陸勁松福州乳腺癌內分泌治療進展

1、乳腺癌內分泌治療進展,復旦大學腫瘤醫(yī)院乳腺外科陸勁松,1,復旦大學腫瘤醫(yī)院乳腺癌研究所,系統(tǒng)輔助治療,在手術完成后殺滅或者抑制臨床陰性的微轉移灶化療、內分泌、生物治療,2,復旦大學腫瘤醫(yī)院乳腺癌研究所,輔助內分泌治療,采用內分泌治療手段抑制微轉移灶的增殖、復蘇,3,復旦大學腫瘤醫(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與月經周期相關。1896年, Beatson 報道在幾個絕經前的乳腺癌患

2、者，在切除了卵巢后其轉移灶出現了退縮。1952年 Huggins和Bergenstal 報道切除腎上腺后可使部分乳腺癌患者的轉移灶出現退縮。 Luft and Olivecrona報道切除垂體后可取得上述相似的效果。,4,復旦大學腫瘤醫(yī)院乳腺癌研究所,內分泌機制,(B) 絕經后,GNRH 類似物,,,,Breastcarcinoma,Breastcarcinoma,,抗雌激素,卵巢,LHFSH,抗雌激素,,(A) 絕經前,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; FSH = 卵泡刺激素,5,復旦大學腫瘤醫(yī)院乳腺癌研究所,在1975年所用的內分泌治療手段,卵巢的切除 手術 (去勢) 放射去勢雙側腎上腺切除垂體切除術雌激素雄激素

4、孕激素糖皮質激素,6,復旦大學腫瘤醫(yī)院乳腺癌研究所,目前所用的乳腺癌內分泌治療手段,芳香化酶抑制劑(非選擇性 和選擇性)選擇性雌激素受體調節(jié)劑（SERM）選擇性雌激素受體下調劑（SERD）GHRH 激動劑和拮抗劑卵巢的切除 手術 (去勢) 放射去勢孕激素其它:雄激素、雌激素、抗孕激素等,7,復旦大學腫瘤醫(yī)院乳腺癌研究所,內分泌治療的目標,抑制或者阻斷雌激素的形成阻雌激素的作用下調節(jié)雌激素受體的表達,8,復旦大學腫

5、瘤醫(yī)院乳腺癌研究所,SERM作用機制,選擇性雌激素受體調節(jié)劑（ SERM ）如：三苯氧胺、托瑞米芬、雷洛昔芬，可競爭性與ER結合，結合后仍能形成二聚體，并與ERE結合。轉錄活性僅保留了部分其產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的共激活因子或共抑制因子的狀態(tài),9,復旦大學腫瘤醫(yī)院乳腺癌研究所,三苯氧胺輔助治療的臨床試NSABP－B14,10,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(yī)院乳腺癌研究所,New trials,復旦大學腫瘤醫(yī)院乳腺癌研究所,14,ATLAS,復旦大學腫瘤醫(yī)院乳腺癌研究所,15,Meta分析,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,氨基導眠能*,法屈唑 蘭他龍,阿那曲唑依西美坦 來曲唑,芳香化酶抑制劑的歷史,皮疹等,無腎上腺功能影響,1,000to10,000,100,1,18,復旦大學腫瘤醫(yī)院乳腺癌研究所,,不同芳香化酶的結構,,載體類抑制劑,Androgen su

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

14、瘤的重量的變化,21,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(yī)院乳腺癌研究所,,,TEAM研究結果：隨訪2.75年(33個月),,,,,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%的疾病風險！,,,TEAM研究結果：隨訪2.75年(33個月),,隨訪2.75年，阿諾新可降低19%的遠處轉移風險！,他莫昔芬,依西美坦,他莫昔芬,隨機分組,,,,治療后隨訪,,,,,,,,,2

28、-3 年,2-3 年治療研究,診斷,研究開始,共5年的內分泌治療,IES 031：研究設計,Coombes, ASCO 2006.,56 個月中位隨訪期 超過 99% 的患者完成了治療,超過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),%絕對差異 (95% CI),,,隨訪5年，阿諾新比他莫西芬降低25%的疾病風險！,IES 031結果：無病生存期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%的死亡風險！,IES 031結果：總生存期OS,IES 031結果：減少對側和遠處復發(fā),Coombes. Lancet 2007; 369: 559–70,降低對側乳腺復發(fā)風險43%

