科室小讲课-乳腺癌的内分泌治疗.ppt

,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,*,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,乳腺癌的内分泌治疗,乳腺癌内分泌治疗的范畴,乳腺癌的内分泌治疗即应用手术、放疗或者药物，降低体内雌激素水平或者阻断雌激素和激素受体的结合，从而阻断雌激素对激素依赖性乳腺癌细胞增殖的促进作用，达到抑制肿瘤生长的目的。,卵巢切除术,卵巢放疗法,人工合成己烯雌酚,三苯氧胺,孕激素,LHRH,类似物,糖皮质激素,分离雌激素受体,3 AIs,氟维司群,托瑞米芬,乳腺癌内分泌治疗的百年历史,1896,1922,1944,1977,1951,1990,1958,1966,1990s,2002,1989,Lancet.1996,348(9036):1189-1196.,1896,年，,Beatson,博士切除患者双侧卵巢治疗,2,例绝经前晚期乳腺癌，其中一例在术后,8,个月肿瘤全部消退。此结果在,1896,年,Lancet,杂志上报道，引起业界广泛关注，自此悄然拉开乳腺癌内分泌治疗帷幕。,100,年后证实：经典卵巢切除术可提高晚期乳腺癌生存获益,Pre/,Po,stmenopausal oestrogen production,LHRH,(hypothalamus),ACTH,Adrenal,glands,Pituitary gland,Androgens Oestrogens,Peripheral conversion(aromatase enzyme),AIs,ACTH,adrenocorticotrophic,hormone,;,LHRH,luteinising hormone-releasing hormone,促性腺激素,(FSH+LH),TAM,LHRH-A,主要内容,复发和转移性乳腺癌患者的姑息性内分泌治疗,早期乳腺癌患者的辅助性内分泌治疗,乳腺癌高风险人群的预防性内分泌治疗,乳腺癌内分泌治疗的几个相关问题,转移性乳腺癌的流行病学,M1=distant metastasis(including metastases,cervical,or,contralateral,internal mammary lymph nodes),20-40%,的可手术乳腺癌最终会出现复发和转移,5%,左右的乳腺癌患者初诊时已有远处转移,一线内分泌治疗与化疗疗效类似,9,SD,的病人仍可获得较长的,OS,10,内分泌治疗优先的原因,一线内分泌治疗与化疗疗效类似,内分泌治疗,SD,的病人仍可获得较长的,OS,内分泌治疗毒副作用小,无多药耐药现象,简便经济,绝经前晚期乳癌的内分泌治疗,TAM,OA/OS,OA/OS+TAM,OA/OS+AI,12,TAMOA/OS,（,绝经前,）,Authors,n,Regimens,RR,%,TTP,days,Ingle,54,OS/TAM,37 vs 27,476 vs 453,Buchanan,122,OS/TAM,21 vs 24,410 vs 600,Sawka,39,OS/TAM,15 vs 25,184 vs 126,Oncology 2008;75(3-4):192-202,三个小样本随机研究一致显示：一线治疗,HR+,或不明的,MBC,，,OS,与,TAM,疗效无差异,TAMOA/OS,（,绝经前,）,1997,年一项,Meta,分析：一线治疗,ER+,或不明的,MBC,，采用卵巢去势（手术或放疗）或口服,TAM,，,疗效相似,（按,RR,和,TTP,）,Breast Cancer Res Treat 1997;44:201210,Klijn JGM,et al.JNCI,2000;92:903-11.,中位随访,7.3,年,LHRH,*,(n,=54),LHRH+Tam,(,n,=53),OR(CR+PR),34%,42%,PFS(months),6.3,9.7,OS(years),2.5,3.7,LHRH,+TAM only One,（绝经前）,*Buserelin,Tam,(n,=54),28%,5.6,2.9,p LHTH,LHRHa+tamoxifen(,n,=250),LHRHa(,n,=256),100,80,60,40,20,0,0,2,4,6,8,10,12,Years,OS(%),100,80,60,40,20,0,0,2,4,6,8,10,12,Years,PFS,(%),Median follow-up of 6.8 years,Median PFS,LHRH5.4 months,LHRH+tam 8.7 months,HR=0.70;,P,诺雷得,+,他莫昔芬,Milla-Santos A et al,S32.,OR=0.28,P=0.0023,PD,缓解率,%,53%,80%,0%,20%,40%,60%,80%,100%,他莫昔芬,阿那曲唑,OS(,月,),14.3,18.9,0,5,10,15,20,他莫昔芬,阿那曲唑,HR=0.41,P=0.0001,AIs,+OS,也是绝经前,MBC,一种合理选择。