陆劲松-乳腺癌的内分泌治疗进展-las--rin.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,第四级,第五级,*,乳腺癌内分泌治疗进展,复旦大学肿瘤医院乳腺外科,陆劲松,1,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,乳腺癌的治疗原则,以手术为主,以其它治疗为辅,综合治疗,2,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,系统辅助治疗,在手术完成后,杀灭或者抑制临床阴性的微转移灶,化疗、放疗、内分泌、生物治疗等,3,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,辅助内分泌治疗,采用内分泌治疗手段,抑制微转移灶的增殖、复苏,4,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,在,1975,年所用的内分泌治疗手段,卵巢的切除,手术,(,去势,),放射去势,双侧肾上腺切除,垂体切除术,雌激素,雄激素,孕激素,糖皮质激素,5,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,目前所用的乳腺癌内分泌治疗手段,芳香化酶抑制剂,(,非选择性 和选择性,),选择性雌激素受体调节剂（,SERM,）,选择性雌激素受体下调剂（,SERD,）,GHRH,激动剂和拮抗剂,卵巢的切除,手术,(,去势,),放射去势,孕激素,其它,:,雄激素、雌激素、抗孕激素等,6,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,内分泌治疗的目标,抑制或者阻断雌激素的形成,阻雌激素的作用,下调节雌激素受体的表达,7,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,SERM,作用机制,选择性雌激素受体调节剂（,SERM,）如：三苯氧胺、托瑞米芬、雷洛昔芬，可竞争性与,ER,结合，结合后仍能形成二聚体，并与,ERE,结合。,转录活性仅保留了部分,其产生对抗雌激素作用还是类雌激素样作用取决于不同组织内的共激活因子或共抑制因子的状态,8,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,%,Years,Actuarial estimate and SE,Allocated tamoxifen,Allocated control,ER+,85.2,76.1,68.2,73.7,62.7,54.9,11.5(SE 0.9),13.4(SE 1.1),13.4(SE 1.4),OVERVIEW:TAMOXIFEN 5 YEARS VS NOT,Recurrences,9,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,Actuarial estimate and SE,Allocated tamoxifen,Allocated control,ER+,89.5,76.8,64.9,86.3,69.4,57.0,3.2(SE 0.7),7.4(SE 1.1),7.9(SE 1.5),%,Years,OVERVIEW:TAMOXIFEN 5 YEARS VS NOT,All Deaths,10,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,毒性,特异性,有效性,第一代,第二代,第三代,氨基导眠能*,法屈唑,兰他龙,阿那曲唑,依西美坦,来曲唑,芳香化酶抑制剂的历史,皮疹等,无肾上腺功能影响,1,000,to,10,000,100,1,11,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,不同芳香化酶的结构,载体类抑制剂,Androgen substrate,非甾体类抑制剂,氨基导眠能,N,O,O,NH,2,C,2,H,5,H,阿那曲唑,N,N,N,NC,H,3,C,CH,3,H,3,C,CH,3,CN,来曲唑,N,N,N,NC,CN,依西美坦,O,CH,2,O,福美斯坦,O,OH,O,雄烯二酮,O,O,12,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,直接芳香化酶辅助治疗,阿那曲唑,复旦大学肿瘤医院乳腺癌研究所,13,2010-12-4,9366 postmenopausal women with invasive breast cancer,Mean age 64 years;84%hormone receptor-positive,61%node-negative;64%with tumour,2cm in diameter,Surgery,radiotherapy,chemotherapy,Randomisation 1:1:1 for 5 years,ARIMIDEX,(,n,=3125),tamoxifen(,n,=3116),Combination,(n,=3125),Regular follow-up,Primary trial endpoints:,Disease-free survival,Safety/tolerability,Secondary trial endpoints:,Incidence of contralateral breast cancer,Time to distant recurrence,Time to recurrence,Overall survival,Death after recurrence,Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm,ATAC Trial Design,Disease-free Survival,HR+Patients,Patients(%),30,25,20,15,10,5,0,26182598,25412516,24532400,23612306,22782196,21592075,19951896,18011711,14921396,608547,At risk:ARIMIDEXtamoxifen,13.9%,16.4%,25.8%,29.9%,0,1,2,3,4,5,6,7,8,9,30,25,20,15,10,5,0,tamoxifen