陸勁松福州乳腺癌的內(nèi)分泌治療進(jìn)展

1、乳腺癌內(nèi)分泌治療進(jìn)展,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺外科陸勁松,1,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,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、生物治療,2,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,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,3,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,歷史的回顧,1836年, Cooper 觀察到乳腺腫瘤的生長(zhǎng)與月經(jīng)周期相關(guān)。1896年, Beatson 報(bào)道在幾個(gè)絕經(jīng)前的乳腺癌患

2、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(bào)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(bào)道切除垂體后可取得上述相似的效果。,4,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,內(nèi)分泌機(jī)制,(B) 絕經(jīng)后,GNRH 類似物,,,,Breastcarcinoma,Breastcarcinoma,,抗雌激素,卵巢,LHFSH,抗雌激素,,(A) 絕經(jīng)前,腎上

3、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(shù); FSH = 卵泡刺激素,5,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,在1975年所用的內(nèi)分泌治療手段,卵巢的切除 手術(shù) (去勢(shì)) 放射去勢(shì)雙側(cè)腎上腺切除垂體切除術(shù)雌激素雄激素

4、孕激素糖皮質(zhì)激素,6,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,目前所用的乳腺癌內(nèi)分泌治療手段,芳香化酶抑制劑(非選擇性 和選擇性)選擇性雌激素受體調(diào)節(jié)劑（SERM）選擇性雌激素受體下調(diào)劑（SERD）GHRH 激動(dòng)劑和拮抗劑卵巢的切除 手術(shù) (去勢(shì)) 放射去勢(shì)孕激素其它:雄激素、雌激素、抗孕激素等,7,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,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(dá),8,復(fù)旦大學(xué)腫

5、瘤醫(yī)院乳腺癌研究所,SERM作用機(jī)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(jìng)爭(zhēng)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(duì)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),9,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,三苯氧胺輔助治療的臨床試NSABP－B14,10,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,%,Years,Actuarial estima

6、te and SEAllocated tamoxifenAllocated control,ER+,,,,,,,,,,,,,,,,,,,,,,,,,,,,,85.2,76.1,68.2,73.7,62.7,54.9,,,11.5 (SE 0.9),13.4 (SE 1.1),13.4 (SE 1.4),,,,,,,OVERVIEW: TAMOXIFEN 5 YEARS VS NOTRecurrences,11,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺

7、癌研究所,Actuarial estimate and SEAllocated tamoxifenAllocated control,ER+,,,,,,,,,,,,,,,,,,,,89.5,76.8,64.9,86.3,69.4,57.0,,,3.2 (SE 0.7),7.4 (SE 1.1),7.9 (SE 1.5),,,,,,,,,,,,,,,,%,Years,OVERVIEW: TAMOXIFEN 5 YEARS VS NOT

8、All Deaths,12,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,NSABP B-14: No Benefit of Extending TAM,,,,,,,,,,,,,,,,P=0.03,P=0.13,P=0.07,Disease-Free Survival,Relapse-Free Survival,Survival,100,90,80,70,60,50,%,0,1,2,3,4,5,6,7,Years*,,,,,,,,,,,,,,,,0,

9、1,2,3,4,5,6,7,,,,,,,,,,,,,,,,0,1,2,3,4,5,6,7,No. atrisk:569531491229531491229554529257583527472209527472209560528239,,,No. of No. ofPts. EventsPlac569106Tam583137,,,No. of Events3447,,,

10、No. of Deaths3957,,,,,,,,,,,,,Fisher et al. J Natl Cancer Inst. 2001;93:684.,After 5 years of adjuvant tamoxifen.,13,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,New trials,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,14,ATLAS,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,15,Meta分析,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,16,抗雌激素以后

11、的選擇,阻斷雌激素受體 (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?,17,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,,,,毒性,特異性,有效性,第一代,第二代,第三代,氨基導(dǎo)眠能*,法屈唑 蘭他龍,阿那曲唑依西美坦 來(lái)曲唑,芳香化酶抑制劑的歷史,皮疹等,無(wú)腎上腺功能影響,1,000to10,000,100,1,18,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,,不同芳香化酶的結(jié)構(gòu),,載體類抑制劑,Androgen su

12、bstrate,非甾體類抑制劑,19,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,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

13、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 Mice,,20,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,腫