,绝经后晚期乳癌的内分泌治疗,TAM,AI,FASLODEX,18,AIs vs TAM in MBC,19,绝经后晚期乳癌的内分泌治疗,Adjuvant,1st-line,2nd-line,AI,1.TAM,2.Fulvestrant,1.,Fulvestrant,2.TAM,3.AI,TAM,AI,or,Fulvestrant,Fulvestrant or AI*,TAMAI,Fulvestrant,AI*,20,如何进一步提高,HR,阳性晚期乳腺癌一线,内分泌治疗的效果,21,AIs+capecitabine as first-or second-line treatment in MBC,ASCO 2012,Abs.e11016,临床前资料显示：两者具有协调作用。机制可能是卡培他滨降低雌激素产生,HR+MBC,n=93,AIs,n=29,卡培他滨,n=27,AIs+,卡培他滨,n=37,PFS,，月,一线,二线,13.0,13.0,3.0,6.0,not-reached,2,年,既往,TAM,治疗,vs,未接受过,TAM,治疗,随,机,来曲唑,2.5mg PO QD,+,达沙替尼,100mg PO QD,来曲唑,2.5mg PO QD,如果出现疾病进展交叉至达沙替尼,+,来曲唑,S3-07,主要研究终点：临床获益率,最佳总体缓解,来曲唑,+,达沙替尼（,n=56,）,来曲唑（,n=61,）,N,（,%,）,95%CI,N,（,%,）,95%CI,CR,1(2),0-10,PR,12(21),12-34,15(25),15-37,SD,32(57),43-70,30(49),36-62,PD,7(13),5-24,16(26),16-39,NE,4(7),2-17,0,0,CBR*,40(71),58-83,40(66),52-77,*CBR=CR+PR+(SD6,月,),方案规定的可评价人群定义为接受研究治疗的合格入组患者（,3,例患者不符合入组标准）,35,例,PD,的患者自,L,组交叉至,L+D,：交叉患者的,CBR=23%,（,8/35,）；,95%CI:10%-40%,S3-07,无进展生存期（,ITT,人群）,S3-07,研究结论,一线,AI,治疗的转移性乳腺癌接受来曲唑,+,达沙替尼的,CBR,达到,71%,；与来曲唑单药的,CBR,（,66%,）没有差异,在这个,II,期非对照、平行研究中，来曲唑,+,达沙替尼治疗的患者的中位,PFS,达到,20.1,月，来曲唑治疗组的中位,PFS,为,9.9,月,这些发现提示达沙替尼可能抑制,AI,治疗的获得性耐药的产生,S3-07,主要内容,复发和转移性乳腺癌患者的姑息性内分泌治疗,早期乳腺癌患者的辅助性内分泌治疗,乳腺癌高风险人群的预防性内分泌治疗,乳腺癌内分泌治疗的几个相关问题,辅助内分泌治疗的目的,Chlebowski R,et al.Breast 2009;S*:S1-S11.,减少,死亡,避免因复发,而导致的,生活质量恶化,治疗目的,避免,复发,他莫昔芬：既往辅助,ET,的标准药物,对照组,45.0%,38.3,26.5,5,年三苯氧胺组,33.2%,24.7,15.1,60,50,40,30,20,10,0,0,5,10,15,随访时间,(,年,),复,发,率,(%),15,年的收益为,11.8%(SE 1.3)Logrank 2p0.00001,60,50,40,30,20,10,0,0,5,10,15,对照组,34.8%,5,年三苯氧胺组,25.6%,25.7,17.8,11.9,8.3,15,年的收益为,9.2%(SE 1.2)Logrank 2p0.00001,60,50,40,30,20,10,0,0,5,10,15,随访时间,(,年),死,亡,率,(,%),EBCTCG.Lancet 2005;365:1687-1717,ZEBRA:,研究设计,N=1640;PremenopausalLymph node positiveER+/ER-,CMF x 