乳腺癌內(nèi)分泌治療策略

1、乳腺癌內(nèi)分泌治療策略歷史的回顧 1836年, Cooper 觀察到乳腺腫瘤的生長與月經(jīng)周期相關(guān)。 1896年, Beatson 報道在幾個絕經(jīng)前的乳腺癌患者，在切除了卵巢后其轉(zhuǎn)移灶出現(xiàn)了退縮。 1952年 Huggins和Bergenstal 報道切除腎上腺后可使部分乳腺癌患者的轉(zhuǎn)移灶出現(xiàn)退縮。 Luft and Olivecrona報道切除垂體后可取得上述相似的效果。 ER的發(fā)現(xiàn) 靶器官對雌激素的高親和性導(dǎo)致了其受體的發(fā)現(xiàn)，其可以和標(biāo)記的雌激素相結(jié)合但不改變其結(jié)構(gòu)。E.V. Jensen and H.I. Jacobson Basic guides to the mechanism of e

2、strogen action Rec Prog Hormone Res 1962. 18: 387-414.ER的作用途徑 雌激素受體位于細(xì)胞內(nèi)，處于無活性，當(dāng)與配體結(jié)合時形成活化狀態(tài)，與相應(yīng)的DNA結(jié)合，誘導(dǎo)相應(yīng)的mRNA 轉(zhuǎn)錄。乳腺癌的進展過程0510年年*非常早期乳腺癌非常早期乳腺癌臨床不能發(fā)現(xiàn)臨床不能發(fā)現(xiàn)細(xì)胞數(shù)細(xì)胞數(shù)細(xì)胞增殖的倍數(shù)細(xì)胞增殖的倍數(shù)0510152025303540101210101081061041021 mm1 cm10 cmDCIS臨床乳腺癌臨床乳腺癌DCIS = Ductal carcinoma in situ.*Note: 90-day doubling 40 do

3、ublings = 3,600 days (approximately 10 years).Harris JR, et al, eds. Breast Diseases, 2nd ed. Philadelphia: JB Lippincott; 1991:165-189.正常 化學(xué)預(yù)防癌前病變 DCIS原發(fā)性乳腺癌 新輔助治療手術(shù)后輔助治療轉(zhuǎn)移性姑息性治療不同階段治療的名稱DCIS = Ductal carcinoma in situ.乳腺癌細(xì)胞的分類 激素依賴性激素依賴性乳腺癌細(xì)胞對生理劑量的性激素具有反應(yīng)性，多數(shù)對內(nèi)分泌治療敏感。 激素非依賴性激素非依賴性乳腺癌細(xì)胞對生理劑量的性激素不具有

4、反應(yīng)性，多數(shù)情況下對內(nèi)分泌治療不敏感。激素依賴性乳腺癌的特點 表達功能性的ER和PR 組織學(xué)分級低 S期細(xì)胞的比例低，多為二倍體細(xì)胞 往往具有長的無病生存間期 轉(zhuǎn)移的部位多為淋巴結(jié)、軟組織等 臨床進程緩慢 在老年患者中多見 對內(nèi)分泌治療具有敏感性內(nèi)分泌機制(B) 絕經(jīng)后絕經(jīng)后GNRH 類似物類似物BreastcarcinomaBreastcarcinoma抗雌激素抗雌激素卵巢卵巢LHFSH抗雌激素抗雌激素(A) 絕經(jīng)前絕經(jīng)前腎上腺腎上腺雌激素雌激素雌激素雄烯二酮雄烯二酮芳香化酶抑制劑芳香化酶抑制劑周圍的芳香化周圍的芳香化Tellez C, et al. Surg Oncol Clin Nort

