唑來(lái)膦酸在乳腺癌中的臨床研究進(jìn)展

1、唑來(lái)膦酸在乳腺癌中的臨床研究進(jìn)展,,唑來(lái)膦酸（擇泰）的研發(fā)歷程,治療晚期乳腺癌骨轉(zhuǎn)移預(yù)防早期乳腺癌AI治療引起的骨丟失預(yù)防早期乳腺癌術(shù)后復(fù)發(fā),,,唑來(lái)膦酸（擇泰）的研發(fā)歷程,治療晚期乳腺癌骨轉(zhuǎn)移預(yù)防早期乳腺癌AI治療引起的骨丟失預(yù)防早期乳腺癌術(shù)后復(fù)發(fā),,,骨相關(guān)事件（SREs）包括：放療緩解重度疼痛治療和預(yù)防病理性骨折或脊髓壓迫病理性骨折錐體骨折其他骨折脊髓壓迫骨骼手術(shù)惡性腫瘤所致高鈣血癥（H

2、CM),FDA已接受骨相關(guān)事件（SREs）作為評(píng)價(jià)雙膦酸鹽臨床療效的主要研究終點(diǎn),Johnson JR,et al.J Clin Oncol.2003;21:1404-1411Williams G et al. J Biopharm Stat. 2004 Feb;14(1):5-21,骨轉(zhuǎn)移導(dǎo)致骨相關(guān)事件（SREs）的發(fā)生,雙膦酸鹽治療目標(biāo)---SRE,SRE發(fā)生導(dǎo)致疾病進(jìn)展、 生活質(zhì)量降低、生存期縮短、并引起醫(yī)療費(fèi)用增加1-3

3、預(yù)防或延緩SRE發(fā)生，減少SRE發(fā)生次數(shù)是減緩疾病進(jìn)展和維持患者功能獨(dú)立性的重要環(huán)節(jié)雙膦酸鹽治療綜合而且全面覆蓋以上目標(biāo)4,Coleman RE. Cancer. 1997;80(suppl):1588-1594.Delea T et al. Oncology. 2004;67:390-396.Jacobson AF et al. Cancer. 2001;91:17-24.4. Coleman RE. Oncologist.

4、 2000;5:463-4670.,乳腺癌骨轉(zhuǎn)移，擇泰對(duì)照帕米膦酸010研究設(shè)計(jì),,,0,,,25 月最終分析,雙盲、雙模擬研究，旨在證實(shí)：與帕米膦酸二鈉相比，唑來(lái)膦酸具有非劣效性,,唑來(lái)膦酸 8 /4mg，1次/3－4 周,隨機(jī)化分組,,,唑來(lái)膦酸 4 mg，1次/3－4 周,n = 564,n = 526,帕米膦酸二鈉 90 mg ，1次/3－4 周三組均每日口服維生素 D 400 IU 及鈣 500 mg,n = 558,

5、1,130例IV期乳腺癌患者518例多發(fā)性骨髓瘤患者,,13月核心分析,Rosen LS et al. Cancer J. 2003;98:1735-44,415,370,349,366,乳腺癌化療,乳腺癌激素治療,延緩30%，P<0.05,P=NS,,,,,,,,,唑來(lái)膦酸 4mg,帕米膦酸二鈉90mg,唑來(lái)膦酸明顯延緩乳腺癌患者骨相關(guān)事件(SREs)的發(fā)生,Rosen LS et al. Cancer J. 2003;9

6、8:1735-44.,至首次骨相關(guān)事件(SREs)天數(shù),唑來(lái)膦酸顯著降低乳腺癌患者骨相關(guān)事件(SREs) 發(fā)生危險(xiǎn)達(dá)20%－多事件分析,,,危險(xiǎn)比(95%可信區(qū)間),P 值,,0.030,0.025,所有患者(n =1,648),乳腺癌患者(n = 1,130),,,,,0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2,,