6 cycles,Goserelin 3.6 mg q 28 days x 2 yrs,Randomization,Median follow-up:7.3 yrs,Kaufmann M,et al.Eur J Cancer.2003;39:1711-1717.,ZEBRA:ER+,亚组无病生存,(DFS),Reprinted from Kaufmann M,et al.Eur J Cancer.2003;39:1711-1717,with permission from Elsevier.,HR:1.05;95%CI:0.88-1.24,Time(Years),0,1,2,3,4,5,6,7,8,9,10,60,59,112,126,181,187,265,263,342,333,397,380,429,427,486,470,559,537,598,591,Patients at risk at the start of each year,0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,(a)1.0,Proportion Alive and Disease Free,GoserelinCMF,OS/OA,对绝经前早期乳癌的意义,-,单用,OS/OA,绝对降低复发危险,11.5%,0,5,10,15,20,years,Control,52.2%,40.8%,Ovarian ablation or suppression,20-y gain 11.5%(SE 2.6),Logrank 2p 0.00001,Recurrence,Entry age 50,0,10,20,30,40,50,60,Recurrence%,OS/OA vs not,No chemo,2006 EBCTCG,41.0%,32.4%,IBCSG VIII:ER+N0,亚组的,DFS,年龄分层,年龄,40,岁，,5-yr DFS 3,组疗效相同。,CMF+goserelin,89%;goserelin,85%;CMF,85%(,P,=.90),CMF+goserelin,明显改善,39,岁乳癌患者,5-,年,DFS,CMF+goserelin,88%;goserelin,63%;CMF,62%(,P,=.04),Castiglione-Gertsch M,et al.J Natl Caner Inst.2003;95:1833-1846.,J Natl Cancer Inst,2003;95:1833,46,n=1111,HR+,68%,LN,surgery,radiotherapy,Gos(18m)+CMF6,From 1990 to 1999,mFU=84m,R,CMF6,Gos(24m),0,1,2,3,4,Years since randomization,0,20,40,100,Disease-free survival%,60,87%,5y-DFS,CMF+Gos,80,5,6,7,8,CMF,82%,RR=0.80(0.57-1.11),p=0.17,0,1,2,3,4,Years since randomization,0,20,40,100,60,85%,5y-DFS,CMF+Gos,80,5,6,7,8,CMF,64%,RR=0.34(0.14-0.87),p=0.02,(ALL),(40 yr),OS+CMF vs CMF,IBCSG VIII trial,E5188/INT 0101:40,岁,DFS,加,Zoledex,改善,40,岁,DFS,CAF-ZT,9-year DFS:64%,CAFZ 9-year DFS:55%,CAF 9-year DFS:48%,表明增加卵巢去势可能增加年轻患者疗效,Davidson NE,et al.J Clin Oncol.2005;23:5973-5982.,0,2,4,6,8,10,0,0.2,0.4,0.6,0.8,1.0,probability,CAFZ,CAF,DFS(years),9yr DFS,60%,57%,E5188,研究结论：,1,、加,Z,至,CAF,中,不能,改善预后,2,、,40,岁以下,患者有益,JCO,2005,23:5973,HR=0.93,p=0.22,0,2,4,6,8,10,0,0.2,0.4,0.6,0.8,1.0,probability,CAFZ,CAF,DFS(years),9yr DFS,55%,48%,HR=0.78,p 0.01,40 yr,All,CAF+Gos vs