ARIMIDEX,HR+,HR,0.85,95%CI,(0.76,0.94),p-value,0.003,Follow-up time(years),2.5%,4.1%,HR+,hormone receptor-positive;HR,hazard ratio;CI,confidence interval;AD,absolute difference,The ATAC Trialists Group.Lancet Oncol 2008;9:45-53,AD,15,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,Time to Distant Recurrence,HR+Patients,26182598,25512533,24702440,2393,2363,23202263,22012151,20421982,18541809,15361484,636591,At risk:ARIMIDEXtamoxifen,Patients(%),30,25,20,15,10,5,0,0,1,2,3,4,5,6,7,8,9,30,25,20,15,10,5,0,7.8%,9.1%,13.2%,15.6%,Follow-up time(years),HR+,HR,0.84,95%CI,(0.72,0.97),p-value,0.022,1.3%,2.4%,The ATAC Trialists Group.Lancet Oncol 2008;9:45-53,tamoxifen ARIMIDEX,AD,16,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,Contralateral Breast Cancer,HR+Patients,Patients(%),5,4,3,2,1,0,0,1,2,3,4,5,6,7,8,9,5,4,3,2,1,0,1.0%,1.8%,2.5%,4.2%,Follow-up time(years),HR+,HR,0.60,95%CI,(0.42,0.85),p-value,0.004,AD,0.8%,1.7%,26182598,25412516,24532400,2361,2306,22782196,21592075,19951896,18011711,14931396,608547,At risk:ARIMIDEX,tamoxifen,The ATAC Trialists Group.Lancet Oncol 2008;9:45-53,tamoxifen ARIMIDEX,17,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,Death:All Causes,HR+Patients,26182598,25672549,25112504,24452432,23892339,22742227,21022068,19111888,15861551,659620,At risk:ARIMIDEXtamoxifen,Patients(%),30,25,20,15,10,5,0,0,1,2,3,4,5,6,7,8,9,30,25,20,15,10,5,0,Follow-up time(years),HR+,HR,0.97,95%CI,(0.86,1.11),p-value,0.70,The ATAC Trialists Group.Lancet Oncol 2008;9:45-53;AstraZeneca data on file,tamoxifen ARIMIDEX,18,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,直接芳香化酶辅助治疗,来曲唑,复旦大学肿瘤医院乳腺癌研究所,19,2010-12-4,BIG 1-98:Design,R,A,N,D,O,M,I,Z,E,0,2,5,Years,Tamoxifen,Letrozole,Tamoxifen,Letrozole,Letrozole,Tamoxifen,A,B,C,D,n=1540,n=1548,n=2463,n=2459,8010 pts,Primary core analysis compares letrozole(Femara,)vs tamoxifen in arms A-D but excludes events and FU beyond switch at 2 y in arms C&D,Initial data analysis at 25.8 months median FU,FU=follow-up.,Update of Thrlimann et al.,J Clin Oncol,.2005;23:6S.Abstract 511.,20,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,BIG 1-98,研究,76,个月,IPCW,分析结果,P0.05,Regan et al.SABCS 2009 abs#16,直接芳香化酶辅助治疗,依西美坦,复旦大学肿瘤医院乳腺癌研究所,22,2010-12-4,TEAM,研究结果：随访,2.75,年,(,33,个月,),2.75,年,3.0,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,23,2.75,年,3.0,在接受治疗的人群中,随访,2.75,年,，在接受治疗人群中，阿诺新可降低,17%,的疾病风险！,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,24,TEAM,研究结果：随访,2.75,年,(,33,个月,),2.75,年,3.0,随访,2.75,年,，阿诺新可降低,19%,的远处转移风险！