24-0.81对于继发性耐药患者，临床获益更大副反应可管理，与既往研究相一致,Bourgier，Abstract,ESMO,2011,正在进行的II期临床研究ER+且AI治疗失败的转移性乳腺癌患者应用Fulvestrant 和Everolimus,11 例AI治疗6个月内出现复发转移的ER+转移性乳腺癌Fulvestrant 500 mg on day 1,then 250 mg on days 14 and 28,and then monthly thereafterEverolimus 5 mg/day in the first mo in first 5 patients then
17、 10 mg/day afterward;10 mg/day for subsequent patients疗效分析平均TTP:8.6 mo临床获益率(CR+PR+SD 24 wk):55%,Badin F,et al.Breast Cancer Res Treat.2010;100 suppl 1;SABCS 2010,abstract P4-02-05.,Abbreviations:AE,adverse event;AI,aromatase inhibitor;CR,complete response;ER,estrogen receptor;MBC,metastatic breast c
18、ancer;PR,partial response;SD,stable disease.,依西美坦 依维莫司 治疗晚期乳腺癌患者(III期),依维莫司 10 mg PO qd+依西美坦 25 mg PO qd(n=485),安慰剂 PO qd+EXE 25 mg PO qd(n=239),R,研究终点：主要:PFS（当地及中央评估）次要:OS,ORR,至ECOG体能状态评分下降时间,安全性,生活质量变化,.,2:1,直到疾病进展或出现严重毒性反应,N=705绝经后 ER+不可切除的局部晚期或转移性乳腺癌 来曲唑或阿那曲唑治疗后疾病进展,22,BOLERO-2:患者基线特征,a All othe
19、r patients had 1 bone lesion.,Presented by J.Baselga at the 2011 European Multidisciplinary Cancer Congress(ECCO/ESMO),September 26,2011.Abstract:9LBA.,23,BOLERO-2:前期治疗,LET:letrozole,ANA:anastrozole,Presented by J.Baselga at the 2011 European Multidisciplinary Cancer Congress(ECCO/ESMO),September 26
20、,2011.Abstract:9LBA.,24,BOLERO-2(随访12个月):PFS当地评估,0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Time(weeks),Probability(%)of Event,HR=0.44(95%CI:0.36-0.53)Log rank P value:1 x 10-16EVE+EXE:7.4 monthsPBO+EXE:3.2 months,EVE+EXE(E/N=267/485),PBO+EXE(E/N=190/239),Everolimus,Placebo,N
21、umber of patients still at risk,485,436,365,303,246,188,136,96,64,45,34,21,13,9,2,2,0,239,190,131,95,63,45,29,19,12,8,6,6,4,2,0,0,0,Hortobagyi G.et al,SABCS 2011(Abstract#S3-7),BOLERO-2(随访12个月):PFS中央评估,Hortobagyi G.et al,SABCS 2011(Abstract#S3-7),Everolimus,Placebo,Number of patients still at risk,4
22、85,422,351,284,224,176,119,86,57,38,32,22,12,7,2,2,0,239,179,112,74,56,36,23,18,8,5,4,4,3,1,0,0,0,0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Probability(%)of Event,HR=0.36(95%CI:0.28-0.45)Log rank P value:1 x 10-16EVE+EXE:11.0 monthsPBO+EXE:4.1 months,EVE+EXE(E/N=155/485),PBO
23、+EXE(E/N=127/239),Time(weeks),Hortobagyi G.et al,SABCS 2011(Abstract#S3-7),BOLERO-2(随访12个月):PFS亚组分析,Hortobagyi G.et al,SABCS 2011(Abstract#S3-7),BOLERO-2(随访12个月):反应率&临床获益率,P 0.0001,Percent,反应率,临床获益率,Hortobagyi G.et al,SABCS 2011(Abstract#S3-7),BOLERO-2(随访12个月):总生存,截止2011年7月8日：共137例患者死亡17.2%在依维莫司组22.
24、7%在安慰机组OS 最终分析需392例死亡事件80%把握度，预估风险下降25%,29,OS=overall survival;PFS=progression-free survival.Hortobagyi G et al.SABCS 2011(Abstract#S3-7),BOLERO-2(长期随访数据):QOLQoL 分级评分:至评分恶化5%的时间,Hortobagyi G.et al,SABCS 2011(Abstract#S3-7),0,20,40,60,80,100,0,6,12,18,24,30,36,42,48,54,60,66,72,78,84,90,96,Time(weeks
25、),Probability(%)of Event,HR=0.81(97.5%CI:0.62-1.06)Log rank p value:0.0396EVE+EXE:7.0 monthsPBO+EXE:5.6 months,EVE+EXE(E/N=246/485),PBO+EXE(E/N=106/239),Everolimus,Placebo,Number of patients still at risk,485,425,299,239,187,149,109,75,56,33,25,14,11,8,2,1,0,239,200,115,82,60,44,27,17,9,7,4,4,1,0,0,
26、0,0,QOL evaluated using the EORTC-QLQ-30 scale,BOLERO-2(随访12个月):骨标记物,EVE=everolimus;EXE=exemestane;PBO=placebo.Hortobagyi G et al.SABCS 2011(Abstract#S3-7),%Change From Baseline,-5.6,-20.3,-6.3,-3.6,-26.7,-0.4,20.9,35.5,29.5,18.1,40.7,40.3,-40,-30,-20,-10,0,10,20,30,40,50,BSAP,P1NP,CTX,BSAP,P1NP,CTX
27、,6 周,12 周,EVE+EXE,PBO+EXE,27%,56%,36%,22%,67%,41%,BOLERO-2:安全性分析,Presented by J.Baselga at the 2011 European Multidisciplinary Cancer Congress(ECCO/ESMO),September 26,2011.Abstract:9LBA.,AE:Adverse Event;AST:Aspartate aminotransferase,32,BOLERO-2 小结,对于非甾体类芳香化酶抑制剂治疗失败的ER+，HER2-的晚期乳腺癌患者，依维莫司联合依西美坦可有效逆
28、转内分泌耐药依西美坦组骨吸收和骨形成标记物均升高，联合组则均降低依维莫司有望改变晚期乳腺癌患者的治疗模式,33,总结,临床前和临床证据证实EGFR/HER2和mTOR信号传导通路在转移性乳腺癌内分泌耐药过程中起了重要作用HR+HER2+的转移性乳腺癌一线治疗中AI+HER2抑制剂优于单用AI在TAMRAD研究中AI治疗过的转移性乳腺癌患者联用依维莫司和TAM现实了很好的疗效和可管理的安全性特征BOLERO-2研究进一步证实了依维莫司可为内分泌治疗失败的ER+乳腺癌患者带来临床获益,Abbreviations:AI,aromatase inhibitor;EGFR,epidermal growth factor receptor;HER2,human epidermal growth factor receptor-2;MBC,metastatic breast cancer;mTOR,mammalian target of rapamycin.,谢谢！,