14、瘤的重量的變化,21,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,9366 postmenopausal women with invasive breast cancer Mean age 64 years; 84% hormone receptor-positive 61% node-negative; 64% with tumour ?2cm in diameter,Randomisation 1:1:1 for 5 years,ARIMI

15、DEX(n=3125),tamoxifen (n=3116),Regular follow-up,Primary trial endpoints:Disease-free survivalSafety/tolerability,Secondary trial endpoints:Incidence of contralateral breast cancerTime to distant recurrenceTime to

16、 recurrenceOverall survival Death after recurrence,Discontinued following initial analysis as no efficacy or tolerability benefit compared with tamoxifen arm,ATAC Trial Design,,,,,,Disease-free Survival HR+ Patients,P

17、atients (%),30,25,20,15,10,5,0,,,,,,,13.9%,16.4%,25.8%,29.9%,,0,1,2,3,4,5,6,7,8,9,,,,,,,,,,,,,,,,HR+,HR0.85,95% CI(0.76, 0.94),p-value0.003,,,,Follow-up time (years),2.5%,4.1%,,HR+, hormone receptor-positive; HR, haz

18、ard ratio;CI, confidence interval; AD, absolute difference,The ATAC Trialists’ Group. Lancet Oncol 2008; 9:45-53,AD,23,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,Time to Distant RecurrenceHR+ Patients,,,Patients (%),30,25,20,15,10,5,0,,,,,,,,,0,

19、1,2,3,4,5,6,7,8,9,,,,,,,,,,,,,,7.8%,9.1%,13.2%,15.6%,Follow-up time (years),HR+,HR0.84,95% CI(0.72, 0.97),p-value0.022,,,,1.3%,2.4%,The ATAC Trialists’ Group. Lancet Oncol 2008; 9:45-53,AD,24,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,Contralate

20、ral Breast CancerHR+ Patients,,,Patients (%),5,4,3,2,1,0,,,,,,,,0,1,2,3,4,5,6,7,8,9,,,,,,,,,,,5,4,3,2,1,0,,,,,,,,,,,1.0%,1.8%,2.5%,4.2%,Follow-up time (years),HR+,HR0.60,95% CI(0.42, 0.85),p-value0.004,,,,AD,0.8%,1.

21、7%,The ATAC Trialists’ Group. Lancet Oncol 2008; 9:45-53,25,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,Death: All CausesHR+ Patients,,,Patients (%),30,25,20,15,10,5,0,,,,,,,,,0,1,2,3,4,5,6,7,8,9,,,,,,,,,,,,Follow-up time (years),HR+,HR0.97,95% C

22、I(0.86, 1.11),p-value0.70,,,,The ATAC Trialists’ Group. Lancet Oncol 2008; 9:45-53;AstraZeneca data on file,26,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,,,Fracture Episode Rates Throughout the Study,,29842976,At risk:ARIMIDEXtamoxifen,28592

23、824,27452699,26402572,24962419,23062208,20772000,17131645,702659,Time since randomisation (years),Annual fracture episode rates (%),,,,,,,,,,,0,1,2,3,4,5,6,7,8,9,,0,,2,,3,,4,,1,,,,,,,,,,,,,,,,,,,,The ATAC Trialist

24、s’ Group. Lancet Oncol 2008; 9:45-53,27,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,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 c

25、ore 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 Thü

26、;rlimann et al. J Clin Oncol. 2005;23:6S. Abstract 511.,,,28,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,,,,,,BIG 1-98 Monotherapy UpdateMedian Follow-up 76 months,*Let:Tam: breast cancer events, 321:363second (non breast) malignancy, 101:115d

27、eaths without prior cancer event, 87:87,29,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,,,TEAM研究結(jié)果：隨訪2.75年(33個(gè)月),,,,,在接受治療的人群中,隨訪2.75年，在接受治療人群中，阿諾新可降低17%的疾病風(fēng)險(xiǎn)！,,,TEAM研究結(jié)果：隨訪2.75年(33個(gè)月),,隨訪2.75年，阿諾新可降低19%的遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)！,他莫昔芬,依西美坦,他莫昔芬,隨機(jī)分組,,,,治療后隨訪,,,,,,,,,2

