1、會計學1乳腺癌內分泌治療策略乳腺癌內分泌治療策略第1頁/共123頁第2頁/共123頁第3頁/共123頁0510年*非常早期乳腺癌臨床不能發現細胞數細胞增殖的倍數0510152025303540101210101081061041021 mm1 cm10 cmDCIS臨床乳腺癌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. Philadel

2、phia: JB Lippincott; 1991:165-189.第4頁/共123頁轉移性姑息性治療DCIS = Ductal carcinoma in situ.第5頁/共123頁第6頁/共123頁第7頁/共123頁(B) 絕經后GNRH 類似物BreastcarcinomaBreastcarcinoma抗雌激素卵巢LHFSH抗雌激素(A) 絕經前腎上腺雌激素雌激素雄烯二酮芳香化酶抑制劑周圍的芳香化Tellez C, et al. Surg Oncol Clin North Am. 1995;4:751-777.GNRH = 促性腺激素釋放激素; LH = 黃體生成數; FSH = 卵泡刺

3、激素第8頁/共123頁第9頁/共123頁第10頁/共123頁第11頁/共123頁第12頁/共123頁第13頁/共123頁E2E2ERE2ER染色質PgR 有絲分裂細胞核RNAER+雌激素細胞漿E2 = 雌二醇ER = 雌激素受體E2ER = ERE2復合物PgR = 孕激素受體第14頁/共123頁雌激素受體ER ERCoactivatorsCorepressors TranscriptionmRNASERMsE2TamRalREs啟動子目標基因SERM = Selective estrogen receptor modifiers; E2 = Estradiol; Tam = Tamoxife

4、n; Ral = Raloxifene; ER = Estrogen receptor.第15頁/共123頁第16頁/共123頁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 Onc

5、ol. 2000; 11(suppl 4): Abstract 610.第17頁/共123頁第18頁/共123頁第19頁/共123頁第20頁/共123頁第21頁/共123頁第22頁/共123頁Pyrhonen S et al. Breast Cancer Research and treatment 56:133143, 1999第23頁/共123頁摘自第36屆ASCO會議：334，23/5/2000第24頁/共123頁1.Kusama M et al, A case of breast cancer patient of CAF resistant lung metastasis with

6、remarkable response to reverse drug resistance by toremifene, Gan To Kagaku Ryoho; 26(8):1171-5 1999 UI:99360267第25頁/共123頁 法樂通及三苯氧胺對膽固醇的不同作用 三苯氧胺 法樂通 +14% 低密度脂蛋白膽固醇 高密度脂蛋白膽固醇 LDL/HDL （LDL） （HDL） 治療12個月后對比治療前基數變化%151050-5-10-15-5%法樂通可潛在成為一降血脂藥，預防冠心病及血栓塞。Tinna Saarto, et al. Journal of Clinical Oncolo

7、gy, Vol 14, No 2(February), 1996.第26頁/共123頁Yoshida Int. J. Oncol.2000 DecSERM副反應脂肪肝第27頁/共123頁Br J Cancer; 84(7): 897-902 , 2001第28頁/共123頁一線二線三線四線第29頁/共123頁抑制雌激素的合成 (芳香化酶抑制劑)效果相似還是更好?第30頁/共123頁第31頁/共123頁第32頁/共123頁雌酮雌二醇睪丸酮雄烯二酮膽固醇氫化考的松孕酮醛固酮孕烯醇酮第33頁/共123頁雄烯二酮E1E2芳香化酶17HSD1睪酮芳香化酶E1SE2S硫酸酶硫酸酯酶硫酸酶硫酸酯酶第34頁/

8、共123頁腎上腺周圍組織絕經后婦女腫瘤= 雌激素= 雄烯二酮受體第35頁/共123頁毒性特異性有效性氨基導眠能*法屈唑 蘭他龍阿那曲唑依西美坦 來曲唑皮疹等無腎上腺功能影響1,000to10,0001001第36頁/共123頁載體類抑制劑Androgen substrate非甾體類抑制劑氨基導眠能NOONH2C2H5H阿那曲唑NNNNCH3CCH3H3CCH3CN來曲唑NNNNCCN依西美坦OCH2O福美斯坦OOHO雄烯二酮OO第37頁/共123頁EstroneEstrone sulfatePre-treatment AnastrozoleFemara (letrozole)Estradiol

9、8075201510 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 = NS第38頁/共123頁2The clinical significanc

