乳腺癌内分泌治疗策略.ppt

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00551010年年年年*非常早期乳腺癌非常早期乳腺癌非常早期乳腺癌非常早期乳腺癌临床不能发现临床不能发现临床不能发现临床不能发现细胞数细胞数细胞数细胞数细胞增殖的倍数细胞增殖的倍数细胞增殖的倍数细胞增殖的倍数0055101015152020252530303535404010101212101010101010881010661010441010221 mm1 mm1 cm1 cm10 cm10 cmDCISDCIS临床乳腺癌临床乳腺癌临床乳腺癌临床乳腺癌DCIS=Ductal carcinoma in situ.DCIS=Ductal carcinoma in situ.*Note:90-day doubling*Note:90-day doubling 40 doublings=3,600 days(approximately 10 years).40 doublings=3,600 days(approximately 10 years).Harris JR,et al,eds.Harris JR,et al,eds.Breast DiseasesBreast Diseases,2nd ed.Philadelphia:JB Lippincott;1991:165-189.,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)(B)绝经后绝经后绝经后绝经后GNRH GNRH 类似物类似物类似物类似物BreastcarcinomaBreastcarcinoma抗雌激素抗雌激素抗雌激素抗雌激素卵巢卵巢LHLHFSHFSH抗雌激素抗雌激素抗雌激素抗雌激素(A)(A)绝经前绝经前绝经前绝经前肾上腺肾上腺肾上腺肾上腺雌激素雌激素雌激素雌激素雌激素雌激素雄烯二酮雄烯二酮雄烯二酮雄烯二酮芳香化酶抑制剂芳香化酶抑制剂芳香化酶抑制剂芳香化酶抑制剂周围的芳香化周围的芳香化周围的芳香化周围的芳香化Tellez C,et al.Surg Oncol Clin North Am.1995;4:751-777.GNRH=促性腺激素释放激素促性腺激素释放激素;LH=黄体生成数黄体生成数;FSH=卵泡刺激素卵泡刺激素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 卵巢的切除卵巢的切除 手术手术(去势去势)放射去势放射去势双侧肾上腺切除双侧肾上腺切除垂体切除术垂体切除术雌激素雌激素雄激素雄激素孕激素孕激素糖皮质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芳香化酶抑制剂(非选择性非选择性 和选择性和选择性)选择性雌激素受体调节剂（选择性雌激素受体调节剂（SERMSERM）选择性雌激素受体下调剂（选择性雌激素受体下调剂（SERDSERD）GHRH GHRH 激动剂和拮抗剂激动剂和拮抗剂卵巢的切除卵巢的切除 手术手术(去势去势)放射去势放射去势孕激素孕激素其它其它:雄激素、雌激素、抗孕激素等雄激素、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E E22E E22ERERE E22ERER染色质染色质染色质染色质PgR PgR 有丝分裂有丝分裂有丝分裂有丝分裂细胞核细胞核细胞核细胞核RNARNAERER+雌激素雌激素雌激素雌激素细胞浆细胞浆细胞浆细胞浆EE22 =雌二醇雌二醇雌二醇雌二醇ERER=雌激素受体雌激素受体雌激素受体雌激素受体EE22ERER=ER=ERE2E2复合物复合物复合物复合物PgRPgR=孕激素受体孕激素受体孕激素受体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雌激素受体雌激素受体雌激素受体ERER ERER CoactivatorsCoactivatorsCorepressorsCorepressors Transcription TranscriptionmRNAmRNASERMsSERMsE E22TamTamRalRalREsREs启动子启动子启动子启动子目标基因目标基因目标基因目标基因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最近的研究三苯氧胺有效率三苯氧胺有效率(CR+PR)18 studies 17%-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）法乐通法乐通与三苯氧胺结构比较与三苯氧胺结构比较与三苯氧胺不同的代谢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%0.007Pyrhonen S et al.Breast Cancer Research and treatment 56:133143,1999 法乐通辅助治疗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 法乐通法乐通40mg/d 40mg/d 或或 三苯氧胺三苯氧胺20mg/d 20mg/d 用三年用三年 平均 3.4年随访899例中期结果 终点终点 法乐通组（法乐通组（459459例）例）三苯氧胺组（三苯氧胺组（440440例）例）P P值值 复发率复发率 23.1%26.1%乳癌死亡率乳癌死亡率 5.3%9.6%P=0.05 继发性子宫内膜癌继发性子宫内膜癌 0 2例 脑心血管意外脑心血管意外 0.4%2.5%P=0.01摘自第36届ASCO会议：334，23/5/2000逆转逆转CAFCAF方案抗药乳腺癌方案抗药乳腺癌,肺转移的良好长期疗效肺转移的良好长期疗效乳腺癌切除术后乳腺癌切除术后6周期周期CMF辅助治疗辅助治疗,16个月后多部个月后多部份肺转移复发份肺转移复发,用用CAF方案治疗方案治疗3周期后抗药无效且肺周期后抗药无效且肺转移恶化，之后即加入大剂量转移恶化，之后即加入大剂量 法乐通法乐通(120mg/日日)作治疗，作治疗，9周期周期CAF后，肺转移在后，肺转移在X线片几乎完全消线片几乎完全消失，之后用失，之后用法乐通法乐通及及UFT作巩固治疗，治疗作巩固治疗，治疗32个个月，肿块无增加。