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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,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 Olivecrona报道切除垂体后可取得上述相似的效果。,ER的发现,靶器官对雌激素的高亲和性导致了其受体的发现，其可以和标记的雌激素相结合但不改变其结构。E.V.Jensen and H.I.Jacobson Basic guides to the mech
2、anism of estrogen action Rec Prog Hormone Res 1962.18:387-414.,ER的作用途径,雌激素受体位于细胞内，处于无活性，当与配体结合时形成活化状态，与相应的DNA结合，诱导相应的mRNA 转录。,乳腺癌的进展过程,0510,年*,非常早期乳腺癌临床不能发现,细胞数,细胞增殖的倍数,0510152025303540,10121010108106104102,1 mm,1 cm,10 cm,DCIS,临床乳腺癌,DCIS=Ductal carcinoma in situ.*Note:90-day doubling 40 doublings=3
3、,600 days(approximately 10 years).Harris JR,et al,eds.Breast Diseases,2nd ed.Philadelphia:JB Lippincott;1991:165-189.,正常化学预防癌前病变DCIS原发性乳腺癌新辅助治疗手术后辅助治疗转移性姑息性治疗,不同阶段治疗的名称,DCIS=Ductal carcinoma in situ.,乳腺癌细胞的分类,激素依赖性乳腺癌细胞对生理剂量的性激素具有反应性，多数对内分泌治疗敏感。激素非依赖性乳腺癌细胞对生理剂量的性激素不具有反应性，多数情况下对内分泌治疗不敏感。,激素依赖性乳腺癌的特点,
4、表达功能性的ER和PR组织学分级低S期细胞的比例低，多为二倍体细胞往往具有长的无病生存间期转移的部位多为淋巴结、软组织等临床进程缓慢在老年患者中多见对内分泌治疗具有敏感性,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,ER 和 PgR 是乳腺
5、癌中最重要的生物学指标,ER和PR的检测结果将是所有乳腺癌治疗开始前所需了解的分子指标包括术前、术后和复发性乳腺癌的治疗是所有乳腺癌治疗手段选择的标准,ER 和 PgR 的临床意义,ER和PR的检测结果提示其预后较好对内分泌治疗敏感并不提示对化疗不敏感,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,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
6、素等,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,E2,E2ER,E2ER,染色质,PgR 有丝分裂,细胞核,RNA,ER,+,雌激素,细胞浆,E2=雌二醇ER=雌激素受体E2ER=ERE2复合物PgR=孕激素受体,激素依赖性乳腺癌,雌激素受体的作用机制,雌激素受体,ER ER,CoactivatorsCorepressors,Transcription,mRNA,SERMsE2TamRal,REs,启动子,目标基因,SERM=Selective estrogen receptor modifiers;E2=Estradiol;Tam=Tamoxifen;R
7、al=Raloxifene;ER=Estrogen receptor.,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,三苯氧胺在转移性乳腺癌中的有效率,最近的研究三苯氧胺有效率(CR+PR)18 studies17%-59%Torimifene(1995)*19%Anastrazole North America(2000)*17%Anastrazole Europe(2000)*32%Fem
8、ara P025(2000)*20%,CR=Complete response;PR=Partial response.*Union Internationale Contre le Cancer(UICC)criteria.Bonneterre J,et al.J Clin Oncol.2000;18:3758-3767.Nabholtz JM,et al.J Clin Oncol.2000;18:3748-3757.Mouridsen H,et al.Ann Oncol.2000;11(suppl 4):Abstract 610.,三苯氧胺辅助治疗的临床试NSABPB14,三苯氧胺的副作用
9、,血栓形成(1.3%vs.0.1%;p.001)肺栓塞(6/1,422 VS.1/1,439;p=.06)子宫内膜癌（年危险度 1.6/1,000 VS.0.2/1,000）,法乐通与三苯氧胺结构比较,与三苯氧胺不同的代谢,法乐通一线治疗晚期乳腺癌的结果,5 项III 随机临床试验的meta分析 法乐通组 三苯氧胺组 P值总例数 725 696 有效数 174 176 缓解率 24%25%CR率 7%5.5%治疗终止 13.7%19.6%0.007,Pyrhonen S et al.Breast Cancer Research and treatment 56:133143,1999,法乐通辅
10、助治疗,芬兰乳腺癌协作组报道：1480例患者按双盲、随机分组对比 法乐通40mg/d 或 三苯氧胺20mg/d 用三年 平均 3.4年随访899例中期结果 终点 法乐通组（459例）三苯氧胺组（440例）P值 复发率 23.1%26.1%乳癌死亡率 5.3%9.6%P=0.05 继发性子宫内膜癌 0 2例 脑心血管意外 0.4%2.5%P=0.01,摘自第36届ASCO会议：334，23/5/2000,耐药,对内分泌治疗反应性,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?,绝经前妇女的雌激素合成,绝经后妇女的雌激素合成,雌酮,雌二醇