,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,25,三苯氧胺后序贯,AI,序贯,依西美坦,对比,三苯氧胺,复旦大学肿瘤医院乳腺癌研究所,26,2010-12-4,他莫昔芬,依西美坦,他莫昔芬,随机分组,治疗后随访,2-3,年,2-3,年治疗研究,诊断,研究开始,共5年的内分泌治疗,IES 031,：研究设计,Coombes,ASCO 2006.,56,个月中位随访期,超过 99%的患者完成了治疗,超过2年的治疗后随访,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,27,HR=0.75,95%CI(0.65 0.87),P,-value0.0001,End of,treatment,ER+/,未明患者,Coombes,ASCO 2006.,339 events,2296 at risk,阿诺新,他莫昔芬,438 events,2306 at risk,2.5,年,3.4,(1.8 5.1),5,年,3.5,(0.1 6.9),%,绝对差异,(95%CI),随访,5,年,，阿诺新比他莫西芬降低,25%,的疾病风险！,IES 031,结果：无病生存期,DFS,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,28,End of,treatment,HR=0.83,95%CI(0.69 1.00),P,-value0.05,Coombes,ASCO 2006.,ER+/,未明患者,2.5 years,0.7,(-0.4 1.9),5 years,1.6,(-1.2 4.3),%,绝对差异,(95%CI),210 events,2296 at risk,阿诺新,251 events,2306 at risk,他莫昔芬,随访,5,年,，阿诺新比他莫西芬降低,17%,的死亡风险！,IES 031,结果：总生存期,OS,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,29,IES 031,结果：减少对侧和,远处,复发,Coombes.,Lancet 2007;369:55970,降低对侧乳腺复发风险,43%,（,P=0.04,）,降低远处转移风险,17%,（,P=0.03,）,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,30,91,个月总生存,(OS):ER+/,不明,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,31,91,个月无病生存,(DFS):ER+/,不明,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,32,无乳腺癌生存,:ER+/,不明,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,33,无乳腺癌生存,:ER+/,不明,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,34,依西美坦减少更多远处转移，尤其骨转移,TTDR:HR=0.83(95%CI 0.72-0.96)p=0.01,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,35,依西美坦对于第二原发肿瘤有显著的降低作用,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,36,结论,长时间的随访（中位随访,91,个月）继续证明了转换到依西美坦对比继续使用他莫昔芬显著改善了无复发生存率，且可持续到治疗结束后至少,5,年。,长时间的随访（中位随访,91,个月）继续证明了转换到依西美坦对比继续使用他莫昔芬显著改善了总生存期（,P=0.04,），这是目前唯一一个经过国际多中心、随机、双盲、大型随机临床试验证实,AIs,能显著提高总生存期的临床研究。,IES,研究的结果表明转换到依西美坦对比继续使用他莫昔芬显著改善了,BCFS,（,P=0.001,），从而进一步揭示了依西美坦对于绝经后激素受体阳性早期乳腺癌患者的疗效。,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,37,三苯氧胺后序贯,AI,序贯,阿那曲唑,对比,三苯氧胺,复旦大学肿瘤医院乳腺癌研究所,38,2010-12-4,三苯氧胺后序贯,AI,三苯氧胺序贯来曲唑,对比来曲唑,复旦大学肿瘤医院乳腺癌研究所,39,2010-12-4,AC,AD,CD,Tamoxifen,BIG1-98,序贯分析：,探索序贯治疗是否优于弗隆单药治疗？,优效性检验设计,分析了未揭盲的组，,两,个配对组,由随机点开始分析,中位随访,71,个月,99%,可信区间来说明多重比较,Mouridsen H et al.Presented at:SABCS 2008,San Antonio,Texas.General Session 1,#13.,Letrozole,Tamoxifen,Letrozole,Letrozole,Tamoxifen,Letrozole,0,2,年,5,Letrozole,Tamoxifen,Tamoxifen,Letrozole,Letrozole,Tamoxifen,Tamoxifen,Tamoxifen,Letrozole,尚未有分析结果的,3,组,BC,BD,N=3086,N=3094,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,40,BIG1-98,序贯分析：显示序贯治疗不优于弗隆单药治疗,Mouridsen H,et al.,SABCS,2008 Abstract,13.,例数,事件,5,年,DFS%,来曲唑,1546,248,87.9,Let Tam,1540,236,87.6,Tam Let,1548,259,86.2,随机分组后时间（年）,DFS(%),60,80,100,40,20,0,0,1,2,3,4,5,6,Let Tam,Tam Let,来曲唑,1548,Let Tam,Tam Let,来曲唑,有风险的例数,1546,1470,1371,565,1540,1467,1369,546,1457,1369,561,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,41,BIG1-98,序贯分析：,乳腺癌相关事件,*42%of the population is node positive;58%node negative.,Mouridsen H et al.Presented at:SABCS 2008,San Antonio,Texas.General Session 