CAF,INT 0101(E5188)trial,40,岁以下女性从卵巢功能抑制中获益,复发率,LHRH+,化疗,vs,化疗,乳腺癌死亡率,LHRH+,化疗,vs,化疗,年龄,40,岁,年龄：,40-49,岁,0,0.5,1.0,1.5,2.0,0,0.5,1.0,1.5,2.0,年事件发生率比值,年事件发生率比值,OA/OS,更好,OA/OS,更差,OA/OS,更好,OA/OS,更差,Lancet,2005,365:1687-1717,0.70,1.08,0.80,哪些患者更有可能从,OFS/OA,治疗中获益,?,探索性分析表明,ZOLADEX,的应用对下列患者有额外获益的趋势,40,岁的患者,雌激素仍维持在绝经前水平的患者,化疗后未闭经的患者,不同临床研究中,LHRHa,的治疗时间,研究名称,治疗时间,ZEBRA,2,年,IBCSG VIII,2,年,ZIPP,2,年,ABCSG 12,3,年,INT 0101,5,年,2007,年早期乳腺癌的主要治疗全球专家共识,绝经前乳腺癌的内分泌治疗,他莫昔芬联合卵巢功能抑制或他莫昔芬单药是标准内分泌治疗,专家组强烈支持,LHRHa,作为卵巢功能抑制的重要方法,专家组倾向于,LHRHa,最合适的使用时间是,5,年,尤其在复发高危人群和,/,或,HER-2,阳性患者中,Goldhirch A et al,Annals of Oncology 2007;18:1133-1144.,ABCSG-12,Gnant M,et al.ASCO 2008.Abstract LBA4.,研究设计：,入组时间,1999-2006,年,1,803,例,（,ER,和,/,或,PR,阳性）绝经前乳腺癌患者,I,期或,II,期，阳性腋窝淋巴结,ANA+,戈舍瑞林,Lancet Oncol.2011,12:631-41,DFS,OS,戈舍瑞林联合,TAM,vs.,联合,AI,P,0.05,戈舍瑞林联合,TAM,明显优于联合阿那曲唑,P,0.05,Adjuvant trials involving ovarian function suppression+AI,ABCSG 12,SOFT,TEXT,PERCHE,PROMISE,主要内容,LHRHa,降低化疗所致的卵巢功能衰竭的,III,期研究,（,POEMS/S0230,研究）,2,依西美坦,/,他莫昔芬联合卵巢功能抑制治疗绝经前,HR+,早期乳腺癌随机研究（,TEXT&SOFT,联合分析）,1,3,3,肥胖对绝经前,HR+,早期乳腺癌患者预后的影响,（回顾性分析,EBCTCG 70,项研究）,Pagani O,et al.2014 ASCO Abstract LBA1.,N,ENGL,J,MED,2014,June 1,比较依西美坦,/,他莫昔芬联合卵巢功能抑制治疗绝经前,HR+,早期乳腺癌的随机,III,期研究：,IBCSG TEXT&SOFT,联合分析,研究背景：,绝经前内分泌治疗现状,绝经前激素受体阳性乳腺癌最佳辅助内分泌治疗方案目前仍不确定,五年或五年以上的他莫昔芬是目前的标准治疗,卵巢功能抑制可以作为额外治疗,IBCSG,设计了,TEXT,和,SOFT,研究寻找和验证绝经前激素受体阳性乳腺癌的最佳内分泌治疗选择,TEXT&SOFT,研究的问题,绝经前激素受体阳性乳腺癌患者中联合卵巢功能抑制的情况下，依西美坦在改善无病生存率方面是否优于他莫昔芬？,评价在适合应用辅助,TAM,治疗的患者中，卵巢功能抑制的作用,本次研究结果报告了随访,68,个月后，,TEXT,及,SOFT,比较依西美坦,+OFS,和,TAM+OFS,疗效及安全性的联合分析结果,TEXT&SOFT,：研究设计,目的：评估绝经前激素受体阳性乳腺癌女性最佳的内分泌治疗，即辅助,AI(,依西美坦,),联合,OFS,是否较他莫昔芬联合,OFS,能改善,DFS,分层因素：化疗与否、淋巴结状态（阳性或阴性）、,OFS,方案（仅,SOFT,研究）,他莫昔芬,+OFS 5,年,依西美坦,+OFS 5,年,合并分析,(N=4690),中位随访,5.7,年,OFS=,卵巢功能抑制,Pagani O,et al.2014 ASCO Abstract LBA1.,绝经前,手术后,12,周,计划,OFS,可进行化疗（与,OFS,同步）,随机,TEXT(N=2672),他莫昔芬,+OFS 5,年,依西美坦,+OFS 5,年,绝经前,手术后,12,周,无化疗,或,化疗后,8,个月保持绝经前状态,随机,SOFT(N=3066),他莫昔芬,+OFS 5,年,依西美坦,+OFS 