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,1,复旦大学肿瘤医院乳腺癌研究所,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、内分泌、生物治疗,2,复旦大学肿瘤医院乳腺癌研究所,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,3,复旦大学肿瘤医院乳腺癌研究所,历史的回顾,1836年, Cooper 观察到乳腺肿瘤的生长与月经周期相关。1896年, Beatson 报道在几个绝经前的乳腺癌患者，在切除了卵巢后其转移灶出现了退缩。1952年 Huggins和Bergenstal 报道切除肾上腺后可使部分乳腺癌患者的转移灶出现退缩。 Luft and Olivec
2、rona报道切除垂体后可取得上述相似的效果。,4,复旦大学肿瘤医院乳腺癌研究所,内分泌机制,(B) 绝经后,GNRH 类似物,Breastcarcinoma,Breastcarcinoma,抗雌激素,卵巢,LHFSH,抗雌激素,(A) 绝经前,肾上腺,雌激素,雌激素,雄烯二酮,芳香化酶抑制剂,周围的芳香化,Tellez C, et al. Surg Oncol Clin North Am. 1995;4:751-777.,GNRH = 促性腺激素释放激素; LH = 黄体生成数; FSH = 卵泡刺激素,5,复旦大学肿瘤医院乳腺癌研究所,在1975年所用的内分泌治疗手段,卵巢的切除 手术 (去
3、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,6,复旦大学肿瘤医院乳腺癌研究所,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,7,复旦大学肿瘤医院乳腺癌研究所,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,8,复旦大学肿瘤医院乳腺癌研究所,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
4、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,9,复旦大学肿瘤医院乳腺癌研究所,三苯氧胺辅助治疗的临床试NSABPB14,10,复旦大学肿瘤医院乳腺癌研究所,%,Years,Actuarial estimate and SEAllocated tamoxifenAllocated 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
5、VS NOTRecurrences,11,复旦大学肿瘤医院乳腺癌研究所,Actuarial estimate and SEAllocated tamoxifenAllocated 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 NOTAll Deaths,12,复旦大学肿瘤医院乳腺癌研究所,NSABP B-14: No Benefit of Extending TAM,P=0.03,P=0.13,P=0.
6、07,Disease-Free Survival,Relapse-Free Survival,Survival,100,90,80,70,60,50,%,0,1,2,3,4,5,6,7,Years*,0,1,2,3,4,5,6,7,0,1,2,3,4,5,6,7,No. atrisk:569531491229531491229554529257583527472209527472209560528239,No. of No. ofPts. EventsPlac569106Tam583137,No. of Events3447,No. of Deaths3957,Fisher et al. J
7、Natl Cancer Inst. 2001;93:684.,After 5 years of adjuvant tamoxifen.,13,复旦大学肿瘤医院乳腺癌研究所,New trials,复旦大学肿瘤医院乳腺癌研究所,14,ATLAS,复旦大学肿瘤医院乳腺癌研究所,15,Meta分析,复旦大学肿瘤医院乳腺癌研究所,16,抗雌激素以后的选择,阻断雌激素受体 (抗雌激素治疗),抑制雌激素的合成 (芳香化酶抑制剂),效果相似还是更好?,17,复旦大学肿瘤医院乳腺癌研究所,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,
8、皮疹等,无肾上腺功能影响,1,000to10,000,100,1,18,复旦大学肿瘤医院乳腺癌研究所,不同芳香化酶的结构,载体类抑制剂,Androgen substrate,非甾体类抑制剂,19,复旦大学肿瘤医院乳腺癌研究所,The clinical significance of these findings has not been established.Adapted by permission of the Society for Endocrinology, from Brodie A, Lu Q, Liu Y, et al. Aromatase inhibitors and th
9、eir antitumor effects in model systems. Endocrine Rel Cancer. 1999;6:205-210.,Effect of letrozole, Anastrozole, and Tamoxifen on Tumor Growth of MCF-7 Transfected With Aromatase Gene in Nude Mice,20,复旦大学肿瘤医院乳腺癌研究所,肿瘤的重量的变化,21,复旦大学肿瘤医院乳腺癌研究所,9366 postmenopausal women with invasive breast cancer Mean
10、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-free survivalSafety/tolerability,Secondary trial endpoints:Incidence of contralateral b
11、reast cancerTime to distant recurrenceTime to recurrenceOverall 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 (%),30,25,20,15,10,5,0,13.9%,16.4%,
12、25.8%,29.9%,0,1,2,3,4,5,6,7,8,9,HR+,HR0.85,95% CI(0.76, 0.94),p-value0.003,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,23,复旦大学肿瘤医院乳腺癌研究所,Time to Distant Recu
13、rrenceHR+ 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+,HR0.84,95% CI(0.72, 0.97),p-value0.022,1.3%,2.4%,The ATAC Trialists Group. Lancet Oncol 2008; 9:45-53,AD,24,复旦大学肿瘤医院乳腺癌研究所,Contralateral Breast CancerHR+ Patients,Patients (%),5,4,