7、,有利于唑來(lái)膦酸,有利于帕米膦酸二鈉,0.799,0.841,唑來(lái)膦酸顯著降低骨相關(guān)事件(SREs) 發(fā)生危險(xiǎn)達(dá)20%，優(yōu)于帕米膦酸二鈉,,,危險(xiǎn)降低,20%,16%,Rosen LS et al. Cancer J. 2003;98:1735-44,010研究－療效總結(jié),唑來(lái)膦酸有效降低乳腺癌患者的骨相關(guān)事件(SREs)危險(xiǎn)，療效優(yōu)于帕米膦酸二鈉,唑來(lái)膦酸4mg 463760.910.799帕米膦酸二鈉90mg4936

8、61.57—P 值.189.186.102.025,,,發(fā)生SREs的患者比例%,至SREs的中位時(shí)間（天）*,骨相關(guān)事件年發(fā)病率*,多事件分析危險(xiǎn)比*,*惡性腫瘤所致的高鈣血癥(HCM)被包括在骨相關(guān)事件(SREs)內(nèi)。,,Rosen LS et al. Cancer J. 2003;98:1735-44,乳腺癌骨轉(zhuǎn)移，擇泰對(duì)照安慰劑1501研究設(shè)計(jì)（日本）,多中心、隨機(jī)、雙盲、安慰劑對(duì)照研究,Kohno N, et

9、 al. J Clin Oncol. 2005;23:3314-3321.,唑來(lái)膦酸顯著降低發(fā)生一次SRE的患者比例,P = .003,相對(duì)值 39%,,,,Kohno N, et al. J Clin Oncol. 2005;23:3314-3321.,唑來(lái)膦酸顯著降低骨并發(fā)癥風(fēng)險(xiǎn)達(dá)41%,*Andersen-Gill多事件分析#采用嚴(yán)格變量，根據(jù)既往是否發(fā)生過(guò)骨折進(jìn)行分層的回歸系數(shù)的Wald檢驗(yàn),降低風(fēng)險(xiǎn),相關(guān)風(fēng)險(xiǎn),有利于唑來(lái)膦

10、酸,有利于安慰劑,,,,,,,,,,,,,,,,0,0.2,0.4,0.6,0.8,1,1.2,1.4,1.6,1.8,2,,.001,P 值,,.59,,41%,Kohno N, et al. J Clin Oncol. 2005;23:3314-3321.,唑來(lái)膦酸顯著降低平均復(fù)合BPI疼痛評(píng)分,較基線變化的平均值,2,4,8,12,16,20,24,28,32,36,40,44,48,52,,自研究開(kāi)始的時(shí)間，周,*,*,*,*,

11、*,*,*,*,*,*,*,0,*,*,,減輕骨痛,增加骨痛,,*P < .05.,Kohno N, et al. J Clin Oncol. 2005;23:3314-3321.,安慰劑對(duì)照試驗(yàn)中雙膦酸鹽治療乳腺癌的療效,氯屈膦酸（口服）1,600 mg(Kristensen)31%(Paterson)17%(Tubiana-Hulin)8%,,,P 值,,,唑來(lái)膦酸 4 mg

12、 41% .001(Kohno 2005),帕米膦酸 90 mg 23%<.001(Aredia study 18 & 19),伊班膦酸 6 mg 18% .004(Body 2003),伊班膦酸 50 mg 14% .08(Body 2004

13、),,.92,,.03,,Pavlakis N, et al. Cochrane Database Syst Rev. 2005;4:1-38.,ASCO 乳腺癌骨轉(zhuǎn)移治療指南,推薦X線/CT/MRI等影像學(xué)檢查有骨破壞時(shí)開(kāi)始使用靜脈雙膦酸鹽推薦每3-4周使用靜脈唑來(lái)膦酸(4 mg via 15-minute infusion)或帕米膦酸(90 mg via 2-hour infusion) 未推薦口服雙膦酸鹽雙膦酸鹽應(yīng)持續(xù)使用

14、直至患者不能耐受或一般狀況顯著下降,Hillner B, et al. J Clin Oncol. 2003;21:4042-4057.,小 結(jié),治療和預(yù)防SRE，維持患者功能獨(dú)立性和生活質(zhì)量是腫瘤骨轉(zhuǎn)移治療的目標(biāo)010和1501試驗(yàn)奠定了擇泰在乳腺癌骨轉(zhuǎn)移治療中的地位指南推薦乳腺癌骨轉(zhuǎn)移優(yōu)先選擇唑來(lái)膦酸，并建議長(zhǎng)期使用，可以最大程度減少SRE發(fā)生,唑來(lái)膦酸（擇泰）的研發(fā)歷程,治療晚期乳腺癌骨轉(zhuǎn)移預(yù)防早期乳腺癌AI治療引