5、h Am. 1995;4:751-777.GNRH = 促性腺激素釋放激素促性腺激素釋放激素; LH = 黃體生成數(shù)黃體生成數(shù); 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學(xué)指標(biāo) ER和PR的檢測結(jié)果 將是所有乳腺癌治療開始前所需了解的分子指標(biāo) 包括術(shù)前、術(shù)后和復(fù)發(fā)性乳腺癌的治療 是所有乳腺癌治療手段選擇的標(biāo)準(zhǔn)ER 和 PgR 的臨床意義 ER和PR的檢測結(jié)果 提示其預(yù)后較好 對內(nèi)分泌治療敏感 并不提示對化療不敏感在1975年所用的內(nèi)分泌治療手段 卵巢的切除卵巢的切除 手術(shù)手術(shù) ( (去勢去勢) ) 放射去勢放射去勢 雙側(cè)腎上腺切除雙側(cè)腎上腺切除 垂體切除術(shù)垂體切

6、除術(shù) 雌激素雌激素 雄激素雄激素 孕激素孕激素 糖皮質(zhì)激素糖皮質(zhì)激素目前所用的乳腺癌內(nèi)分泌治療手段 芳香化酶抑制劑芳香化酶抑制劑( (非選擇性非選擇性 和選擇性和選擇性) ) 選擇性雌激素受體調(diào)節(jié)劑（選擇性雌激素受體調(diào)節(jié)劑（SERMSERM） 選擇性雌激素受體下調(diào)劑（選擇性雌激素受體下調(diào)劑（SERDSERD） GHRH GHRH 激動劑和拮抗劑激動劑和拮抗劑 卵巢的切除卵巢的切除 手術(shù)手術(shù) ( (去勢去勢) ) 放射去勢放射去勢 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、抗孕激素等內(nèi)分泌治療的目標(biāo) 抑制或者阻斷雌激素的形成 阻雌激素的作用 下調(diào)節(jié)雌激素受體的表達E2

7、E2ERE2ER染色質(zhì)染色質(zhì)PgR 有絲分裂有絲分裂細(xì)胞核細(xì)胞核RNAER+雌激素雌激素細(xì)胞漿細(xì)胞漿E2 = 雌二醇雌二醇ER = 雌激素受體雌激素受體E2ER = ERE2復(fù)合物復(fù)合物PgR = 孕激素受體孕激素受體激素依賴性乳腺癌雌激素受體的作用機制雌激素受體雌激素受體ER ER CoactivatorsCorepressors TranscriptionmRNASERMsE2TamRalREs啟動子啟動子目標(biāo)基因目標(biāo)基因SERM = Selective estrogen receptor modifiers; E2 = Estradiol; Tam = Tamoxifen; Ral =

8、Raloxifene; ER = Estrogen receptor.SERM作用機制 選擇性雌激素受體調(diào)節(jié)劑（ SERM ）如：三苯氧胺、托瑞米芬、雷洛昔芬，可競爭性與ER結(jié)合，結(jié)合后仍能形成二聚體，并與ERE結(jié)合。 轉(zhuǎn)錄活性僅保留了部分 其產(chǎn)生對抗雌激素作用還是類雌激素樣作用取決于不同組織內(nèi)的共激活因子或共抑制因子的狀態(tài)三苯氧胺在轉(zhuǎn)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%Anastrazol

9、e 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)

10、: Abstract 610.三苯氧胺輔助治療的臨床試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) 子宮內(nèi)膜癌 （年危險度 1.6 /1,000 VS. 0.2/1,000）法樂通法樂通與三苯氧胺結(jié)構(gòu)比較與三苯氧胺結(jié)構(gòu)比較與三苯氧胺不同的代謝與三苯氧胺不同的代謝法樂通一線治療晚期乳腺癌的結(jié)果5 項III 隨機臨床試驗的meta分析 法樂通組 三苯氧胺組 P值總例數(shù) 725 696 有效數(shù) 174 176 緩解率 24% 25% CR率 7% 5.5% 治療終止 13.7% 19

11、.6% 0.007Pyrhonen S et al. Breast Cancer Research and treatment 56:133143, 1999 法樂通輔助治療法樂通輔助治療芬蘭乳腺癌協(xié)作組報道：1480例患者按雙盲、隨機分組對比 法樂通法樂通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年隨訪899例中期結(jié)果 終點終點 法樂通組（法樂通組（459459例）例） 三苯氧胺組（三苯氧胺組（440440例）例） P P值值 復(fù)發(fā)率復(fù)發(fā)率 23.1% 26.1% 乳癌死亡率乳癌死亡率 5.3% 9.6% P=0.05 繼發(fā)性子宮