11、,睾丸酮,芳香化酶失活剂芳香化酶抑制剂,雄烯二酮,雌激素的合成途径,胆固醇,氢化考的松,孕酮,醛固酮,孕烯醇酮,参与肿瘤局部雌激素形成的途径,雄烯二酮,E1,E2,芳香化酶,17HSD1,睾酮,芳香化酶,E1S,E2S,硫酸酶,硫酸酯酶,硫酸酶,硫酸酯酶,芳香化酶,芳香化酶,芳香化酶的分布及其作用,肾上腺,周围组织,绝经后妇女,肿瘤,=雌激素=雄烯二酮,受体,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,1,000to10,000,100,1,不同芳香化酶的结构,载体类抑制剂,Androge
12、n substrate,非甾体类抑制剂,雌激素的血浆浓度,Estrone,Estrone sulfate,Pre-treatment AnastrozoleFemara(letrozole),Estradiol,The clinical significance of these findings has not been established.Geisler J,et al.Proc Am Soc Clin Oncol.2000;19:102a.Abstract 394.,P=NS,Mean Estrogen Plasma Levels,2,The clinical significanc
13、e of these findings has not been established.Geisler J,et al.Proc Am Soc Clin Oncol.2000;19:102a.Abstract 394.,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 their ant
14、itumor 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,肿瘤的大小变化与治疗的时间依赖性改变,肿瘤的重量的变化,转移性乳腺癌的治疗目标,转移性乳腺癌目前尚不能治愈芳香化酶抑制剂作为二线用药与孕激素同样有效，但副反应较低芳香化酶抑制剂已成为转移性乳腺癌的一线治疗用药,ORR=客观缓解率;
15、CR=完全缓解;PR=部分缓解.*,Difference statistically significant in favor of first agent;=,Difference not significant.Kaufmann M,et al.J Clin Oncol.2000;18:1399-1411;Buzdar AU,et al.Cancer.1998;83:1142-1152;Dombernowsky P,et al.J Clin Oncol.1998;16:453-461.,芳香化酶与醋酸甲地孕酮比较(MA)*,Femara(letrozole)Phase III Study,
16、Prospective,double-dummy,double-blind,randomized,well-controlled,international,multicenter study in postmenopausal women with breast cancer comparing Femara 2.5 mg versus tamoxifen 20 mg 916,Pivotal Study 025First-line therapy in advanced breast cancer,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,Tim
17、e,months,0,3,6,9,12,15,18,21,24,Progression-free,Time to Progression,Study 025,Log-rank P.0001,FemaraTamoxifen,HR=Hazard ratio;CI=Confidence interval.,30%,20%,Objective Response Rate(CR+PR),8%*,23%*,17%,3%,0,10,20,30,40,50,60,Femara,Tamoxifen,Study 025,N=453,N=454,Response rate,%,CR(P=.002),PR(P=.04
18、5),Odds ratio95%CIP value1.711.26-2.31.0006,CI=Confidence interval;CR=Complete response;PR=Partial response.*Rounded to the nearest whole number.,芳香化酶的治疗优点,在进展期乳腺癌、转移性乳腺癌中疗效优于三苯氧胺和孕激素二线用药与MA一线用药与三苯氧胺服药方便 每日一次较三苯氧胺和孕激素具有好的耐受性和低的副作用,乳腺癌的治疗原则,以手术为主以其它治疗为辅综合治疗,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,微转移
19、灶的研究,已经形成的微转移灶可能对预后的影响更为明显增殖动力学等分子生物学特性可为辅助化疗奠定生物学的基础,1974，Fisher:NSABP:LN，苯丙氨酸氮芥(l-Pam)手术后2年治疗10年的随访结果改善了DFS绝经前患者改善了OS,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,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+,HR0.85,95%CI(0.76,0.94),p-value0.003,
20、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,Time to Recurrence HR+Patients,Patients(%),30,25,20,15,10,5,0,0,1,2,3,4,5,6,7,8,9,30,25,20,15,10,5,0,12.5%,17.0%,21.8%,Fol
21、low-up time(years),9.7%,2.8%,4.8%,HR+,HR0.76,95%CI(0.67,0.87),p-value0.0001,The ATAC Trialists Group.Lancet Oncol 2008;9:45-53,AD,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+,HR0.84,95%CI(0.72,0.97),p-value0.