15、起的骨丟失預(yù)防早期乳腺癌術(shù)后復(fù)發(fā),,,Years,Lumbar spine BMD,,ATAC1 Anastrozole vs tamoxifen upfront,IES2 Exemestane vs tamoxifen following switch after 2-3 years tamoxifen,MA-173 Letrozole vs placebo following switch after 5 ye

16、ars on tamoxifen,TEAM4 Exemestane vs tamoxifen for 2-3 years (before switching from TAM to EXE vs. EXE for 5 years),芳香化酶抑制劑治療導(dǎo)致快速骨丟失,1. Howell A, et al. Lancet 2005;365:60-62; 2. Coleman RE, et al. Lancet Oncol. 2007;

17、8:119-127; 3. Goss PE, et al. J Natl Cancer inst. 2005;97:1262-1271;4. Hadji P, et al. Presented at 31st Annual San Antonio Breast Cancer Symposium, San Antonio, TX, USA; December 10-14, 2008; Abstract 1143.,F/U, follow

18、-up; NS, not significant; ATAC, Arimidex tamoxifen alone or in combination; IES, intergroup exemestane study; BIG 1-98, breast international group 1-98 collaborative group; TEAM, Tamoxifen exemestane adjuvant multinatio

19、nal.1. Adapted from Hadji P, et al. US Oncological Disease. 2007;1:18-21; 2. Howell A, et al. Lancet. 2005;365(9453):60-62; 3. Coleman RE, et al. Lancet Oncol. 2007;8:119-127; 4. Thurlimann B, et al. N Engl J Med. 200

20、5;353(26):2747-2757; 5. Goss PE, et al. J Natl Cancer Inst. 2005;97(17):1262-1271; 6. Jones SE, et al. Presented at 31st Annual San Antonio Breast Cancer Symposium, San Antonio, TX, USA; December 10-14, 2008; Abstract 1

21、5..,Fractures, %,11,7.7,5.7,4.0,5.3,4.6,7.0,5.0,P < .0001,P < .001,,,,,,,,,P = .003,,P = .25,,Tamoxifen,,Letrozole,,Anastrozole,,Placebo,,Exemestane,ATAC26,18668 months,IES34,72458 months,BIG 1-9848,01026 mon

22、ths,MA.1755,18730 months,所有的芳香化酶抑制劑均增加骨折風(fēng)險(xiǎn)1,N = Median F/U =,,,2.3,2.7,P = NS,TEAM69,67033 months,維護(hù)骨健康可以減少后續(xù)骨折和死亡風(fēng)險(xiǎn)AIBL比絕經(jīng)后骨丟失更快速1,2雙膦酸鹽等有效的骨代謝治療，可以預(yù)防潛在的骨丟失雙膦酸鹽治療還可能進(jìn)一步減少骨轉(zhuǎn)移風(fēng)險(xiǎn)3,4,5,AIBL, aromatase inhibitor-a

23、ssociated bone loss.1. Osteoporosis Int. 1997;7(1):1-6; 2. Eastell R, et al. J Bone Miner Res. 2006; 21(8):1215-1223; 3. Daubine F, et al. J Natl Cancer Inst. 2007;99(4):322-330; 4. Mystakidou K, et al. Med Oncol. 2005

24、;22(2):195-201; 5. Diel I, et al. New Eng J Med. 1998;339(6):357-363.,雙膦酸鹽治療AIBL機(jī)理,ABCSG-12: 絕經(jīng)前女性接受輔助內(nèi)分泌治療+唑來(lái)膦酸,1999 to 2006 1,800 例絕經(jīng)前女性乳腺癌患者 I & II期, LNM< 10 個(gè), ER+ 和/或 PgR+治療時(shí)間: 3年允許接受術(shù)前化療骨研究（n=404）于 6/0