12、內(nèi)膜癌繼發(fā)性子宮內(nèi)膜癌 0 2例 腦心血管意外腦心血管意外 0.4% 2.5% P=0.01摘自第36屆ASCO會議：334，23/5/2000逆轉(zhuǎn)逆轉(zhuǎn)CAFCAF方案抗藥乳腺癌方案抗藥乳腺癌, ,肺轉(zhuǎn)移的良好長期療效肺轉(zhuǎn)移的良好長期療效乳腺癌切除術(shù)后乳腺癌切除術(shù)后6周期周期CMF輔助治療輔助治療,16個月后多部個月后多部份肺轉(zhuǎn)移復(fù)發(fā)份肺轉(zhuǎn)移復(fù)發(fā),用用CAF方案治療方案治療3周期后抗藥無效且肺周期后抗藥無效且肺轉(zhuǎn)移惡化，之后即加入大劑量轉(zhuǎn)移惡化，之后即加入大劑量 法樂通法樂通(120mg/日日)作治療，作治療，9周期周期CAF后，肺轉(zhuǎn)移在后，肺轉(zhuǎn)移在X線片幾乎完全消線片幾乎完全消失，之后用失，

13、之后用法樂通法樂通及及UFT作鞏固治療，治療作鞏固治療，治療32個個月，腫塊無增加。月，腫塊無增加。小結(jié)小結(jié): 大劑量大劑量法樂通法樂通及化療及化療CAF有潛在效有潛在效果治療阿霉素類耐藥的乳腺癌。果治療阿霉素類耐藥的乳腺癌。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):1171-5 199

14、9 UI:99360267SERM副反應(yīng)血脂 Saarto 1996報告報告 49 例，例，用用法樂通法樂通60mg/日作術(shù)后日作術(shù)后輔助治療早期乳腺癌發(fā)現(xiàn)：輔助治療早期乳腺癌發(fā)現(xiàn)：比三苯氧胺顯著提高有益的比三苯氧胺顯著提高有益的血脂血脂/HDL(P 30% （ P 0.01）Yoshida Int. J. Oncol.2000 DecSERM副反應(yīng)脂肪肝Br J Cancer; 84(7): 897-902 , 2001術(shù)后輔助用法樂通對比三苯氧胺隨機、前瞻性研究術(shù)后輔助用法樂通對比三苯氧胺隨機、前瞻性研究一線一線二線二線三線三線四線四線對內(nèi)分泌治療反應(yīng)性抗雌激素以后的選擇阻斷雌激素受體 (

15、抗雌激素治療) 抑制雌激素的合成 (芳香化酶抑制劑)效果相似還是更好效果相似還是更好? ?絕經(jīng)前婦女的雌激素合成絕經(jīng)后婦女的雌激素合成雌酮雌酮雌二醇雌二醇睪丸酮睪丸酮雄烯二酮雄烯二酮雌激素的合成途徑膽固醇膽固醇?xì)浠嫉乃蓺浠嫉乃稍型型┕掏┕掏邢┐纪邢┐纪獏⑴c腫瘤局部雌激素形成的途徑雄烯二酮E1E2芳香化酶芳香化酶17HSD1睪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的分布及其作用芳香化酶的分布及其作用腎上腺腎上腺周圍組織周圍組織絕經(jīng)后婦女絕經(jīng)后婦女腫瘤腫瘤= 雌激素雌激素= 雄烯二酮雄烯二酮受體受體毒性毒性特異性特異性有效性有效性氨基導(dǎo)眠能氨基導(dǎo)眠能*法屈

16、唑法屈唑 蘭他龍?zhí)m他龍阿那曲唑阿那曲唑依西美坦依西美坦 來曲唑來曲唑芳香化酶抑制劑的歷史皮疹等皮疹等無腎上腺功能影響無腎上腺功能影響1,000to10,0001001不同芳香化酶的結(jié)構(gòu)載體類抑制劑載體類抑制劑Androgen substrate非甾體類抑制劑非甾體類抑制劑氨基導(dǎo)眠能氨基導(dǎo)眠能NOONH2C2H5H阿那曲唑阿那曲唑NNNNCH3CCH3H3CCH3CN來曲唑來曲唑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 雌激素的血漿濃度EstroneEstrone sulfatePre-treatment AnastrozoleFemara (letr

17、ozole)Estradiol8075201510 5 014.812.3P = .019Plasma concentration, pmol/L78.142540302010P = .0037420422.827.68.918171632 1 02.62.117.2 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

18、 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 = .