14、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+,HR0.60,95% CI(0.42, 0.85),p-value0.004,AD,0.8%,1.7%,The ATAC Trialists Group. Lancet Oncol 2008; 9:45-53,25,复旦大学肿瘤医院乳腺癌研究所,Death: All CausesHR+ Patients,Patients (%),30,25,20,15,10,5,0,0,1,2,3,4,5,6,7,8,9,Follow-u
15、p time (years),HR+,HR0.97,95% CI(0.86, 1.11),p-value0.70,The ATAC Trialists Group. Lancet Oncol 2008; 9:45-53;AstraZeneca data on file,26,复旦大学肿瘤医院乳腺癌研究所,Fracture Episode Rates Throughout the Study,29842976,At risk:ARIMIDEXtamoxifen,28592824,27452699,26402572,24962419,23062208,20772000,17131645,70265
16、9,Time since randomisation (years),Annual fracture episode rates (%),0,1,2,3,4,5,6,7,8,9,0,2,3,4,1,The ATAC Trialists Group. Lancet Oncol 2008; 9:45-53,27,复旦大学肿瘤医院乳腺癌研究所,BIG 1-98: Design,RANDOMIZE,0,2,5,Years,Tamoxifen,Letrozole,Tamoxifen,Letrozole,Letrozole,Tamoxifen,A,B,C,D,n=1540,n=1548,n=2463,n=
17、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 & DInitial data analysis at 25.8 months median FU,FU = follow-up.Update of Thrlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.,28,复旦大学肿瘤医院乳腺癌研究所,BIG
18、 1-98 Monotherapy UpdateMedian Follow-up 76 months,*Let:Tam: breast cancer events, 321:363second (non breast) malignancy, 101:115deaths without prior cancer event, 87:87,29,复旦大学肿瘤医院乳腺癌研究所,TEAM研究结果：随访2.75年(33个月),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！,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
19、险！,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,HR = 0.7595% CI (0.65 0.87)P-value0.0001,End oftreatment,ER+/未明患者,Coombes, ASCO 2006.,339 events2296 at risk,阿诺新,他莫昔芬,438 events2306 at risk,2.5 年3.4 (1.8 5.1),5 年3.5
20、 (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,End oftreatment,HR = 0.8395% CI (0.69 1.00)P-value0.05,Coombes, ASCO 2006.,ER+/未明患者,2.5 years0.7 (-0.4 1.9),5 years1.6 (-1.2 4.3),% 绝对差异 (95% CI),210 events2296 at risk,阿诺新,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,IES 031结果：减少对侧和
21、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）,ABCSG 8研究设计,手术治疗,随机化分组,他莫昔芬20mg/d（2年）,他莫昔芬20mg/d（3年）,他莫昔芬20mg/d（2年）,阿那曲唑1mg/d（3年）,转换分析,序贯分析,Jakesz et al, Lancet 2005,ABCSG 8研究入组条件,可行手术治疗的绝经后乳腺癌患者（依据激素水平确定绝经后3年内）80 岁雌激素受体阳性（ER+）和/或孕激素受体阳性（PR+）1级或2级导管癌和小叶癌乳腺改良根治术或保乳手术淋
22、巴结手术（前哨淋巴结或腋下淋巴结切除）不允许化疗,不同于其他研究,不同于其他研究,ABCSG 8研究统计分析,主要终点 无复发生存期 RFS（局部和远处复发病灶、对侧乳腺癌、非复发相关性死亡）（不同于DFS）次要终点 总生存期 OS（各种原因导致的死亡） 安全性分析,ABCSG 8研究：无复发生存率RFS序贯样本、交叉分析、截尾数据,所有患者HR=0.815年龄60岁 HR0.814ER和PR低表达 HR1.083ER和PR高表达 HR0.6861级 HR0.832级或小叶癌 HR0.803,时间（月） 0 12 24 36 48 60 72 84 96 事件（序贯治疗组） 18 26 19
23、33 20 27 20 15 15事件（他莫昔芬治疗组） 14 26 40 35 33 30 22 10 10,0 12 24 36 48 60 72 84 96,10.950.90.850.80.750.70.650.60.550.5,0.5 0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4,事件(序贯e):202 of 1469事件(TAM):235 of 1452P-value(Log-Rank):0.038Cox回归: HR 0.820,95% CI 0.679-0.990,无复发生存率（月）,TAM 序贯,危险比和可信限,ABCSG 8研究：总生存期总样本，交叉
24、分析，截尾数据,43,BIG 1-98 Sequential Therapy Two Pairwise Comparisons,Letrozole,Letrozole,Tamoxifen,N=3,094,Letrozole,Letrozole,Tamoxifen,0,2,5,YEARS,N=3,086,3 blinded armsSequential vs. letrozole monotherapyEvaluated from randomizationMedian Follow Up 71 mos.99% confidence intervals to account for multip
25、le comparisons,复旦大学肿瘤医院乳腺癌研究所,44,BIG 1-98 Sequential Treatment Disease-Free Survival,复旦大学肿瘤医院乳腺癌研究所,MA.17: Trial Design,Primary end point: DFSSecondary end points: OS / rate of CBCancer/ safety / QOL,Randomization(all patients disease-free),Tamoxifen,Placebo daily,Letrozole 2.5 mg daily, 5 years,5 y
