乳腺癌内分泌治疗策略

乳腺癌内分泌治疗策略,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 mechanism 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 = 3,600 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,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; Ral = 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%Femara 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,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,逆转CAF方案抗药乳腺癌,肺转移的良好长期疗效,乳腺癌切除术后6周期CMF辅助治疗,16个月后多部份肺转移复发,用CAF方案治疗3周期后抗药无效且肺转移恶化，之后即加入大剂量 法乐通(120mg/日)作治疗，9周期CAF后，肺转移在X线片几乎完全消失，之后用法乐通及UFT作巩固治疗，治疗32个月，肿块无增加。小结: 大剂量法乐通及化疗CAF有潜在效果治疗阿霉素类耐药的乳腺癌。,1.Kusama M et al, A case of breast cancer patient of CAF resistant lung metastasis with remarkable response to reverse drug resistance by toremifene, Gan To Kagaku Ryoho; 26(8):1171-5 1999 UI:99360267,SERM副反应血脂,Saarto 1996报告 49 例，用法乐通60mg/日作术后辅助治疗早期乳腺癌发现：比三苯氧胺显著提高有益的血脂/HDL(P 30% （ P 0.01）,Yoshida Int. J. Oncol.2000 Dec,SERM副反应脂肪肝,共取339子宫内膜组织（159个Tam组，180个法乐通组）检查， Tam组 Tor组 P值 子宫内膜增厚（相对于基数） 47.8% 32.2% 0.0001 息肉块生长数目 17 9 , 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,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,Time, 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 = .045),Odds ratio95% CIP value1.711.26 - 2.31.0006,CI = Confidence interval; CR = Complete response; PR = Partial response.*Rounded to the nearest whole number.,Stratified Analysis of Time to Progression,Femara TamoxifenMedian TTP, Median TTP,Log-rankn/Nmonthsn/NmonthsP valuePrior adjuvant treatment None250/3699.7284/3716.0.0001 Adjuvant treatment58/848.866/835.9.04Receptor status ER+ and/or PgR+ 199/2949.7235/3056.0.0002 Unknown 109/1599.2115/1496.0.02Dominant site Soft tissue only 68/11312.984/1166.4.05 Bone soft tissue100/1469.797/1306.2.01 Viscera bone 140/1948.3169/208 4.7.001 soft tissue,Study 025,Stratified Analysis of Overall Objective Response,n/N (%) Femara Tamoxifen P value*Prior adjuvant treatment None113/369 (31)85/371 (23).02 Adjuvant treatment24/84 (29)7/83 (8).002Receptor status ER+ and/or PgR+ 92/294 (31)63/305 (21).003 Unknown 45/159 (28)29/149 (20).07Dominant site Soft tissue only 54/113 (48)40/116 (35).04 Bone soft tissue32/146 (22)18/130 (14).08 Viscera bone soft tissue 51/194 (20)34/208 (16).02,Study 025,Selected Adverse Events,n (%)FemaraTamoxifenAdverse event N = 455N = 455Thromboembolic events* 6 (1)11 (2)Pulmonary embolism 1 ( 1) 1 ( 1)Cardiovascular events15 (3)13 (3)Cerebrovascular events12 (3) 9 (2),Study 025,*Thromboembolic events included: venous thrombosis deep limb, thrombophlebitis superficial, venous thrombosis NOS limb, phlebitis NOS, thrombosis NOS, and thrombophlebitis deep.,作为一线用药芳香化酶抑制剂与三苯氧胺比较,交替用药,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,Let耐药,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,ATAC副反应比较,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 extended 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(0.45-0.84),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 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 similar degree of reduction in local recurrences, new primaries, and distant recurrences occurred as in thenode-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 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 & 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.,BIG 1-98 Compared With ATAC: Summary of Key Efficacy Results,1. Thrlimann et al. New Engl J Med. 2005;363:2747; 2. Howell et al. Lancet. 2005;365:60; 3. Arimidex PI, 2005; 4. Baum et al. Lancet. 2002;359:2131.,Letrozole (Femara) in BIG 1-98 more effective than anastrozole in ATAC in improving distant metastasis-related end points, efficacy and possibly OS,HR+ = hormone receptor-positive; NR = not reported; ITT = intent-to-treat.,Clinical Implications,Breast cancer recurrence remains a significant and ongoing risk throughout the entire treatment of breast cancer regardless of lymph node statusRecurrence at distant sites leads to poor and often fatal outcomesLetrozole demonstrates an improvement in risk of distant recurrence Letrozole is effective as initial adjuvant therapy. Further follow-up needed to determine if sequential therapy is superior to initial letrozole therapy,4 Year DFS HRATAC Anastrozole Up Front 2.4% 0.83BIG 1-98 Letrozole Up Front 2.7%* 0.81IES Exemestane 2yr 4.7% 0.73ARNO/ABCSG A 2yr 3.1%* 0.60MA-17 Letrozole 5yr 4.9% 0.58,* approx *3yrs,SUMMARY: AI upfront, after 2 yrs and after 5yr tamoxifen beneficial,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 modifications,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,PituitaryCell,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,300250200150100500,0,1,2,3,4,5,6,7,8,12,16,20,35302520151050,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 Trials,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.,ZEBRA: 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,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.,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 95% of goserelin by 6 months versus 58.6% of CMF. Menses returned in most goserelin after therapy stopped, whereas amenorrhea was 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 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 nodev