5,年,他莫昔芬,5,年,TEXT&SOFT,：主要入组标准,绝经前激素受体阳性,(ER,和,/,或,PgR,1,0%),的浸润性乳腺癌，限于乳房,腋窝淋巴结,接受合理的局部区域治疗且无残留疾病,TEXT,研究中所有患者于术后,12,周内接受随机,SOFT,研究中未接受化疗的患者于术后,12,周内接受随机,SOFT,研究中既往接受,(,新,),辅助化疗的患者，当证明为绝经前状态时，在完成化疗,8,个月内接受随机,SOFT,研究中允许在随机前接受口服内分泌药物治疗,Pagani O,et al.2014 ASCO Abstract LBA1.,TEXT&SOFT,：治疗,OFS,（卵巢功能抑制）,TEXT,所有患者开始曲普瑞林治疗,(3.75 mg,IM q28d),如有患者接受化疗，化疗与曲普瑞林同步,曲普瑞林治疗,6,个月后，可选择双侧卵巢切除术或放疗作为替代方法,SOFT,曲谱瑞林治疗、双侧卵巢切除或卵巢放疗,口服内分泌治疗,依西美坦,25mg/d,或他莫昔芬,20mg/d,TEXT,研究中,如有患者接受化疗，化疗与曲普瑞林同步；待化疗结束后，开始内分泌治疗,如不接受化疗，在曲普瑞林治疗,6-8,周开始内分泌治疗,如有适应症，允许患者接受辅助曲妥珠单抗；推荐每年进行乳房,X,线摄影和骨密度检测；不允许接受双磷酸盐，,T,评分,-1.5,或患者参与随机辅助研究除外,Pagani O,et al.2014 ASCO Abstract LBA1.,TEXT&SOFT,：终点,主要终点：,无疾病生存（,DFS,）,包括出现浸润性复发,(,局部、区域、远处,),、对侧浸润性乳腺癌、继发,(,非,乳腺,),浸润性恶性肿瘤、非肿瘤事件造成的死亡,次要终点：,无乳腺癌间期,(BCFI),：浸润性复发或对侧浸润性乳腺癌,无远处复发间期,(DRFI),：远处复发,总生存期,(OS),：任何原因导致的死亡,Pagani O,et al.2014 ASCO Abstract LBA1.,从人口统计学特征来看，入组人群同时涵盖了,:,40,岁年轻患者（,27%,）,；,40,岁以上,(73%),淋巴结阳性,(42%),；淋巴结阴性,（,58%,）,肿块,2cm,以上,(36%),；,2cm,及以下,(64%),HER2,阳性,(12%),；,HER2,阴性,(88%),TEST,和,SOFT,研究中小于,40,岁年轻患者中未接受化疗的占全部入组患者,5%,，接受化疗的占全部入组患者,21.6%,SOFT,研究中，接受化疗的患者从手术到入组的中位时间约为,8,个月；接受化疗的患者中年龄小于,40,岁的比例较,TEXT,研究高，占,49.3%,；同时淋巴结阴性的患者比例亦较高。,入组患者特征统计,TEXT&SOFT,：患者特征,无化疗,TEXT,(n=1053),无化疗,SOFT,(n=943),化疗,TEXT,(n=1607),既往化疗,SOFT,(n=1087),总体,(n=4690),年龄,2cm(%),19,15,53,47,36,HER2,阳性,(%),5,3,17,19,12,中位手术至随机时间,(,月,),1.5,1.8,1.2,8.0,1.6,Pagani O,et al.2014 ASCO Abstract LBA1.,TEXT&SOFT,：依西美坦联合,OFS,改善,DFS,DFS(%),时间,(,年,),依西美坦,+OFS(n=2346),他莫昔芬,+OFS(n=2344),P=0.0002,HR=0.72(0.60-0.85),91.1%,87.3%,100,80,60,40,20,0,0,1,2,3,4,5,6,5,年,DFS,差异,3.8%,中位随访,5.7,年,Pagani O,et al.2014 ASCO Abstract LBA1.,TEXT&SOFT,：依西美坦联合,OFS,降低复发,依西美坦联合,OFS,的,5,年无乳腺癌事件绝对获益,4%,（,P0.0001,）,目前两组总生存期分析未见统计学差异，考虑成熟度问题，需待后续继续分析,Pagani O,et al.2014 ASCO Abstract LBA1.,BCFI,(%),时间,(,年,),E+OFS(n=2346),T+OFS(n=2344),P97%,Pagani O,et al.2014 ASCO Abstract