1,#13,.,TAM,来曲唑,vs.,来曲唑,总体,15,10,5,20,0,0,1,2,3,4,5,6,来曲唑,T,AM,来曲唑,4.1,9.1,7.3,2.5,随机分组后时间（年）,根据淋巴结状态*,15,10,5,20,0,0,1,2,3,4,5,6,乳腺癌复发,来曲唑,T,AM,来曲唑,随机分组后时间（年）,淋巴结阳性,淋巴结阴性,14.7,12.4,4.9,3.5,7.9,4.7,1.3,0.9,乳腺癌复发,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,42,BIG1-98,序贯分析：,乳腺癌相关事件,来曲唑,来曲唑,TAM,15,10,5,20,0,0,1,2,3,4,5,6,随机分组后时间（年）,2.5,7.3,7.3,2.5,来曲唑,来曲唑,T,AM,12.5,12.4,3.9,3.5,4.7,1.5,0.9,15,10,5,20,0,0,1,2,3,4,5,6,随机分组后时间（年）,3.9,*42%,的患者淋巴结阳性,;58%,淋巴结阴性,.,Mouridsen H et al.Presented at:SABCS 2008,San Antonio,Texas.General Session 1,#13.,总体,根据淋巴结状态*,来曲唑,TAM,vs.,来曲唑,乳腺癌复发,乳腺癌复发,淋巴结阳性,淋巴结阴性,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,43,BIG1-98,序贯分析：中位随访,71,月结果,DFS,OS,TDR*,T,AM,来曲唑,vs.,来曲唑,来曲唑更好,Hazard Ratio(99%CI),1.05(0.84-1.32),Hazard Ratio(99%CI),来曲唑,T,AM,vs.,来曲唑,0.5,0.75,1,1.25,1.5,0.5,0.75,1,1.25,1.5,1.13(0.83-1.53),1.22(0.88-1.69),0.96(0.76-1.21),0.90(0.65-1.24),1.05(0.75-1.47),*,至远处转移时间,.,Mouridsen H et al.Presented at:SABCS 2008,San Antonio,Texas.General Session 1,#13.,TAM,来曲唑更好,来曲唑更好,DFS,OS,TDR*,来曲唑,TAM,更好,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,44,三苯氧胺后序贯,AI,序贯,依西美坦,对比,依西美坦,复旦大学肿瘤医院乳腺癌研究所,45,2010-12-4,TEAM Trial:Design,复旦大学肿瘤医院乳腺癌研究所,46,2010-12-4,Disease Free Survival 5y(ITT),复旦大学肿瘤医院乳腺癌研究所,47,2010-12-4,Overall Survival(ITT),复旦大学肿瘤医院乳腺癌研究所,48,2010-12-4,按淋巴结状态分层的,DFS,两组间无显著差异,0.25,0.20,0.15,0.10,0.05,0.00,概率,0 1 2 3 4 5,0.25,0.20,0.15,0.10,0.05,0.00,0 1 2 3 4 5,他莫昔芬 依西美坦,依西美坦,N,阳性,N,阴性,所有,DFS,随访年数,(ITT),所有,DFS,随访年数,(ITT),他莫昔芬 依西美坦,依西美坦,不管是淋巴结阴性还是淋巴结阳性的患者，,两组间,DFS,均无显著差异,概率,Jones SE,et al.SABCS 2008;Abstract 15,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,49,TEAM,病理学亚组研究：,HER2/3,阴性表达预测依西美坦起始治疗疗效更好,他莫昔芬,依西美坦,暴露例数,T:,1508145513651201,E:,1524147914181230,HR=0.6995%CI,0.53-0.88,3,2,1,0,0,5,10,15,随机化后时间（年）,HER2/3,阴性,(70.6%),暴露例数,T:,650623576477,E:,624597564473,HR=1.1395%CI,0.82-1.55,3,2,1,0,0,5,10,15,随机化后时间（年）,HER2/3,阳性,(29.4%),他莫昔芬依西美坦,交互检验,(,p,=0.02),HR 0.60,95%CI 0.39-0.91;(,校正后,p,=0.01),%,患病患者,%,患病患者,Bartlett et al,SABCS 2009,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,50,5,年后是否需要进一步治疗？,复旦大学肿瘤医院乳腺癌研究所,51,2010-12-4,MA.17:Trial Design,Primary end point:,DFS,Secondary end points:,OS/rate of CBCancer/safety/QOL,Randomization,(all patients disease-free),Tamoxifen,Placebo daily,Letrozole 2.5 mg daily,5 years,5 years extended adjuvant,0-3months,n=2593,n=2594,Goss PE et al:J Natl Cancer Inst 97:1262,2005,52,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,MA.17:Preplanned AnalysisKey Endpoints in Nodal Subgroups(n=5187),Letrozole reduced risk of recurrence by 42%,DFS*,Distant*DFS,Node,*,pos,Node,*,pos,Node,*,neg,Node neg,Node neg,Node,*,pos,*Statistically significant,HR=0.61,(0.45-0.84),HR=0.45,(0.27-0.75),HR=0.63,(0.31-1.27),HR=0.53,(0.36-0.78),HR=1.52,(0.76-3.06),HR=0.61,(0.38-0.98),Goss