22、022,1.3%,2.4%,The ATAC Trialists Group.Lancet Oncol 2008;9:45-53,AD,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+,HR0.60,95%CI(0.42,0.85),p-value0.004,AD,0.8%,1.7%,The ATAC Trialists Group.Lancet Oncol 200
23、8;9:45-53,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+,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,Additional Effect of ARIMIDEX on Recurrences at 9 years,38%risk of recurr
24、ence with no adjuvant treatment1,50%risk reduction with tamoxifen1,Further 24%risk reduction with ARIMIDEX2,1.EBCTCG.Lancet 1998;351:14511467;2.ATAC Trialists Group.Lancet Oncol 2008;9:4553,Time to Recurrence:Smoothed Hazard EstimatesHR+Patients,Annual hazard rates(%),4.0,3.0,2.0,1.0,0.0,4.0,3.0,2.0
25、,1.0,0.0,0,1,2,3,4,5,6,7,8,9,Follow-up time(years),The ATAC Trialists Group.Lancet Oncol 2008;9:45-53,Fracture Episode Rates Throughout the Study,29842976,At risk:ARIMIDEXtamoxifen,28592824,27452699,26402572,24962419,23062208,20772000,17131645,702659,Time since randomisation(years),Annual fracture e
26、pisode 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,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 years extende
27、d adjuvant,0-3months,n=2593,n=2594,Goss PE et al:J Natl Cancer Inst 97:1262,2005,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
28、-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,MA.17:Efficacy Conclusions,LET significantly reduced the risk of recurrences(43%)regardless of nodal
29、status and prior chemotherapyLET significantly reduced the risk of distant metastases by 39%compared with placeboLET reduced occurrences(37.5%)of new contralateral breast cancers(prevention)LET significantly improved OS in node-positive patientsOS was not improved in node-negative patients,but a sim
30、ilar degree of reduction in local recurrences,new primaries,and distant recurrences occurred as in the node-positive patients,612182430364248,Optimal Duration of letrozole-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
31、 and Treat-in press,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=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&DIniti
32、al data analysis at 25.8 months median FU,FU=follow-up.Update of Thrlimann et al.J Clin Oncol.2005;23:6S.Abstract 511.,BIG 1-98 Monotherapy UpdateMedian Follow-up 76 months,*Let:Tam:breast cancer events,321:363second(non breast)malignancy,101:115deaths without prior cancer event,87:87,78,BIG 1-98 Se
33、quential 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 multiple comparisons,79,BIG 1-
34、98 Sequential Treatment Disease-Free Survival,后期伸展AI治疗,2008-12-30,80,MA-17,2008-12-30,81,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。,Discovery of Zoladex,Zoladex,LHRH,Thick bonds indicate modificat
35、ions,Ser(But),Azgly,Administration of Zoladex,Figure AHypersecretion of LH following acute administration of Zoladex,Figure BHyposecretion of LH following chronic administration of Zoladex,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,PituitaryCell,LH,Pitu