25、3結(jié)束,他莫昔芬,他莫昔芬 +唑來(lái)膦酸 (4 mg)* q 6 mo,阿那曲唑 + 唑來(lái)膦酸 (4 mg)* q 6 mo,阿那曲唑,,,3 years,final BMD,,隨機(jī),*8 mg reduced to 4 mg. ABCSG-12 = Austrian Breast and Colorectal Cancer Study Group Trial 12. Gnant MF, et al. J Clin

26、Oncol. 2007;25:820-828.,手術(shù)(+放療),戈舍瑞林3.6 mg/28 days,,基線BMD,,,6-month BMD,,60個(gè)月隨訪數(shù)據(jù)： 腰椎BMD %變化結(jié)束唑來(lái)膦酸治療后BMD繼續(xù)改善,Gnant MF. Presented at SABCS 2007, Abstract #26,,,Z-FAST,1 ZO-FAST2, E-ZO-FAST3 試驗(yàn)設(shè)計(jì),0,5 yearsFinal analy

27、sis,,,ZOL 4 mg q 6 mo + LET 2.5 mg die (DELAYED)*,ZOL 4 mg q 6 mo + LET 2.5 mg die (UP FRONT),,,,RANDOMIZED,,,3 years,1 year,,,PMW = Postmenopausal women; CT = Chemotherapy. *Initiation of zoledronic acid determ

28、ined by postbaseline BMD T-score < –2.0, any clinical fracture, or any asymptomatic fracture at 36 months.1. Adapted with permission from Brufsky A, et al. Presented at SABCS, 2007. Abstract 27;2. Bundred N, et al.

29、 Presented at EBBC, 2006. Abstract 12; 3. Schenk N, et al. Presented at ECCO, 2007. Abstract 2008.,Accrual completed: Z-FAST: N = 602 ZO-FAST: N = 1066 E-ZO-FAST: N = 526,Eligibilit

30、yER+/PgR+ BCaPMW withT-score ≥ –2 StratificationAdjuvant CT(yes or no)T score (> –1 or between –1 and –2 ),P values correspond to intergroup comparisons.DMD, bone mineral density; ZOL, zoledronic acid.a Init

31、iated only after T-score decreases below –2 or clinical fracture unrelated to trauma.1. Brufsky A, et al. Presented at: 6th Annual EBCC; April 15-19, 2008. Abstract 494; 2. Brufsky A, et al. Presented at: 30th Annual

32、SABCS; December 13-16, 2007. Abstract 27.,,Upfront ZOL,,Delayed ZOL,Z-FAST 36個(gè)月：初始唑來(lái)膦酸治療明顯改善腰椎和膝關(guān)節(jié)BMD (N = 602),Multicenter, open-label, randomized phase III study of upfront vs. delayeda zoledronic acid (4 mg q 6 mont

33、hs) in postmenopausal women receiving letrozole (N = 602) for 5 years,,,,,,,,,Month 241,,腰椎,膝關(guān)節(jié),Mean (SEM) change BMD, %,P < .0001,P < .0001,P < .0001,P < .0001,Month 121,Month 241,Month 121,,,,,,,,,,,,,,,,,,

34、,,,,,,,,,,,,,,,,,–4%,–3%,–2%,–1%,0%,1%,2%,3%,4%,,Month 362,,Month 362,P < .001,P < .001,n=251,n=256,n=204,n=199,n=189,n=188,n=251,n=256,n=206,n=197,n=189,n=187,Δ 4.4%,Δ 5.9%,Δ 6.7%,Δ 3.3%,Δ 4.7%,Δ 5.2%,,,,,,ZO-FAST

35、 36個(gè)月：初始唑來(lái)膦酸治療明顯改善腰椎和膝關(guān)節(jié)BMD (N = 1,064)3,P < .0001 for all; correspond to intergroup comparisons.BMD, bone mineral density; ZOL, zoledronic acid.a Initiated only after T-score decreases below –2 or clinical fractur

36、e unrelated to trauma. 1. Bundred N, et al. Presented at: 5th EBCC; March 21-25, 2006. Abstract 12; 2. De Boer R, et al. Presented at: 30th Annual SABCS; December 13-16, 2007. Abstract 501; 3. Eidtmann H, et al. Presen