26、ears extended adjuvant,0-3months,n=2593,n=2594,Goss PE et al: J Natl Cancer Inst 97:1262, 2005,45,复旦大学肿瘤医院乳腺癌研究所,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
27、,* 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,46,复旦大学肿瘤医院乳腺癌研究所,612182430364248,Optimal Duration of letr
28、ozole - HR for DFS MA.17,Placebo,Letrozole,Hazard Rate,Months after randomization,0.52,0.45,0.35,0.19,HR,Ingle J et al. Breast Cancer Res and Treat - in press,47,复旦大学肿瘤医院乳腺癌研究所,后期伸展AI治疗,48,复旦大学肿瘤医院乳腺癌研究所,MA-17,49,复旦大学肿瘤医院乳腺癌研究所,LHRH类似物激动剂,“诺雷德” 长期使用抑制脑垂体促黄体生成素合成，从而引起 女性血清雌二醇的下降，初期用药时“诺雷德”同其它LHRH激动剂一
29、样，可暂时增加男性血清睾丸酮和女性血清雌二醇的浓度。女性患者在初次给药后21天左右血清中雌二醇浓度受到抑制，并在以后每28天的治疗中维持在绝经后水平。,50,复旦大学肿瘤医院乳腺癌研究所,Discovery of Zoladex,Zoladex,LHRH,Thick bonds indicate modifications,Ser(But),Azgly,51,复旦大学肿瘤医院乳腺癌研究所,Figure AHypersecretion of LH following acute administration of Zoladex,Figure BHyposecretion of LH follo
30、wing chronic administration of Zoladex,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,PituitaryCell,LH,PituitaryCell,LH,Mechanism of Action of Zoladex 2,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,52,复旦大学肿瘤医院乳腺癌
31、研究所,诺雷德与三苯氧胺联合应用,A Meta-Analysis of Four Randomized Trials,53,复旦大学肿瘤医院乳腺癌研究所,ZEBRA: Trial Design,Surgery radiotherapy,Zoladex 3.6mg every 28 daysfor 2 years,Pre-/perimenopausal patients with node-positive early breast cancer, aged 50 years,Follow-up,CMF 6 28-daycycles,Randomised 1:1 (open, multicent
32、re),Tumour recurrence,Death,Death,54,复旦大学肿瘤医院乳腺癌研究所,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.
33、J Clin Oncol 2002; 20: 462835.,55,复旦大学肿瘤医院乳腺癌研究所,ZEBRA: Efficacy Results Overall Survival,Overall survival,Number ofdeaths,HR,95%,CI,p value,ER+,225,0.99,0.761.28,0.92,ER,104,1.77,1.192.63,0.0043,(n=1,189),(n=304),Jonat W, et al. J Clin Oncol 2002; 20: 462835.,An HR 1.00 favours Zoladex 3.6mg,56,复旦大
34、学肿瘤医院乳腺癌研究所,CMF x 6 cycles,Zoladex 3.6mg/28 days for 3 years PLUStamoxifen 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 eva
35、luable patientsNode+ve or nodeveIncluded 28% of all eligible patients in Austria,ABCSG AC05 TrialAustrian Adjuvant Breast Cancer Trial (Zoladex 3.6mg + tamoxifen vs chemotherapy),57,复旦大学肿瘤医院乳腺癌研究所,Randomized Adjuvant Trial of Tamoxifen and Goserelin Versus CMF: Evidencefor the Superiority of Treatme
36、nt With Endocrine Blockade inPremenopausal Patients With Hormone-Responsive BreastCancerAustrian Breast and Colorectal Cancer Study GroupTrial 5,58,复旦大学肿瘤医院乳腺癌研究所,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,59,1999 2006年共入组1,803名患者 中位随访48个月 2008年3月:
37、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,61,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,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).593TAM65/900,Gnant M, et al. Presented at: ASCO 2008.
38、Chicago, IL, USA. Abstract LBA4.,主要终点: 无疾病生存TAM和ANA之间无显著差异,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),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
39、生数vs TAMP 值ANA271.791 (0.95 to 3.37).065TAM15,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,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 ZO
40、LZOL54/9040.643 (0.46 to 0.91)No ZOL83/899,P = .011,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,两者在DFS, RFS或OS方面无显著性差异 - 这可能是因为绝经前患者使用戈舍瑞林强烈的卵巢抑制作用ANA与TAM相比，潜在的威胁生命的严重不良反应更少见,子宫息肉,血栓形成,绝经前妇女使用芳香化酶抑制剂的明确指南出台前，还需要进一步的试验 - 正在进行的内分泌治疗联合卵巢抑制辅助治疗的试验： SOFT N=3,000; TEXT N=1,845,阿那曲唑 vs 三苯氧胺,小结,12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,复旦大学肿瘤医院乳腺癌研究所,66,谢谢！,67,复旦大学肿瘤医院乳腺癌研究所,