P et al,J Natl Cancer Inst 2005;97:1262-71,HR=0.58,(0.45-0.76),HR=0.61,HR=0.82,(0.57-1.19),OS,53,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,绝经前内分泌治疗,卵巢去势,药物去势,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,54,Discovery of Zoladex,Zoladex,LHRH,Thick bonds indicate modifications,Ser(Bu,t,),Azgly,55,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,ZEBRA:,试验设计,手术,放疗,诺雷得,3.6,mg,每,28,天一次，共,2,年,绝经前,/,围绝经期,淋巴结阳性的早期乳腺癌，年龄,50 岁,随访,CMF 28,天,/,周期,，共,6,周期,随即分组 1:1(开放性，多中心),肿瘤复发,死亡,死亡,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,56,ZEBRA:KaplanMeier Plot of DFS in ER+Patients,Zoladex 3.6mg,CMF,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,1,2,3,4,5,6,7,8,9,10,Disease-free survival(years),Proportion alive and free of disease,Number of events:,ER+(,n,=1,189)487,Jonat W,et al.J Clin Oncol 2002;20:462835.,57,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,ZEBRA:,疗效结果,总生存期,总生存,死亡例数,HR,95%,CI,p,值,ER+,225,0.99,0.76,1.28,0.92,ER,104,1.77,1.19,2.63,0.0043,(,n,=1,189),(,n,=304),Jonat W,et al.J Clin Oncol 2002;20:4628,35.,HR 1.00,显示,诺雷得,3.6,mg,有优势,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,58,绝经前内分泌治疗,药物去势,+,三苯氧胺,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,59,CMF x 6 cycles,Zoladex 3.6mg/28 days for 3 years PLUS,tamoxifen 20mg/day for 5 years,randomise 1:1,Premenopausal women with ER+ve and/or PgR+vebreast cancer,Jakesz R,et al.Breast Cancer Res Treat 1999;57:25,Abstr 2.,Jakesz R,et al.Eur J Surg Oncol 2000;26:281,Abstr 110.,1,045 evaluable patients,Node+ve or nodeve,Included 28%of all eligible patients in Austria,ABCSG AC05 TrialAustrian Adjuvant Breast Cancer Trial,(Zoladex 3.6mg+tamoxifen vs chemotherapy),60,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,Randomized Adjuvant Trial of Tamoxifen and Goserelin Versus CMF:Evidencefor the Superiority of Treatment With Endocrine Blockade inPremenopausal Patients With Hormone-Responsive BreastCancerAustrian Breast and Colorectal Cancer Study GroupTrial 5,61,复旦大学肿瘤医院乳腺癌研究所,2010-12-4,绝经前内分泌治疗,药物去势,+,阿那曲唑,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,62,ABCSG-12,试验设计,1999-2006,年,1,803,例绝经前乳腺癌患者,内分泌治疗有效,(ER,和,/,或,PR,阳性,),I&II,期,10,个淋巴结转移,除新辅助化疗外未接受其他化疗,治疗期,:3,年,63,随机分组,1:1:1:1,手术,(+,放疗,),三苯氧胺,20 mg/,d,戈舍瑞林,3.6 mg,每,28,天一次,阿那曲唑,1 mg/d,+,唑来膦酸,4 mg,6,个月一次,阿那曲唑,1 mg/d,三苯氧胺,20 mg/d,+,唑来膦酸,4 mg,6,个月一次,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,63,与三苯氧胺相比，芳香化酶抑制剂阿那曲唑能改善临床结局吗？,在内分泌疗法中加入唑来膦酸能进一步改善预后吗？,ABCSG-12,:,回答两个问题,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,64,Peter Dubsky,绝经后激素敏感的乳腺癌患者，芳香化酶抑制剂,(AIs),比三苯氧胺（,TAM),更有效,1-7,。,对于,TAM,联合戈舍瑞林治疗但疾病进展的绝经前患者，阿那曲唑,(ANA),联合戈舍瑞林治疗显著降低平均雌激素水平,8,。