19、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 Can

20、cer. 1999;6:205-210.Effect of letrozole, Anastrozole, and Tamoxifen on Tumor Growth of MCF-7 Transfected With Aromatase Gene in Nude Mice400350300250200150100500Tumor weight, mgControlFemara5 g/dP .05Anastrozole5 g/dP .05Tamoxifen3 g/dP , Difference statistically significant in favor of first agent;

21、 =, 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.芳香化酶與醋酸甲地孕酮比較 (MA)*患者數(shù)患者數(shù)ORR (CR + PR), %反應(yīng)維持時間反應(yīng)維持時間 疾病進展時間疾病進展時間總生存總生存 263 vs 253AN = MANot reportedAN = MAAN MA 阿那曲唑

22、阿那曲唑瑞寧德瑞寧德1 mg 與與 MA來曲唑來曲唑 弗隆弗隆2.5 mg 與與 MA174 vs 189LET MALET MALET MALET = MA依西美坦依西美坦阿諾新阿諾新25 mg 與與 MA366 vs 403EXE = MAEXE = MAEXE MAEXE MAFemara (letrozole) Phase III StudyProspective, double-dummy, double-blind, randomized, well-controlled, international, multicenter study in postmenopausal wom

23、en with breast cancer comparing Femara 2.5 mg versus tamoxifen 20 mg 9160.00.10.20.30.40.50.60.70.80.91.0Time, months0 3 6 91215182124Progression-freeTime to ProgressionStudy 025Log-rank P .0001Events,Wald Nn (%)HR95% CIP value453308 (68)0.700.60 - 0.82 .0001454350 (77)Femara TamoxifenHR = Hazard ra

24、tio; CI = Confidence interval.30%20%Objective Response Rate (CR + PR)8%*23%*17%3%0102030405060FemaraTamoxifenStudy 025N = 453N = 454Response rate, %CR (P = .002)PR (P = .045)Odds ratio95% CIP value1.711.26 - 2.31.0006CI = Confidence interval; CR = Complete response; PR = Partial response.*Rounded to

25、 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

26、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 025Stratified Analysis of Overall Objective Response n/N (%) Femara Tamoxifen P value*Prior adjuvant treatment None113/369 (31)

27、 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).02St

28、udy 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 025*Thromboembolic events included: venous thrombosis deep limb, thrombophlebitis

29、 superficial, venous thrombosis NOS limb, phlebitis NOS, thrombosis NOS, and thrombophlebitis deep.作為一線用藥芳香化酶抑制劑與三苯氧胺比較作為一線用藥芳香化酶抑制劑與三苯氧胺比較交替用藥芳香化酶的治療優(yōu)點 在進展期乳腺癌、轉(zhuǎn)移性乳腺癌中療效優(yōu)于三苯氧胺和孕激素 二線用藥與MA 一線用藥與三苯氧胺 服藥方便 每日一次 較三苯氧胺和孕激素具有好的耐受性和低的副作用Let耐藥乳腺癌的治療原則 以手術(shù)為主 以其它治療為輔 綜合治療系統(tǒng)輔助治療 在手術(shù)完成后 殺滅或者抑制臨床陰性的微轉(zhuǎn)移灶 化療、內(nèi)分泌、

30、生物治療微轉(zhuǎn)移灶的研究 已經(jīng)形成的微轉(zhuǎn)移灶可能對預(yù)后的影響更為明顯 增殖動力學(xué)等分子生物學(xué)特性可為輔助化療奠定生物學(xué)的基礎(chǔ) 1974，F(xiàn)isher: NSABP :LN，苯丙氨酸氮芥 (l-Pam) 手術(shù)后2年治療 10年的隨訪結(jié)果改善了DFS絕經(jīng)前患者改善了OS輔助內(nèi)分泌治療 采用內(nèi)分泌治療手段 抑制微轉(zhuǎn)移灶的增殖、復(fù)蘇ATAC副反應(yīng)比較MA.17: Trial DesignPrimary end point: DFSSecondary end points: OS / rate of CBCancer/ safety / QOL Randomization(all patients dis