LBA1.,100,80,60,40,20,0,0,1,2,3,4,5,6,TEXT,（无化疗）,BCFI(%),E+OFS(n=526),T+OFS(n=527),HR=0.41(0.22-0.79),时间,(,年,),94.6%,97.6%,100,80,60,40,20,0,0,1,2,3,4,5,6,SOFT,（无化疗）,BCFI(%),E+OFS(n=470),T+OFS(n=473),HR=0.53(0.26-1.06),时间,(,年,),94.8%,97.5%,16%2cm,，,21%,淋巴结阳性,9%2cm,，,8%,淋巴结阳性,N=1996,TEXT&SOFT,：接受化疗亚组,依西美坦联合,OFS,的绝对获益：,5,年无乳腺癌：,TEXT,研究,5.5%,，,SOFT,研究,3.9%,5,年无远处复发：,TEXT,研究,2.6%,，,SOFT,研究,3.4%,时间,(,年,),时间,(,年,),时间,(,年,),时间,(,年,),100,80,60,40,20,0,0,1,2,3,4,5,6,100,80,60,40,20,0,0,1,2,3,4,5,6,100,80,60,40,20,0,0,1,2,3,4,5,6,100,80,60,40,20,0,0,1,2,3,4,5,6,BCFI(%),BCFI(%),DRFI(%),DRFI(%),化疗,TEXT,既往化疗，,SOFT,化疗，,TEXT,既往化疗，,SOFT,E+OFS(n=806),T+OFS(n=801),HR=0.64,(0.48-0.85),E+OFS(n=544),T+OFS(n=543),HR=0.82,(0.60-1.12),E+OFS(n=806),T+OFS(n=801),HR=0.77,(0.56-1.06),E+OFS(n=544),T+OFS(n=543),HR=0.81,(0.56-1.13),88.0%,84.6%,91.8%,89.2%,86.1%,82.2%,91.5%,86.0%,30%2cm,，,66%,淋巴结阳性,49%2cm,，,57%,淋巴结阳性,Pagani O,et al.2014 ASCO Abstract LBA1.,TEXT&SOFT,：部分不良事件,依西美坦,+OFS(n=2318),他莫昔芬,+OFS,(n=2325),CTCAE v3.0,1-4,级,3-4,级,1-4,级,3-4,级,抑郁,(%),50,3.8,50,4.4,肌肉骨骼,(%),89,11,76,5.2,骨质疏松,(T-2.5)(%),39(13),0.4,25(6),0.3,骨折,(%),6.8,1.3,5.2,0.8,高血压,(%),23,6.5,22,7.3,心肌缺血,/,梗死,(%),0.7,0.3,0.3,0.1,血栓形成,/,栓塞,(%),1.0,0.8,2.2,1.9,CNS,缺血,(%),0.7,0.3,0.3,0.1,CNS,出血,(%),0.6,0.1,0.9,0.1,热潮红,(%),92,10,93,12,出汗,(%),55,-,59,-,阴道干燥,(%),52,-,47,-,性欲减退,(%),45,-,41,-,精神性性交困难,(%),31,2.3,26,1.4,尿失禁,(%),13,0.3,18,0.3,Pagani O,et al.2014 ASCO Abstract LBA1.,TEXT&SOFT,：不良事件与生活质量,不良事件特征与绝经后女性相似,预期的,3-4,级不良事件发生率相似,31%&29%,依西美坦联合,OFS,组出现更多的早期中止治疗事件,16%vs.11%,患者自述报告存在差异，但两组总体生活质量相似,Pagani O,et al.2014 ASCO Abstract LBA1.,TEXT&SOFT,联合分析结论,相比于他莫昔芬联合,OFS,，依西美坦联合,OFS,显著改善,DFS,、,BCFI,与,DRFI,，是绝经前激素受体阳性早期乳腺癌患者新的治疗选择,两组总生存期无显著性差异，但该结论还为时过早，需继续随访,依西美坦联合,OFS,的,AE,特征与,AI,治疗绝经后女性相似,部分确诊为绝经前激素受体阳性的乳腺癌患者有非常良好的预后，对单纯的内分泌治疗效果显著,需要长期随访,Pagani O,et al.2014 ASCO Abstract LBA1.,BIG1-98-DFS,IES 031-DFS,ATAC,TEXT&SOFT,研究中绝经前乳腺癌患者使用依西美坦,OFS,治疗与他莫昔芬,+OFS,治疗相比，在改善疾病复发及乳腺癌复发方面与既往,AI,在绝经后人群中与他莫昔芬比较所得到的结果类似。