,1)Howell A,et al.,Lancet.,2005;365:60-62;2)Thurlimann B,et al.,N Engl J.Med.,2005;353:2747-2757;,3)Coates A.,et al.,J Clin Oncol,.2007;25:486-492;4)Coombes RC,et al.,N Engl J Med.,2004;350:1081-1092;,5)Coombes RC,et al.,Lancet.,2007;369:559-570;6)Jakesz R,et al.,Lancet.,2005;366:455-462;,7)Goss P,et al.,J Natl Cancer Inst.,2005;97:1262-1271;8)Forward DP,et al.,Br J Cancer,.2004;90:590-594;,芳香化酶抑制剂能改善绝经前患者的临床结局吗？,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,65,1999 2006,年共入组,1,803,名患者,中位随访,48,个月,2008,年,3,月,:137,例首次,DFS,事件，,42,例死亡,-30,例局部复发,-70,例远处转移,包括,40,例骨转移事件,-16,例对侧乳腺癌,-19,例非乳腺原发肿瘤,总计,:4,年无病生存率,:92.4%;4,年总生存率,:97.7%,试验情况,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,66,67,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,随机分组后的时间，月,无疾病生存率,%,风险比,(95%CI),发生数,vs TAM,P,值,ANA72/9031.096(0.78,1.53).593,TAM65/900,Gnant M,et al.Presented at:ASCO 2008.Chicago,IL,USA.Abstract LBA4.,患者数,TAM,900,840,736,580,439,264,141,60,ANA,903,849,743,558,436,271,151,59,主要终点,:,无疾病生存,TAM,和,ANA,之间无显著差异,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,67,14,29,41,10,6,9,10,1,1,16,0,10,20,30,40,50,60,70,80,90,TAM,(n=900),ANA,(n=903),无复发死亡,继发恶性肿瘤,对侧乳腺癌,远处,转移,局部复发,第一事件病人人数,TAM vs ANA,首次,DFS,事件,(,意向治疗人群,),2010-12-4,复旦大学肿瘤医院乳腺癌研究所,68,无复发生存,总生存,随机分组后时间，月,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,总生存,%,风险比,(95%CI),发生数,vs TAM,P,值,ANA271.791(0.95 to 3.37).065,TAM15,风险比,(95%CI),发生数,vs TAM,P,值,ANA721.116(0.80 to 1.56).529,TAM64,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,随机分组后时间，月,无复发生存,%,危险患者数,900,834,719,553,411,243,129,50,903,844,725,540,411,255,139,51,TAM,ANA,900,840,736,580,439,264,141,60,903,849,743,558,436,271,151,59,次要终点,:,ANA vs.TAM,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,69,TAM alone vs ANA ASCO 2010,DFS,：单用,TAM,与单用,ANA,相似,(HR=1.11 0.84,1.50;P=.44,OS:,ANA,差于,Tam(HR=1.74 1.05,2.87;p=0.03,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,70,62,月随访,ASCO 2010,Conclusions,在阿那曲唑和三苯氧胺间,DFS,无统计学差别，但阿那曲唑的,OS,差于三苯氧胺，可能是由于阿那曲唑组缺乏解救性芳香化酶抑制剂治疗,There,was no DFS difference between ANA and TAM,but ANA pts had inferior OS vs TAM;probably because ANA pts lack palliative aromatase inhibitor treatment.,2008-8-28,复旦大学肿瘤医院乳腺癌研究所,71,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,随机分组后时间，月,无疾病生存,%,风险比,(95%CI),发生数,vs No ZOL,ZOL54/9040.643(0.46 to 0.91),No ZOL83/899,P,=.011,危险患者数,No ZOL,904,838,735,565,441,265,161,60,ZOL,899,851,744,573,434,270,131,59,Gnant M,et al.Presented at:ASCO 2008.Chicago,IL,USA.Abstract LBA4.,主要终点：无疾病生存,与单独内分泌治疗相比，合用唑来膦酸显著改善,DFS,2010-12-4,复旦大学肿瘤医院乳腺癌研究所,72,Conclusions ASCO 2010,With longer follow-up of ABCSG-12,the addition of ZOL(4 mg q 6 mo)consistently improves both DFS and OS in the ANA and TAM subgroups,and in N+and N-pts.,2008-8-28,复旦大学肿瘤医院乳腺癌研究所,73,内分泌治疗的策略,复旦大学肿瘤医院乳腺癌研究所,74,2010-12-4,小结,14,个前瞻性临床研究，,内分泌治疗的药物选择,持续的时间,用药的顺序,合用的药物,和其他药物,复旦大学肿瘤医院乳腺癌研究所,75,2010-12-4,2007