28、-3 年,2-3 年治療研究,診斷,研究開(kāi)始,共5年的內(nèi)分泌治療,IES 031：研究設(shè)計(jì),Coombes, ASCO 2006.,56 個(gè)月中位隨訪期 超過(guò) 99% 的患者完成了治療,超過(guò)2年的治療后隨訪,,HR = 0.7595% CI (0.65 – 0.87)P-value0.0001,End oftreatment,ER+/未明患者,Coombes, ASCO 2006.,339 events2296 at ri

29、sk,阿諾新,,他莫昔芬,,438 events2306 at risk,2.5 年3.4 (1.8 – 5.1),5 年3.5 (0.1 – 6.9),%絕對(duì)差異 (95% CI),,,隨訪5年，阿諾新比他莫西芬降低25%的疾病風(fēng)險(xiǎn)！,IES 031結(jié)果：無(wú)病生存期DFS,End oftreatment,HR = 0.8395% CI (0.69 – 1.00)P-value0.05,Coombes, ASCO 2006

30、.,ER+/未明患者,2.5 years0.7 (-0.4 – 1.9),5 years1.6 (-1.2 – 4.3),% 絕對(duì)差異 (95% CI),,,210 events2296 at risk,阿諾新,,隨訪5年，阿諾新比他莫西芬降低17%的死亡風(fēng)險(xiǎn)！,IES 031結(jié)果：總生存期OS,IES 031結(jié)果：減少對(duì)側(cè)和遠(yuǎn)處復(fù)發(fā),Coombes. Lancet 2007; 369: 559–70,降低對(duì)側(cè)乳腺?gòu)?fù)發(fā)風(fēng)險(xiǎn)43%

31、（P=0.04）降低遠(yuǎn)處轉(zhuǎn)移風(fēng)險(xiǎn)17% （P=0.03）,ABCSG 8研究設(shè)計(jì),手術(shù)治療,隨機(jī)化分組,他莫昔芬20mg/d（2年）,他莫昔芬20mg/d（3年）,他莫昔芬20mg/d（2年）,阿那曲唑1mg/d（3年）,,,,,,,,轉(zhuǎn)換分析,序貫分析,Jakesz et al, Lancet 2005,ABCSG 8研究入組條件,可行手術(shù)治療的絕經(jīng)后乳腺癌患者（依據(jù)激素水平確定絕經(jīng)后3年內(nèi)）≤80 歲雌激素受體

32、陽(yáng)性（ER+）和/或孕激素受體陽(yáng)性（PR+）1級(jí)或2級(jí)導(dǎo)管癌和小葉癌乳腺改良根治術(shù)或保乳手術(shù)淋巴結(jié)手術(shù)（前哨淋巴結(jié)或腋下淋巴結(jié)切除）不允許化療,不同于其他研究,,不同于其他研究,,ABCSG 8研究統(tǒng)計(jì)分析,主要終點(diǎn) – 無(wú)復(fù)發(fā)生存期 RFS（局部和遠(yuǎn)處復(fù)發(fā)病灶、對(duì)側(cè)乳腺癌、非復(fù)發(fā)相關(guān)性死亡）（不同于DFS）次要終點(diǎn) – 總生存期 OS（各種原因?qū)е碌乃劳觯?– 安全性分析,ABCSG 8研究：無(wú)復(fù)發(fā)生

33、存率RFS序貫樣本、交叉分析、截尾數(shù)據(jù),所有患者HR=0.815年齡60歲 HR＝0.814ER和PR低表達(dá) HR＝1.083ER和PR高表達(dá) HR＝0.6861級(jí) HR＝0.832級(jí)或小葉癌 HR＝0.803,時(shí)間（月） 0 12 24 36 48 60 72 84 96 事件（序貫治療組） 18 26 19 33 20 27 20

34、 15 15事件（他莫昔芬治療組） 14 26 40 35 33 30 22 10 10,,,,,,,,,,,,,,,,,,,,,,0 12 24 36 48 60 72 84 96,10.950.90.850.80.750.70.650.60.550.5,,,,,,,,,,,,,,,,,,,,,0.5 0.6 0.7

35、 0.8 0.9 1.0 1.1 1.2 1.3 1.4,,,,,,,,,,,事件(序貫e):202 of 1469事件(TAM):235 of 1452P-value(Log-Rank):0.038Cox回歸: HR 0.820,95% CI 0.679-0.990,無(wú)復(fù)發(fā)生存率（月）,TAM 序貫,危險(xiǎn)比和可信限,ABCSG 8研究：總生存期總樣本，交叉分析，截尾數(shù)據(jù),43,BIG