月，肿块无增加。小结小结:大剂量大剂量法乐通法乐通及化疗及化疗CAF有潜在效有潜在效果治疗阿霉素类耐药的乳腺癌。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:99360267SERM副反应血脂 Saarto 1996报告报告 49 例，例，用用法乐通法乐通60mg/日作术后日作术后辅助治疗早期乳腺癌发现：辅助治疗早期乳腺癌发现：比三苯氧胺显著提高有益的比三苯氧胺显著提高有益的血脂血脂/HDL(P 30%（P 0.01）Yoshida Int.J.Oncol.2000 DecSERM副反应脂肪肝共取共取共取共取339339339339子宫内膜组织（子宫内膜组织（子宫内膜组织（子宫内膜组织（159159159159个个个个TamTamTamTam组，组，组，组，180180180180个法乐通组）检查，个法乐通组）检查，个法乐通组）检查，个法乐通组）检查，Tam Tam Tam Tam组组组组 Tor Tor Tor Tor组组组组 P P P P值值值值 子宫内膜增厚（相对于基数）子宫内膜增厚（相对于基数）子宫内膜增厚（相对于基数）子宫内膜增厚（相对于基数）47.8%32.2%0.0001 47.8%32.2%0.0001 47.8%32.2%0.0001 47.8%32.2%0.0001 息肉块生长数目息肉块生长数目息肉块生长数目息肉块生长数目 17 9 0.05 17 9 0.05 17 9 0.05 17 9 0.05结论：结论：结论：结论：法乐通法乐通相比三苯氧胺在子宫内膜类雌激素作用较弱。相比三苯氧胺在子宫内膜类雌激素作用较弱。相比三苯氧胺在子宫内膜类雌激素作用较弱。相比三苯氧胺在子宫内膜类雌激素作用较弱。Br J Cancer;84(7):897-902,2001术后辅助用法乐通对比三苯氧胺随机、前瞻性研究术后辅助用法乐通对比三苯氧胺随机、前瞻性研究耐药一线一线一线一线二线二线二线二线三线三线三线三线四线四线四线四线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)抑制雌激素的合成抑制雌激素的合成(芳香化酶抑制剂芳香化酶抑制剂)效果相似还是更好效果相似还是更好效果相似还是更好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酮雌酮雌酮雌二醇雌二醇雌二醇雌二醇睾丸酮睾丸酮睾丸酮睾丸酮芳香化酶失活剂芳香化酶失活剂芳香化酶失活剂芳香化酶失活剂芳香化酶失活剂芳香化酶失活剂芳香化酶抑制剂芳香化酶抑制剂芳香化酶抑制剂芳香化酶抑制剂芳香化酶抑制剂芳香化酶抑制剂雄烯二酮雄烯二酮雄烯二酮雄烯二酮雌激素的合成途径胆固醇胆固醇氢化考的松氢化考的松孕酮孕酮醛固酮醛固酮孕烯醇酮孕烯醇酮参与肿瘤局部雌激素形成的途径雄烯二酮E1E2芳香化酶芳香化酶17HSD1睾酮芳香化酶芳香化酶E1SE2S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芳香化酶芳香化酶芳香化酶芳香化酶芳香化酶芳香化酶的分布及其作用芳香化酶的分布及其作用肾上腺肾上腺肾上腺肾上腺周围组织周围组织周围组织周围组织绝经后妇女绝经后妇女绝经后妇女绝经后妇女肿瘤肿瘤肿瘤肿瘤=雌激素雌激素雌激素雌激素=雄烯二酮雄烯二酮雄烯二酮雄烯二酮受体受体受体受体毒性毒性毒性毒性特异性特异性特异性特异性有效性有效性有效性有效性第一代第一代第一代第一代第二代第二代第二代第二代第三代第三代第三代第三代氨基导眠能氨基导眠能氨基导眠能氨基导眠能*法屈唑法屈唑法屈唑法屈唑 兰他龙兰他龙兰他龙兰他龙阿那曲唑阿那曲唑阿那曲唑阿那曲唑依西美坦依西美坦依西美坦依西美坦 来曲唑来曲唑来曲唑来曲唑芳香化酶抑制剂的历史芳香化酶抑制剂的历史皮疹等皮疹等皮疹等皮疹等无肾上腺功能影响无肾上腺功能影响无肾上腺功能影响无肾上腺功能影响1,0001,000toto10,00010,0001001001 1不同芳香化酶的结构不同芳香化酶的结构载体类抑制剂载体类抑制剂载体类抑制剂载体类抑制剂Androgen substrateAndrogen substrate非甾体类抑制剂非甾体类抑制剂非甾体类抑制剂非甾体类抑制剂氨基导眠能氨基导眠能NOONH2C2H5H阿那曲唑阿那曲唑NNNNCH3CCH3H3CCH3CN来曲唑来曲唑NNNNCCN依西美坦依西美坦OCH2O福美斯坦福美斯坦OOHO雄烯二酮雄烯二酮OO 雌激素的血浆浓度EstroneEstrone sulfatePre-treatment AnastrozoleFemara (letrozole)Estradiol8075201510 5 014.814.812.312.3P=.019Plasma concentration,pmol/L78.178.142540302010P=.0037420422.8422.827.627.68.98.918171632 1 02.62.62.12.117.217.2 0The clinical significance of these findings has not been established.Geisler J,et al.Proc Am Soc Clin Oncol.2000;19:102a.Abstract 394.P=NSMean Estrogen Plasma Levels2The clinical significance of these findings has not been established.Geisler J,et al.Proc Am Soc Clin Oncol.2000;19:102a.Abstract 394.Femara(letrozole)AnastrozoleEstroneGeometric