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1、乳癌内分泌治疗新思路和临床实践,乳癌的治疗手段,Surgery 手术Radiation therapy 放疗Chemotherapy 化疗Hormone therapy 内分泌治疗Biotherapy 生物治疗New therapies 新的治疗,乳癌内分泌治疗的发展,1970,1980,1990,2000,Tamoxifen,Tamoxifen,MAAG,新的芳香化酶抑制剂,Exemestane/MA,新的芳香化酶抑制剂,Tamoxifenpure A.E.?,MA,III,I,II,III,Hormone Therapy Response Rate(%)in Different Recep
2、tor Status,Survival by Response Arimidex 1 mg,0,20,40,60,80,100,0,1,2,3,4,CR or PR,Stable,24 wks,Progression,Years from Randomisation,%Survival,MAAG,Prevention DCIS/Neoadj,5 years,MetastaticDisease,1st,2nd,3rd,Adjuvant,TAM,TAM,TAM,TAM,OVABL,三苯氧胺（TAM)最重要的乳癌内分泌治疗药物,Tamoxifen for 5 Years vs No Treatmen
3、t,Percent,Years,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),68.2%,54.9%,0,20,40,60,80,100,0,5,10,15,vs,Recurrences,Breast Deaths,0,20,40,60,80,100,0,5,10,15,ER+,73.0%,64.0%,91.4,80.9,73.0,87.8,73.2,64.0,3.6(SE 0.7),7.8(SE 1.0),9.0(SE 1.4),vs,Years,Percent,8,Tamoxifen Adj
4、uvant Therapy for EBC辅助内分泌治疗的决定因素是激素受体状况ER阳性效果最好,9,Tamoxifen Adjuvant Therapy for EBC合适的TAM服药时间为5年,10,Tamoxifen Adjuvant Therapy for EBC ER阳性无论年龄大小都可用TAM,11,Tamoxifen Adjuvant Therapy for EBC降低对侧乳癌发生增加子宫内膜癌的风险,Tamoxifen Adjuvant Therapy for EBC ER阳性TAM和化疗合用比单用TAM更有效CAF与TAM 序贯合用比同时效果更好,MAAG,Preventio
5、n DCIS/Neoadj,5 years,MetastaticDisease,1st,2nd,3rd,Adjuvant,1,TAM,TAM,TAM,TAM,OVABL,TamoxifenIndications in Breast Cancer,三苯氧胺 乳癌内分泌治疗不可动摇的地位！？,Survival DataAnastrozole/MA,Median time to death(months),2 year survival rate(%),P 0.05,瑞宁得用药9个月没有明显的体重变化,瑞宁得(Arimidex)比 MA更有效、更安全,瑞宁得(Arimidex)1 mg 在复发转移乳
6、癌治疗中缓解率/临床获益率相当生存期更长耐受性更好,Prevention DCIS/Neoadj,5 years,MetastaticDisease,1st,2nd,3rd,AI,AI,Adjuvant,TAM,TAM,TAM,TAM,1,Arimidex in Breast Cancer,MA,Anastrozole is Superior to Tamoxifen in First Line Therapy（0030）,JCO 2000;18:3748,*Hazard ratio(tam:Arimidex)1.44,lower CL 1.16.Study powered for equiv
7、alence.Median follow-up of 18 months.71%progressed,Trial 0030:Kaplan-Meier Curve of Probability of Time to Progression,AIs is Superior to Tamoxifenas First-line Therapy for Advanced Breast Cancer,芳香化酶抑制剂取代三苯氧胺成为标准的一线内分泌治疗,Prevention DCIS/Neoadj,5 years,MetastaticDisease,AI,1st,2nd,3rd,AI,AI,Adjuvant
8、,TAM,TAM,TAM,TAM,1,Arimidex in Breast Cancer,MA,Rationale for Adjuvant Therapy With Aromatase Inhibitors(AIs),AIs Effective after tamoxifenBetter than tamoxifen first lineWell toleratedMay overcome tamoxifen“resistance”,The Gold Standard,Tamoxifen,First-Line Letrozole is Anastrozole is=Exemestane is
9、?Neoadjuvant Letrozole is Adjuvant？Anastrozole,MilestonesActivated1996Planned accrual9366Accrual to dateClosed 1999,Ongoing AI Adjuvant Trials:