10、e 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

11、 0 162346Weeks0612P = NS第39頁/共123頁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 antitumor effects in model systems. Endocrine Rel Cancer. 1999;6:205-210.40

12、0350300250200150100500Tumor weight, mgControlFemara5 g/dP .05Anastrozole5 g/dP .05Tamoxifen3 g/dP , 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; Dombernowsk

13、y P, et al. J Clin Oncol. 1998;16:453-461.患者數ORR (CR + PR), %反應維持時間 疾病進展時間總生存 263 vs 253AN = MANot reportedAN = MAAN MA 阿那曲唑瑞寧德1 mg 與 MA來曲唑 弗隆2.5 mg 與 MA174 vs 189LET MALET MALET MALET = MA依西美坦阿諾新25 mg 與 MA366 vs 403EXE = MAEXE = MAEXE MAEXE MA第46頁/共123頁第47頁/共123頁0.00.10.20.30.40.50.60.70.80.91.0Tim

14、e, months0 3 6 91215182124Progression-freeStudy 025Log-rank P .0001Events,Wald Nn (%)HR95% CIP value453308 (68)0.700.60 - 0.82 .0001454350 (77)FemaraTamoxifenHR = Hazard ratio; CI = Confidence interval.第48頁/共123頁30%20%8%*23%*17%3%0102030405060FemaraTamoxifenStudy 025N = 453N = 454Response rate, %CR

15、(P = .002)PR (P = .045)Odds ratio95% CIP value1.711.26 - 2.31.0006CI = Confidence interval; CR = Complete response; PR = Partial response.*Rounded to the nearest whole number.第49頁/共123頁 Bone soft tissue100/1469.797/1306.2.01 Viscera bone 140/1948.3169/208 4.7.001 soft tissue Study 025第50頁/共123頁 Soft

16、 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 025第51頁/共123頁 9 (2)Study 025*Thromboembolic events included: venous thrombosis deep limb, thrombophlebitis superficial, venous thrombosis NOS limb, phlebitis NOS,

17、thrombosis NOS, and thrombophlebitis deep.第52頁/共123頁第53頁/共123頁第54頁/共123頁第55頁/共123頁第56頁/共123頁第57頁/共123頁第58頁/共123頁第59頁/共123頁第60頁/共123頁第61頁/共123頁第62頁/共123頁第63頁/共123頁第64頁/共123頁第65頁/共123頁第66頁/共123頁第67頁/共123頁第68頁/共123頁第69頁/共123頁第70頁/共123頁第71頁/共123頁第72頁/共123頁第73頁/共123頁第74頁/共123頁第75頁/共123頁第76頁/共123頁Primary

18、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第77頁/共123頁 MA.17: Preplanned AnalysisKey En

19、dpoints 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

20、Natl Cancer Inst 2005; 97:1262-71HR=0.58(0.45-0.76)HR=0.61HR=0.82(0.57-1.19)OS第78頁/共123頁第79頁/共123頁612182430364248Optimal Duration of letrozole - HR for DFS MA.17PlaceboLetrozoleHazard RateMonths after randomization0.520.450.350.19HRIngle J et al. Breast Cancer Res and Treat - in press第80頁/共123頁RANDO

21、MIZE025 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

22、-up.Update of Thrlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.第81頁/共123頁 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.

23、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

24、possibly OSHR+ = hormone receptor-positive; NR = not reported; ITT = intent-to-treat.第82頁/共123頁第83頁/共123頁第84頁/共123頁第85頁/共123頁第86頁/共123頁第87頁/共123頁* approx *3yrs第88頁/共123頁第89頁/共123頁ZoladexLHRHThick bonds indicate modificationsSer(But)Azgly第90頁/共123頁第91頁/共123頁第92頁/共123頁West CP, et al. Clin Endocrinol 1

25、987; 26: 21320.第93頁/共123頁A Meta-Analysis of Four Randomized Trials第94頁/共123頁第95頁/共123頁Surgery radiotherapyPre-/perimenopausal patients with node-positive early breast cancer, aged 50 years Follow-upTumour recurrenceDeathDeath第96頁/共123頁Jonat W, et al. J Clin Oncol 2002; 20: 462835.Median follow-up 6 years第97頁/共123頁Zoladex 3.6mgCMF00.10.20.30.40.50.60.70.80.91.0012345678910Disease-free survival (years)Proportion alive and free of diseaseNumber of events:ER+ (n=1,189) 487Jonat W, et al. J Clin On