36、 1-98 Sequential Therapy Two Pairwise Comparisons,Letrozole,Letrozole,,,,,,,Tamoxifen,N=3,094,Letrozole,Letrozole,Tamoxifen,,,,,0,2,5,,,,YEARS,N=3,086,3 blinded armsSequential vs. letrozole monotherapyEvaluated from r

37、andomizationMedian Follow Up 71 mos.99% confidence intervals to account for multiple comparisons,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,44,BIG 1-98 Sequential Treatment Disease-Free Survival,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,MA.17: Trial Design,,Primary end po

38、int: 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

39、=2594,,,Goss PE et al: J Natl Cancer Inst 97:1262, 2005,45,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,MA.17: Preplanned AnalysisKey Endpoints in Nodal Subgroups (n=5187) Letrozole reduced risk of recurrence by 42%,DFS*,Distant* DFS,Node*

40、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 Na

41、tl Cancer Inst 2005; 97:1262-71,,,,,HR=0.58(0.45-0.76),HR=0.61,HR=0.82(0.57-1.19),OS,46,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,612182430364248,,,Optimal Duration of letrozole - HR for DFS MA.17,Placebo,Letrozole,Hazard Rate,Months aft

42、er randomization,0.52,0.45,0.35,0.19,HR,Ingle J et al. Breast Cancer Res and Treat - in press,47,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,后期伸展AI治療,48,,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,MA-17,49,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,LHRH類似物－激動(dòng)劑,“諾雷德” 長(zhǎng)期使用抑制腦垂體促黃體生成素合成，從而引起 女性血清雌二醇的下降，初期用

43、藥時(shí)“諾雷德”同其它LHRH激動(dòng)劑一樣，可暫時(shí)增加男性血清睪丸酮和女性血清雌二醇的濃度。女性患者在初次給藥后21天左右血清中雌二醇濃度受到抑制，并在以后每28天的治療中維持在絕經(jīng)后水平。,50,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,Discovery of ‘Zoladex’,‘Zoladex’,LHRH,Thick bonds indicate modifications,Ser(But),Azgly,51,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,,

44、,,,,,,,,,,,,,,,,,Figure AHypersecretion of LH following acute administration of ‘Zoladex’,Figure BHyposecretion of LH following chronic administration of ‘Zoladex’,,,,,,,,,,,goserelin,goserelin,goserelin,goserelin,gose

45、relin,goserelin,goserelin,goserelin,goserelin,PituitaryCell,LH,,,,,PituitaryCell,LH,Mechanism of Action of ‘Zoladex’ — 2,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,goserelin,52,復(fù)旦大學(xué)

46、腫瘤醫(yī)院乳腺癌研究所,諾雷德與三苯氧胺聯(lián)合應(yīng)用,A Meta-Analysis of Four Randomized Trials,53,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,ZEBRA: Trial Design,,Surgery ± radiotherapy,‘Zoladex’ 3.6mg every 28 daysfor 2 years,Pre-/perimenopausal patients with node-posit

47、ive early breast cancer, aged ?50 years,Follow-up,CMF 6 ´ 28-daycycles,Randomised 1:1 (open, multicentre),,,,,,Tumour recurrence,Death,Death,,,,,,,,54,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,ZEBRA: Kaplan–Meier Plot of DFS in ER+ Patient

48、s,,,‘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,,

49、Jonat W, et al. J Clin Oncol 2002; 20: 4628–35.,55,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,ZEBRA: Efficacy Results — Overall Survival,Overall survival,Number ofdeaths,HR,95%,CI,p value,ER+,225,0.99,0.76–1.28,0.92,ER–,104,1.77,1.19–2.63,0.0043,,

50、(n=1,189),(n=304),,,,Jonat W, et al. J Clin Oncol 2002; 20: 4628–35.,An HR <1.00 favours ‘Zoladex’ 3.6mg,56,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,,,,,,CMF x 6 cycles,‘Zoladex’ 3.6mg/28 days for 3 years PLUStamoxifen 20mg/day for 5 years,

51、,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 patien

52、tsNode+ve or node–veIncluded 28% of all eligible patients in Austria,ABCSG AC05 TrialAustrian Adjuvant Breast Cancer Trial (‘Zoladex’ 3.6mg + tamoxifen vs chemotherapy),57,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,Randomized Adjuvant Trial of