37、ted at: 31st Annual SABCS, December 11-14, 2008. Abstract 44.,腰椎,,,,,,,,,,,,,–6,–4,–2,0,2,4,,膝關(guān)節(jié),BMD change, %,,,,,Month 242,Month 121,Month 242,Month 121,,Upfront ZOL,Delayed ZOL,,Δ 5.2%,Δ 8.2%,Δ 3.3%,Δ 4.7%,Month 363,M

38、onth 363,Δ 9.3%,Δ 5.4%,,,,,,6,Multicenter, open-label, randomized phase III study of upfront vs. delayeda zoledronic acid (4 mg q 6 months) in postmenopausal women receiving letrozole (N = 1,064) for 5 years,,,BMD監(jiān)測(cè)的重要性

39、ASCO 2003 乳腺癌骨健康BMD篩查指南,ASCO乳腺癌骨健康BMD篩查指南年齡> 65歲年齡60 - 64歲骨折家族史體重 < 70 公斤既往非外傷性骨折史其他風(fēng)險(xiǎn)因素任何年齡接受芳香化酶抑制劑患者絕經(jīng)前患者因?yàn)橹委熞痖]經(jīng)建議每年一次的BMD監(jiān)測(cè),Hillner BE, et al. J Clin Oncol. 2003;21(21):4042-4057.,Hillner BE, et a

40、l. J Clin Oncol. 2003;21:4042-4057.,ASCO 2003 指南: 根據(jù)BMD變化治療,T-score < –2.0,任意2項(xiàng)以下風(fēng)險(xiǎn)因素:T-score 65 years低體重指數(shù) ( 6 months吸煙（現(xiàn)在或既往）,T-score ≥ –2.0, 沒(méi)有其他危險(xiǎn)因素,每1-2年監(jiān)測(cè)風(fēng)險(xiǎn)狀態(tài)和BMD*,唑來(lái)膦酸(4 mg / 6 months)補(bǔ)充鈣和維生素D,每2年監(jiān)測(cè)BMD,補(bǔ)充鈣

41、和維生素D,*≥ 5% drop in BMD should trigger zoledronic acid treatment (4 mg / 6 months). Use lowest T-score from 3 sites.Hadji P, et al. Presented at: SABCS 2007. Abstract 504.,專家指南更新：結(jié)合BMD和其他風(fēng)險(xiǎn)因素治療,,,,,目前已經(jīng)有了口服雙膦酸鹽的試驗(yàn)結(jié)果4個(gè)臨

42、床試驗(yàn)的數(shù)據(jù)提示唑來(lái)膦酸預(yù)防AIBL,,小 結(jié),AI治療減少BMD并增加骨折風(fēng)險(xiǎn)多項(xiàng)大型臨床試驗(yàn)證實(shí)唑來(lái)膦酸治療獲益超過(guò)了單純的骨保護(hù)作用內(nèi)分泌治療聯(lián)合唑來(lái)膦酸 (4 mg q 6 mo)保持BMD，而且改善疾病進(jìn)展(DFS)1,2,3臨床指南的權(quán)威推薦建議高危患者積極篩查BMD雙膦酸鹽治療不僅參考BMD，也應(yīng)結(jié)合其他風(fēng)險(xiǎn)因素,AI, aromatase inhibitor; BMD, bone mineral dens

43、ity; BP, bisphosphonate; AIBL, aromatase inhibitor-associated bone loss; DFS, disease-free survival.1. Gnant M, et al. J Clin Oncol. 2008(suppl). Abstract LBA4; 2. Frassoldati A, et al. Presented at: 33rd Annual ESMO; S

44、eptember 12-16, 2008. Abstract 185PD; 3. Eidtmann H, et al. Presented at: 31st Annual SABCS; December 10-14, 2008. Abstract 44.,唑來(lái)膦酸（擇泰）的研發(fā)歷程,治療晚期乳腺癌骨轉(zhuǎn)移預(yù)防早期乳腺癌AI治療引起的骨丟失預(yù)防早期乳腺癌術(shù)后復(fù)發(fā),,,減少細(xì)胞因子的產(chǎn)生 (如IL-6)1直接的抗腫瘤活性(細(xì)胞抑