mean(pmol/L)90 80 6025 5 0 7010152030P=.0037Weeks0612Estrone sulfate 600 500 3005010 0 40020304060P=.019Weeks0612Estradiol 20 18 1451 0 162346Weeks0612P=NSThe 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 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 Mice400350300250200150100500Tumor weight,mgControlControlFemaraFemara5 5 g/dg/dPP .05 .05AnastrozoleAnastrozole5 5 g/dg/dPP .05 .05TamoxifenTamoxifen3 3 g/dg/dPP .05,Difference statistically significant in favor of first agent;,Difference statistically significant in favor of first agent;=,Difference not significant.,Difference not significant.Kaufmann M,et al.Kaufmann M,et al.J Clin OncolJ Clin Oncol.2000;18:1399-1411;Buzdar AU,et al.2000;18:1399-1411;Buzdar AU,et al.CancerCancer.1998;83:1142-1152;Dombernowsky P,et al.1998;83:1142-1152;Dombernowsky P,et al.J Clin OncolJ Clin Oncol.1998;16:453-461.1998;16:453-461.芳香化酶与醋酸甲地孕酮比较(MA)*患者数患者数患者数患者数ORR(CR+PR),%ORR(CR+PR),%反应维持时间反应维持时间反应维持时间反应维持时间 疾病进展时间疾病进展时间疾病进展时间疾病进展时间总生存总生存总生存总生存 263 vs 253263 vs 253AN=MAAN=MANot reportedNot reportedAN=MAAN=MAAN MAAN MA 阿那曲唑阿那曲唑阿那曲唑阿那曲唑瑞宁德瑞宁德瑞宁德瑞宁德1 mg 1 mg 与与与与 MA MA来曲唑来曲唑来曲唑来曲唑 弗隆弗隆弗隆弗隆2.5 mg 2.5 mg 与与与与 MA MA174 vs 189174 vs 189LET MALET MALET MALET MALET MALET MALET=MALET=MA依西美坦依西美坦依西美坦依西美坦阿诺新阿诺新阿诺新阿诺新25 mg 25 mg 与与与与 MA MA366 vs 403366 vs 403EXE=MAEXE=MAEXE=MAEXE=MAEXE MAEXE MAEXE MAEXE MAFemara(letrozole)Phase III StudyProspective,double-dummy,double-blind,randomized,Prospective,double-dummy,double-blind,randomized,well-controlled,international,multicenter study in well-controlled,international,multicenter study in postmenopausal women with breast cancer comparing postmenopausal women with breast cancer comparing Femara 2.5 mg versus tamoxifen 20 mg 916Femara 2.5 mg versus tamoxifen 20 mg 916Pivotal Study 025Pivotal Study 025First-line therapy in advanced breast cancerFirst-line therapy in advanced breast cancer0.00.10.20.30.40.50.60.70.80.91.0Time,months0 3 6 91215182124Progression-freeTime to ProgressionStudy 025Study 025Log-rank Log-rank PP .0001 .0001Events,Events,Wald Wald NNn(%)n(%)HRHR95%CI95%CIP P valuevalue453453308(68)308(68)0.700.700.60-0.820.60-0.82.0001.0001454454350(77)350(77)FemaraFemara TamoxifenTamoxifenHR=Hazard ratio;CI=Confidence interval.30%20%Objective Response Rate(CR+PR)8%*23%*17%3%0102030405060FemaraTamoxifenStudy 025Study 025N=453N=453N=454N=454Response rate,%CR(P=.002)PR(P=.045)Odds Odds ratioratio95%CI95%CIP P valuevalue1.711.711.26-2.311.26-2.31.0006.0006CI=Confidence interval;CR=Complete response;PR=Partial response.