53、Tamoxifen and Goserelin Versus CMF: Evidencefor the Superiority of Treatment With Endocrine Blockade inPremenopausal Patients With Hormone-Responsive BreastCancer—Austrian Breast and Colorectal Cancer Study GroupTrial 5

54、,,58,復(fù)旦大學(xué)腫瘤醫(yī)院乳腺癌研究所,,ABCSG-12 試驗(yàn)設(shè)計(jì),1999-2006年1,803例絕經(jīng)前乳腺癌患者內(nèi)分泌治療有效 (ER和/或PR陽(yáng)性)I&II期, <10個(gè)淋巴結(jié)轉(zhuǎn)移除新輔助化療外未接受其他化療治療期: 3年,59,1999 ~ 2006年共入組1,803名患者 中位隨訪48個(gè)月 2008年3月: 137例首次DFS事件，42例死亡 - 30例局部復(fù)發(fā) - 70例遠(yuǎn)處轉(zhuǎn)移

55、 包括40例骨轉(zhuǎn)移事件 - 16 例對(duì)側(cè)乳腺癌 - 19 例非乳腺原發(fā)腫瘤 總計(jì): 4年無(wú)病生存率: 92.4%; 4年總生存率: 97.7%,試驗(yàn)情況,61,,,,,,,,,,,,,,,,,,,,,,,,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,隨機(jī)分組后的時(shí)間，月,無(wú)疾病生存率, %,風(fēng)險(xiǎn)比 (95% CI)發(fā)生數(shù)vs TAMP 值A(chǔ)N

56、A72/9031.096 (0.78, 1.53).593TAM65/900,,Gnant M, et al. Presented at: ASCO 2008. Chicago, IL, USA. Abstract LBA4.,主要終點(diǎn): 無(wú)疾病生存TAM和ANA之間無(wú)顯著差異,,,,,,,,,,,,,,,,,,,,,,,,14,29,41,10,6,9,10,1,1,16,0,10,20,30,40,50,60,70,80

57、,90,TAM (n=900),ANA (n=903),,無(wú)復(fù)發(fā)死亡,,繼發(fā)惡性腫瘤,,對(duì)側(cè)乳腺癌,,遠(yuǎn)處轉(zhuǎn)移,,局部復(fù)發(fā),第一事件病人人數(shù),TAM vs ANA,首次DFS事件 (意向治療人群),無(wú)復(fù)發(fā)生存,總生存,隨機(jī)分組后時(shí)間，月,,,,,,,,,,,,,,,,,,,,,,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,總生存, %,,,風(fēng)險(xiǎn)比 (95% CI)

58、發(fā)生數(shù)vs TAMP 值A(chǔ)NA271.791 (0.95 to 3.37).065TAM15,,危險(xiǎn)患者數(shù),900,834,719,553,411,243,129,50,903,844,725,540,411,255,139,51,TAM,ANA,900,840,736,580,439,264,141,60,903,849,743,558,436,271,151,59,次要終點(diǎn): ANA vs. TAM,,,,,,,,

59、,,,,,,,,,,,,,,,,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,隨機(jī)分組后時(shí)間，月,無(wú)疾病生存, %,風(fēng)險(xiǎn)比 (95% CI)發(fā)生數(shù)vs No ZOLZOL54/9040.643 (0.46 to 0.91)No ZOL83/899,,P = .011,Gnant M, et al. Presented at: ASCO 2008. Chic

60、ago, IL, USA. Abstract LBA4.,主要終點(diǎn)：無(wú)疾病生存與單獨(dú)內(nèi)分泌治療相比，合用唑來(lái)膦酸顯著改善DFS,兩者在DFS, RFS或OS方面無(wú)顯著性差異 - 這可能是因?yàn)榻^經(jīng)前患者使用戈舍瑞林強(qiáng)烈的卵巢抑制作用ANA與TAM相比，潛在的威脅生命的嚴(yán)重不良反應(yīng)更少見(jiàn),,子宮息肉,,血栓形成,絕經(jīng)前婦女使用芳香化酶抑制劑的明確指南出臺(tái)前，還需要進(jìn)一步的試驗(yàn) - 正在進(jìn)行的內(nèi)分泌治療聯(lián)合卵巢抑制輔助治療的