45、制和細(xì)胞溶解)2-5抑制腫瘤細(xì)胞擴(kuò)散、侵犯及與骨基質(zhì)的粘附6,7抑制血管生成8,Reference 1-8,唑來(lái)膦酸比傳統(tǒng)雙膦酸鹽更加獨(dú)特的作用機(jī)理,1.Derenne S, J Bone Miner Res. 1999;14:2048-2056.2. Aparicio A,. 1998;12:220-229.3. FromiguéO, J Bone Miner Res. 2000;15:2211-2221.4. Sen

46、aratne SG, Br JCancer. 2000;82:1459-1468.5. Jagdev SP, Bone. 2000;26:S30. Abstract B11.6. Boissier S, Cancer Res. 2000;60:2949-2954.7. Marion G, Bone. 1998;23:S279. Abstract8. Wood J, Pharm Exp Ther. In press.,絕經(jīng)前乳腺癌：A

47、BCSG-12試驗(yàn)設(shè)計(jì),收集于1999-20061,803例絕經(jīng)前的乳腺癌患者內(nèi)分泌療法有效 (雌激素受體和/或孕激素受體陽(yáng)性)I&II期, <10處淋巴結(jié)轉(zhuǎn)移除新輔助化療外未接受其他化療治療時(shí)程: 3年,32,Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4,試驗(yàn)情況,1999年至2006年間共征募了1,803位患者中位隨

48、訪時(shí)間: 48個(gè)月2008年3月: 137例發(fā)生事件, 42例死亡30例局部復(fù)發(fā)病例70例遠(yuǎn)處復(fù)發(fā)病例包括40例骨轉(zhuǎn)移事件16例對(duì)側(cè)乳腺癌19例新生非乳腺腫瘤總計(jì): 4年無(wú)病生存率 = 94%; 4年總生存率=98.2%,33,Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4,與單獨(dú)使用內(nèi)分泌治療相比唑來(lái)膦酸顯著提高無(wú)病生存率 36%

49、 (DFS),平均隨訪時(shí)間 = 60月.DFS = 無(wú)病生存率; CI = 置信區(qū)間; ZOL = 唑來(lái)膦酸. Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.,與單獨(dú)使用內(nèi)分泌治療相比 唑來(lái)膦酸顯著提高無(wú)復(fù)發(fā)生存率 35% (RFS),平均隨訪時(shí)間 = 60月.RFS = 無(wú)復(fù)發(fā)生存率; CI = 可信區(qū)間; ZOL = 唑來(lái)膦酸. Gn

50、ant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.,經(jīng)唑來(lái)膦酸治療的病人中表現(xiàn)出非顯著性趨勢(shì)總生存率(os)增高,,平均隨訪時(shí)間 = 60月.OS = 總生存率; CI = 可信區(qū)間; ZOL = 唑來(lái)膦酸. Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.,主要

51、無(wú)病存活事件 (意向治療人群 ITT),主要事件/病人, n,(n = 904),(n = 899),不使用ZOL vs ZOL,DFS = 無(wú)病生存率; ITT = 意向治療; ZOL = 唑來(lái)膦酸. Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abstract LBA4.,需要治療病人數(shù)(NNT)估算,為了使1位患者獲得無(wú)病生存（DFS）的臨床收益需要治療的病人數(shù)N

52、NT = 1 / 絕對(duì)風(fēng)險(xiǎn)減低唑來(lái)膦酸具有與其他化療藥物相似的改善DFS功效(ie,紫杉烷類 ),*Bria E, et al. Cancer. 2006;106:2337-2344.,,小結(jié)：唑來(lái)膦酸治療和非唑來(lái)膦酸治療,與單純內(nèi)分泌治療相比，唑來(lái)膦酸顯著延長(zhǎng)DFS和RFS? 36% DFS事件風(fēng)險(xiǎn) (HR = 0.64; P = .01)? 35% RFS事件風(fēng)險(xiǎn) (HR = 0.65; P = .015)無(wú)論在骨內(nèi)還是在