*Rounded to the nearest whole number.Stratified Analysis of Time to ProgressionStratified 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 025Study 025Stratified Analysis of Overall Objective ResponseStratified 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).02Study 025Study 025Selected 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 025Study 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 DesignPrimary end point:DFSSecondary end points:OS/rate of CBCancer/safety/QOL Randomization(all patients disease-free)TamoxifenPlacebo dailyLetrozole 2.5 mg daily 5 years5 years extended adjuvant0-3monthsn=2593n=2594Goss 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*DFSNode*posNode*posNode*negNode negNode negNode*pos*Statistically significantHR=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;97:1262-71HR=0.58(0.45-0.76)HR=0.61HR=0.82(0.57-1.19)OSMA.17:Efficacy ConclusionsLET 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 patients612182430364248Optimal Duration of letrozole-HR for DFS MA.17PlaceboLetrozoleHazard RateMonths after randomization0.520.450.350.19HRIngle J et al.Breast Cancer Res and Treat-in pressBIG 1-98:DesignRANDOMIZE025 YearsTamoxifenLetrozoleTamoxifenLetrozoleLetrozoleTamoxifenABCDn=1540n=1548n=2463n=24598010 ptsPrimary 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 FUFU=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.Hazard Ratio Parameter BIG 1-981 ATAC(HR+)2DFS(w/o 2nd malignancy)0.79(P=0.002)0.83(P=0.005)Distant DFS 0.73(P=0.001)0.93(NR)Time to distant recurrence 0.73(P=0.001)0.84(P=0.06)Overall survival(OS)0.86(P=0.16)0.97(NR)Letrozole(Femara)in BIG 1-98 more effective than anastrozole in ATAC in improving distant metastasis-related end points,efficacy and possibly OSHR+=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 beneficialLHRHLHRH类似物激动剂类似物激动剂“诺雷德诺雷德”长期使用抑制脑垂体促长期使用抑制脑垂体促黄体生成素合成，从而引起黄体生成素合成，从而引起 女性血女性血清雌二醇的下降，清雌二醇的下降，初期用药时初期用药时“诺雷德诺雷德”同其它同其它LHRHLHRH激激动剂一样，可暂时增加男性血清睾丸动剂一样，可暂时增加男性血清睾丸酮和女性血清雌二醇的浓度。酮和女性血清雌二醇的浓度。女性患者在初次给药后女性患者在初次给药后2121天左右血清天左右血清中雌二醇浓度受到抑制，并在以后每中雌二醇浓度受到抑制，并在以后每2828天的治疗中维持在绝经后水平。天的治疗中维持在绝经后水平。Discovery of ZoladexZoladexLHRHThick bonds indicate modificationsSer(But)AzglyAdministration of ZoladexFigure AFigure An nHypersecretionHypersecretion of LH of LH following acute following acute administration of administration of ZoladexZoladex Figure BFigure Bn nHyposecretionHyposecretion of LH following of LH following chronic administration of chronic administration of ZoladexZoladex goserelingoserelingoserelingoserelingoserelingoserelingoserelingoserelingoserelingoserelingoserelingoserelingoserelingoserelingo