31、（P=0.04）降低遠處轉移風險17% （P=0.03）,ABCSG 8研究設計,手術治療,隨機化分組,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）,,,,,,,,轉換分析,序貫分析,Jakesz et al, Lancet 2005,ABCSG 8研究入組條件,可行手術治療的絕經后乳腺癌患者（依據激素水平確定絕經后3年內）≤80 歲雌激素受體

32、陽性（ER+）和/或孕激素受體陽性（PR+）1級或2級導管癌和小葉癌乳腺改良根治術或保乳手術淋巴結手術（前哨淋巴結或腋下淋巴結切除）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)計分析,主要終點 – 無復發(fā)生存期 RFS（局部和遠處復發(fā)病灶、對側乳腺癌、非復發(fā)相關性死亡）（不同于DFS）次要終點 – 總生存期 OS（各種原因導致的死亡） – 安全性分析,ABCSG 8研究：無復發(fā)生

33、存率RFS序貫樣本、交叉分析、截尾數據,所有患者HR=0.815年齡60歲 HR＝0.814ER和PR低表達 HR＝1.083ER和PR高表達 HR＝0.6861級 HR＝0.832級或小葉癌 HR＝0.803,時間（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,無復發(fā)生存率（月）,TAM 序貫,危險比和可信限,ABCSG 8研究：總生存期總樣本，交叉分析，截尾數據,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,復旦大學腫瘤醫(yī)院乳腺癌研究所,44,BIG 1-98 Sequential Treatment Disease-Free Survival,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(yī)院乳腺癌研究所,后期伸展AI治療,48,,復旦大學腫瘤醫(yī)院乳腺癌研究所,MA-17,49,復旦大學腫瘤醫(yī)院乳腺癌研究所,LHRH類似物－激動劑,“諾雷德” 長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“諾雷德”同其它LHRH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。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后水平。,50,復旦大學腫瘤醫(yī)院乳腺癌研究所,Discovery of ‘Zoladex’,‘Zoladex’,LHRH,Thick bonds indicate modifications,Ser(But),Azgly,51,復旦大學腫瘤醫(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,復旦大學

46、腫瘤醫(yī)院乳腺癌研究所,諾雷德與三苯氧胺聯合應用,A Meta-Analysis of Four Randomized Trials,53,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(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,復旦大學腫瘤醫(yī)院乳腺癌研究所,,ABCSG-12 試驗設計,1999-2006年1,803例絕經前乳腺癌患者內分泌治療有效 (ER和/或PR陽性)I&II期, <10個淋巴結轉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個月 2008年3月: 137例首次DFS事件，42例死亡 - 30例局部復發(fā) - 70例遠處轉移

55、 包括40例骨轉移事件 - 16 例對側乳腺癌 - 19 例非乳腺原發(fā)腫瘤 總計: 4年無病生存率: 92.4%; 4年總生存率: 97.7%,試驗情況,61,,,,,,,,,,,,,,,,,,,,,,,,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,隨機分組后的時間，月,無疾病生存率, %,風險比 (95% CI)發(fā)生數vs TAMP 值AN

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: 無疾病生存TAM和ANA之間無顯著差異,,,,,,,,,,,,,,,,,,,,,,,,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),,無復發(fā)死亡,,繼發(fā)惡性腫瘤,,對側乳腺癌,,遠處轉移,,局部復發(fā),第一事件病人人數,TAM vs ANA,首次DFS事件 (意向治療人群),無復發(fā)生存,總生存,隨機分組后時間，月,,,,,,,,,,,,,,,,,,,,,,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,總生存, %,,,風險比 (95% CI)

58、發(fā)生數vs TAMP 值ANA271.791 (0.95 to 3.37).065TAM15,,危險患者數,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: ANA vs. TAM,,,,,,,,

59、,,,,,,,,,,,,,,,,100,90,80,70,60,50,40,30,20,10,0,0,12,24,36,48,60,72,84,隨機分組后時間，月,無疾病生存, %,風險比 (95% CI)發(fā)生數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：無疾病生存與單獨內分泌治療相比，合用唑來膦酸顯著改善DFS,兩者在DFS, RFS或OS方面無顯著性差異 - 這可能是因為絕經前患者使用戈舍瑞林強烈的卵巢抑制作用ANA與TAM相比，潛在的威脅生命的嚴重不良反應更少見,,子宮息肉,,血栓形成,絕經前婦女使用芳香化酶抑制劑的明確指南出臺前，還需要進一步的試驗 - 正在進行的內分泌治療聯合卵巢抑制輔助治療的