53、骨外，唑來(lái)膦酸均顯示了獲益：降低對(duì)側(cè)乳腺癌復(fù)發(fā)降低局部復(fù)發(fā)降低非骨轉(zhuǎn)移仍需要開(kāi)展進(jìn)一步的臨床研究探討最佳劑量、給藥方法和給藥間隔。應(yīng)考慮將唑來(lái)膦酸列入輔助治療以改善絕經(jīng)前乳腺癌婦女的治療,ZOL = 唑來(lái)膦酸; DFS = 無(wú)病生存率; RFS = 無(wú)復(fù)發(fā)生存率; OS = 總體存活率; HR 風(fēng)險(xiǎn)比.,Gnant M, et al. Presented at: ASCO 2008. Chicago, IL. Abst

54、ract LBA4,絕經(jīng)后乳腺癌：ZO-FAST 36個(gè)月隨訪,來(lái)自亞太、中南美、埃及和歐洲128個(gè)研究中心的1065 患者入選,入選標(biāo)準(zhǔn)：ER+/PgR+ 早期乳腺癌；絕經(jīng)后；骨密度T值 ≥ –2?；颊叻謱樱狠o助CTT 值確診的和近期絕經(jīng),,,,,來(lái)曲唑 2.5 mg/天,加用唑來(lái)膦酸，如果:BMD T 值<?2 或 非創(chuàng)傷性骨折或36個(gè)月隨訪中確認(rèn)的無(wú)癥狀的骨折,5 年,唑來(lái)膦酸4 mg，IV，1次/6個(gè)月,

55、來(lái)曲唑 2.5 mg/天,早期使用,延遲使用,1065例患者隨機(jī)分組,主要研究終點(diǎn)：12個(gè)月時(shí)腰椎（L2-L4）BMD變化百分比。次要研究終點(diǎn)：3年骨折發(fā)生率；至疾病復(fù)發(fā)時(shí)間；總生存時(shí)間；兩治療組的總體安全性。,Adapted from Eidtmann H, et al. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10

56、-14, 2008; San Antonio, TX. Abstract 44.,,,時(shí)間（月）,無(wú)病生存率（DFS），%,,60,0,40,20,80,100,10,20,15,5,35,30,25,0,,,—— 早期治療組—— 延遲治療組,擇泰早期治療顯著降低無(wú)病生存率，風(fēng)險(xiǎn)比0.588，P=0.0314,早期治療組顯著降低無(wú)病生存率 DFS,Adapted from Eidtmann H, et al. Presented

57、at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, TX. Abstract 44.,疾病復(fù)發(fā)：局部復(fù)發(fā)，遠(yuǎn)處轉(zhuǎn)移或死亡,Adapted from Eidtmann H, et al. Presented at: 31st Annual San Antonio Breast Cancer Symposium; De

58、cember 10-14, 2008; San Antonio, TX. Abstract 44.,復(fù)發(fā)部位,*患者可能有多個(gè)復(fù)發(fā)部位,Adapted from Eidtmann H, et al. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, TX. Abstract 44.,死亡率（治

59、療期間任何原因引起）,死亡率，%,Adapted from Eidtmann H, et al. Presented at: 31st Annual San Antonio Breast Cancer Symposium; December 10-14, 2008; San Antonio, TX. Abstract 44.,ZO-FAST 36個(gè)月結(jié)論,使用AI輔助治療的早期乳腺癌患者早期使用擇泰（4mg IV 1次/6個(gè)月）能夠預(yù)防

60、骨質(zhì)丟失；早期使用擇泰和延遲使用擇泰在骨折發(fā)生率方面無(wú)顯著差異；早期使用擇泰顯著提高無(wú)病生存率；藥物安全性結(jié)果與以往一致：無(wú)藥物相關(guān)腎損害; 下頜骨壞死 ，早期治療組1例（0.2%），接受6次唑來(lái)膦酸治療，延遲治療組：無(wú)這些結(jié)果進(jìn)一步證明擇泰治療早期乳腺癌具有抗腫瘤活性并延長(zhǎng)無(wú)病生存期。,總 結(jié),唑來(lái)膦酸已經(jīng)成為乳腺癌骨轉(zhuǎn)移的標(biāo)準(zhǔn)治療之一，有效減少SRE發(fā)生，并維護(hù)患者功能獨(dú)立性和生活質(zhì)量唑來(lái)磷酸可以預(yù)防早期乳腺癌接受AI治療