31、ease-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* p

32、osNode* 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 sig

33、nificantly 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

34、-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 aft

35、er randomization0.520.450.350.19HRIngle J et al. Breast Cancer Res and Treat - in pressBIG 1-98: DesignRANDOMIZE025 YearsTamoxifenLetrozoleTamoxifenLetrozoleLetrozoleTamoxifenABCDn=1540n=1548n=2463n=24598010 pts Primary core analysis compares letrozole (Femara) vs tamoxifen in arms A-D but excludes

36、events and FU beyond switch at 2 y in arms C & D Initial 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

37、 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

38、 (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 sig

39、nificant and ongoing risk throughout the entire treatment of breast cancer regardless of lymph node status Recurrence at distant sites leads to poor and often fatal outcomes Letrozole demonstrates an improvement in risk of distant recurrence Letrozole is effective as initial adjuvant therapy. Furthe

40、r 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 *3yrsLHRHLHRH類似物激動劑類似物激動劑

41、“諾雷德諾雷德” ” 長期使用抑制腦垂體促長期使用抑制腦垂體促黃體生成素合成，從而引起黃體生成素合成，從而引起 女性血女性血清雌二醇的下降，清雌二醇的下降， 初期用藥時初期用藥時“諾雷德諾雷德”同其它同其它LHRHLHRH激動劑一樣，可暫時增加男性血清激動劑一樣，可暫時增加男性血清睪丸酮和女性血清雌二醇的濃度。睪丸酮和女性血清雌二醇的濃度。 女性患者在初次給藥后女性患者在初次給藥后2121天左右血天左右血清中雌二醇濃度受到抑制，并在以清中雌二醇濃度受到抑制，并在以后每后每2828天的治療中維持在絕經(jīng)后水天的治療中維持在絕經(jīng)后水平。平。Discovery of ZoladexZoladexLHR

42、HThick bonds indicate modificationsSer(But)AzglyAdministration of ZoladexMechanism of Action of Zoladex 2Zoladex 3.6mg as Adjuvant Treatment: Rationale (2) Zoladex 3.6mg provides a medical ovarian ablation Effect of Zoladex 3.6mg on LH and oestradiol levelsWest CP, et al. Clin Endocrinol 1987; 26: 2

43、1320.諾雷德與三苯氧胺聯(lián)合應(yīng)用A Meta-Analysis of Four Randomized TrialsZEBRA: Trial DesignSurgery radiotherapyPre-/perimenopausal patients with node-positive early breast cancer, aged 50 years Follow-up Tumour recurrenceDeathDeathJonat W, et al. J Clin Oncol 2002; 20: 462835.ZEBRA: Efficacy Results DFS In ER+ pa

44、tients (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 yearsZEBRA: KaplanMeier Plot of DFS in ER+ PatientsZoladex 3.6mgCMF00.10.20.30.40.50.60.70.

45、80.91.0012345678910Disease-free survival (years)Proportion alive and free of diseaseNumber of events:ER+ (n=1,189) 487Jonat W, et al. J Clin Oncol 2002; 20: 462835.ZEBRA: Efficacy Results Overall SurvivalOverall survivalNumber ofdeathsHR95% CI p valueER+2250.990.761.280.92ER1041.771.192.630.0043(n=1

46、,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 yearGoserelin Versus Cyclophosphamide, Methotrex

47、ate, andFluorouracil as Adjuvant Therapy in Premenopausal PatientsWith Node-Positive Breast Cancer: The Zoladex Early BreastCancer Research Association StudyCMF x 6 cyclesZoladex 3.6mg/28 days for 3 years PLUStamoxifen 20mg/day for 5 yearsrandomise 1:1Premenopausal women with ER+ve and/or PgR+vebreast cancerJakesz 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.l1,045 eval