36、itaryCell,LH,Mechanism of Action of Zoladex 2,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,Zoladex 3.6mg as Adjuvant Treatment:Rationale(2)Zoladex 3.6mg provides a medical ovarian ablation Effect of Zoladex 3.6mg on LH and oestradiol levels,30025020015010
37、0500,0,1,2,3,4,5,6,7,8,12,16,20,35302520151050,LH(mU/ml),Oestradiol(pg/ml),Time(weeks),Zoladex 3.6mg depot,0,1,2,3,4,5,6,7,8,12,16,20,Time(weeks),Zoladex 3.6mg depot,(n=7),(n=7),1,2,3,4,5,6,1,2,3,4,5,6,West CP,et al.Clin Endocrinol 1987;26:21320.,诺雷德与三苯氧胺联合应用,A Meta-Analysis of Four Randomized Trial
38、s,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,multicentre),Tumour recurrence,Death,Death,Jonat W,et al.J Clin Oncol 2002;20:462835.,ZE
39、BRA:Efficacy Results DFS,In ER+patients(74%),Zoladex 3.6mg was equivalent to CMF for DFS(HR=1.01;95%CI 0.841.20;p=0.94)In ER patients(19%),CMF was superior to Zoladex 3.6mg for DFS(HR=1.76;95%CI 1.272.44;p=0.0006),Median follow-up 6 years,ZEBRA:KaplanMeier Plot of DFS in ER+Patients,Zoladex 3.6mg,CM
40、F,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.,ZEBRA:Efficacy Results Overall Survival,Overall survival,Number ofdeaths,HR,95%,CI,p value,
41、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,ZEBRA试验,Amenorrhea occurred 95%of goserelin by 6 months versus 58.6%of CMF.Menses returned in most goserelin after therapy stopped,whereas amenorrhea w
42、as generally permanent in CMF(22.6%v 76.9%amenorrheic at 3 year,Goserelin Versus Cyclophosphamide,Methotrexate,andFluorouracil as Adjuvant Therapy in Premenopausal PatientsWith Node-Positive Breast Cancer:The Zoladex Early BreastCancer Research Association Study,CMF x 6 cycles,Zoladex 3.6mg/28 days
43、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 evaluable patientsNode+ve or nodeveIncluded 28%of all eligible
44、 patients in Austria,ABCSG AC05 TrialAustrian Adjuvant Breast Cancer Trial(Zoladex 3.6mg+tamoxifen vs chemotherapy),Randomized Adjuvant Trial of Tamoxifen and Goserelin Versus CMF:Evidencefor the Superiority of Treatment With Endocrine Blockade inPremenopausal Patients With Hormone-Responsive Breast
45、CancerAustrian Breast and Colorectal Cancer Study GroupTrial 5,St Gallen 乳腺癌风险内分泌治疗敏感性不明,1.ER102.PR阴性3.表达对某药物耐药指标（Neu对Tam）4.淋巴结转移数较多5.肿瘤高表达uPA/PAI-16.高增殖指数PCNA,St Gallen 乳腺癌风险,patients are often divided into low-and high-risk groups.,年龄合并症器官转移的程度和分布重要器官的功能 肿瘤对内分泌治疗的反应性发病的过程,Excellent candidates for
46、hormone therapy as the first intervention for metastatic breast cancer.,low risk:长的DFS 转移部位局限-通常在 软组织和骨转移.包括一些 局限性的内脏转移.年龄大的绝经后患者ER/PR+.除了骨痛外，无明显其它症状.,Excellent candidates for chemotherapy metastatic breast cancer,对内分泌治疗的耐药Symptomatic with widespread/aggressive visceral metastases-anorexia,weight loss DFS2yrER/PR Carcinomatous meningitis,extensive liver metastases,lymphangitic lung metastases,or brain metastases even if ER/PR+,Case 判断,术后6年第二肋软骨表面结节，增大ER PR,清平乐会昌1934夏东方欲晓，莫道君行早。踏遍青山人未老，风景这边独好。会昌城外高峰，颠连直接东溟。战士指看南粤，更加郁郁葱葱。,谢谢！,