,讨论,1,：,绝经前,vs.,绝经后,（,TEXT&SOFT vs.BIG1-98/ATAC/IES031,）,TEXT&SOFT,TEXT&SOFT,讨论,2,：,绝经前,vs.,绝经前,（,TEXT SOFT vs.ABCSG-12,）,ABCSG-12,HR=1.08,95%CI(0.811.44);p=0.591,TEXT&SOFT,ABCSG-12,DFS,依西美坦,+OFS,显著优于他莫昔芬,+OFS,阿那曲唑,OFS,与他莫昔芬,OFS,无统计学差异,OS,依西美坦,OFS,与他莫昔芬,OFS,无统计学差异,阿那曲唑,OFS,显著低于他莫昔芬,OFS(HR=1.75,95%CI(1.082.83);p=0.02),AI,在绝经后的研究设计,他莫昔芬,(N=2459),来曲唑,(N=2463),来曲唑,BIG 1-98,依西美坦,TEAM,他莫昔芬,(N=4868),依西美坦,(N=4898),1,2,3,4,5,阿那曲唑,ATAC,他莫昔芬,(N=3116),阿那曲唑,(N=3125),绝,经,后,早,期,乳,腺,癌,IES,研究阳性结果,依西美坦,年,ATAC,研究结果（,100,月中位随访时间）,ATAC Trialists Group.Lancet 2005;365:60-62.,The ATAC Trialists Group,Lancet Oncol 2008;9:45-53.,ER+,人群,(,占所有人群,83%),0.76(0.67-0.87),P=0.0001,0.84(0.72-0.97),P=0.022,阿那曲唑更有利,他莫昔芬更有利,HR(95%CI),100,个月,0.85(0.76-0.94),P=0.003,DFS,TTR,TTDR,68,个月,HR 0.83,P=0.005,HR 0.74,P=0.0002,HR 0.84,P=0.06,BIG 1-98 Monotherapy UpdateMedian Follow-up 76 months,*Let:Tam:breast cancer events,321:363,second(non breast)malignancy,101:115,deaths without prior cancer event,87:87,AI vs.,他莫昔芬：直接比较,(n=9856),他莫昔芬,AI,治疗,5,年,R,Ingel J et al,presented at 8th San Antonio Breast Cancer Symposium,Trials,ATAC,BIG 1-98,5,年,AI vs.TAM,ER+,荟萃分析结果：序贯对照,相关研究,GABG/ARNO,BIG 2-97/IES,ABSCG 8,Ingel J et al,presented at 31th San Antonio Breast Cancer Symposium,他莫昔芬,AI,治疗,2-3,年,R,他莫昔芬,治疗,2-3,年,MA27,研究方法：,绝经后,ER,阳性早期乳腺癌患者开放随机对照研究,阿那曲唑起始治疗,5,年对比依西美坦起始治疗,5,年,Percentage,#At Risk,Anastrozole,Exemestane,Anastrozole,Exemestane,0,60,40,20,MA.27,临床预后,(EFS),80,时间,(,年,),#At Risk(Anastrozole),#At Risk(Exemestane),0,3787,3789,1,3674,3655,2,3487,3461,3,3182,3190,4,2190,2230,5,723,734,6,56,52,中位随访,4.1,年,分层,HR:1.02(0.87-1.18)p=0.85,Exemestane,n(%),Anastrozole,n(%),P-,value,3761(100),3759(100),2051(55),253(7),649(17),40(1),53(1),47(1),59(2),12(0),36(1),38(1),32(1),72(2),80(2),577(15),1171(31),358(10),136(4),2101(56),231(6),606(16),61(2),23(1),19(1),24(1),3(0),11(0),32(1),38 (1),46(1),124(3),665(18),1304(35),354(9),136(4),0.24,0.32,0.19,0.04,0.001,0.001,0.0001,0.04,0.0001,0.55,0.47,0.02,0.002,0.01,0.001,0.91,0.98,潮热,关节炎,/,关节痛,肌肉痛,阴道出血,ALT,AST,胆红素,痤疮,雄性化,心梗,中风,/,一过性脑缺血,/TIA,房颤,高甘油三酯,a,高胆固醇,骨质疏松,任何临床骨折*,脆