陆劲松 乳腺癌的内分泌治疗进展 lasrinppt课件

1、2010-12-4,.,1,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,2010-12-4,.,2,乳腺癌的治疗原则,以手术为主 以其它治疗为辅 综合治疗,2010-12-4,.,3,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,2010-12-4,.,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,2010-12-4,.,5,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,2010-12-4,.,6,目前所用的乳腺癌内分泌治疗手段

2、,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,2010-12-4,.,7,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,2010-12-4,.,8,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

3、抑制因子的状态,2010-12-4,.,9,%,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,2010-12-4,.,10,Actuarial estimate and SE Allocated tamoxifen Allocated control,ER+,

4、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,2010-12-4,.,11,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 10,000,100,1,2010-12-4,.,12,不同芳香化酶的结构,载体类抑制剂,Androgen substrate,非甾体类抑制剂,2010-

5、12-4,.,13,直接芳香化酶辅助治疗,阿那曲唑,9366 postmenopausal women with invasive breast cancer Mean age 64 years; 84% hormone receptor-positive 61% node-negative; 64% with tumour 2cm in diameter,Randomisation 1:1:1 for 5 years,ARIMIDEX (n=3125),tamoxifen (n=3116),Regular follow-up,Primary trial endpoints: Disease-

6、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

7、Trial Design,2010-12-4,.,15,Disease-free Survival HR+ Patients,Patients (%),30,25,20,15,10,5,0,13.9%,16.4%,25.8%,29.9%,0,1,2,3,4,5,6,7,8,9,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, abso

8、lute difference,The ATAC Trialists Group. Lancet Oncol 2008; 9:45-53,AD,2010-12-4,.,16,Time to Distant RecurrenceHR+ Patients,Patients (%),30,25,20,15,10,5,0,0,1,2,3,4,5,6,7,8,9,7.8%,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 Gr

9、oup. Lancet Oncol 2008; 9:45-53,AD,2010-12-4,.,17,Contralateral Breast CancerHR+ 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%,The ATAC Trialists Group. Lancet Oncol 2008; 9:45-5

10、3,2010-12-4,.,18,Death: All CausesHR+ Patients,Patients (%),30,25,20,15,10,5,0,0,1,2,3,4,5,6,7,8,9,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,2010-12-4,.,19,直接芳香化酶辅助治疗,来曲唑,2010-12-4,.,20,BIG 1-98:

11、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 23:6S. Abstract 511.,21,B

12、IG 1-98研究 76个月 IPCW分析结果,P0.05,Regan et al. SABCS 2009 abs #16,2010-12-4,.,22,直接芳香化酶辅助治疗,依西美坦,2010-12-4,.,23,TEAM研究结果：随访2.75年(33个月),2010-12-4,.,24,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,.,25,TEAM研究结果：随访2.75年(33个月),随访2.75年，阿诺新可降低19%的远处转移风险！,2010-12-4,.,26,三苯氧胺后序贯AI,序贯依西美坦 对比三苯氧胺,2010-12-

13、4,.,27,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,.,28,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

14、.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,.,29,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,随访5年，阿诺新比他

15、莫西芬降低17%的死亡风险！,IES 031结果：总生存期OS,2010-12-4,.,30,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,.,31,91个月总生存(OS): ER+/不明,2010-12-4,.,32,91个月无病生存(DFS): ER+/不明,2010-12-4,.,33,无乳腺癌生存:ER+/不明,2010-12-4,.,34,无乳腺癌生存: ER+/不明,2010-12-4,.,35,依西美坦减少更多远处

16、转移，尤其骨转移,TTDR:HR=0.83(95%CI 0.72-0.96) p=0.01,2010-12-4,.,36,依西美坦对于第二原发肿瘤有显著的降低作用,2010-12-4,.,37,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

17、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,.,38,三苯氧胺后序贯AI,序贯阿那曲唑 对比三苯氧胺,2010-12-4,.,39,三苯氧胺后序贯AI,三苯氧胺序贯来曲唑 对比来曲唑,2010-12-4,.,40,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,

18、 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,.,41,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

19、. SABCS 2008 Abstract 13.,随机分组后时间（年）,DFS (%),1548,561,2010-12-4,.,42,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,来曲唑,TAM 来曲唑,4.1,9.1,7.3,2.5,随机分组后时间（年）,根据淋巴结

20、状态*,乳腺癌复发,来曲唑,TAM 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,.,43,BIG1-98序贯分析：乳腺癌相关事件,来曲唑,来曲唑 TAM,随机分组后时间（年）,2.5,7.3,7.3,2.5,来曲唑,来曲唑 TAM,12.5,12.4,3.9,3.5,4.7,1.5,0.9,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,

21、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,.,44,BIG1-98序贯分析：中位随访71月结果,DFS,OS,TDR*,TAM 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 TAMvs. 来曲唑,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

22、(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,.,45,三苯氧胺后序贯AI,序贯依西美坦 对比依西美坦,2010-12-4,.,46,TEAM Trial: Design,2010-12-4,.,47,Disease Free Survival 5y (ITT),2010-12-4,.,48,Overall Survival (I

23、TT),2010-12-4,.,49,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,.,50,TEAM病理

24、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%

25、 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,.,51,5年后是否需要进一步治疗？,2010-12-4,.,52,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 dail

26、y, 5 years,5 years extended adjuvant,0-3months,n=2593,n=2594,Goss PE et al: J Natl Cancer Inst 97:1262, 2005,2010-12-4,.,53,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 ne

27、g,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,2010-12-4,.,54,绝经前内分泌治疗,卵巢去势 药物去势,2010-

28、12-4,.,55,Discovery of Zoladex,Zoladex,LHRH,Thick bonds indicate modifications,Ser(But),Azgly,2010-12-4,.,56,ZEBRA: 试验设计,手术 放疗,诺雷得 3.6mg 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,.,57,ZEBRA: KaplanMeier Plot of DFS in ER+ Patients,Zoladex 3.6mg

29、,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.,2010-12-4,.,58,ZEBRA: 疗效结果 总生存期,总生存,死亡例数,HR,95%,CI,p 值,ER+,225,0.99,0.761.28,0.9

30、2,ER,104,1.77,1.192.63,0.0043,(n=1,189),(n=304),Jonat W, et al. J Clin Oncol 2002; 20: 462835.,HR 1.00 显示 诺雷得 3.6mg有优势,2010-12-4,.,59,绝经前内分泌治疗,药物去势+三苯氧胺,2010-12-4,.,60,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 an

31、d/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 (Zola

32、dex 3.6mg + tamoxifen vs chemotherapy),2010-12-4,.,61,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

33、5,2010-12-4,.,62,绝经前内分泌治疗,药物去势+阿那曲唑,2010-12-4,.,63,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) I365:60-62; 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) Coombe

34、s 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,.,66,1999 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

35、 - 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,.,67,67,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,随机分组后的时间，月,无疾病生存率, %,风险比 (95% CI)发生数vs TAMP 值 ANA72/9031.096 (0.78, 1.53).593 TAM65/900,Gnant M, et al. Presented at: ASCO 2008. Chicago, I

36、L, USA. Abstract LBA4.,主要终点: 无疾病生存TAM和ANA之间无显著差异,2010-12-4,.,68,14,29,41,10,6,9,10,1,1,16,0,10,20,30,40,50,60,70,80,90,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,.,69,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 TAMP 值 ANA271.791 (0.95 to 3.37).065 TAM15,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,.,70,TAM alone vs ANA ASCO 2010,DFS：单用TAM 与单用ANA相似 (HR = 1.11 0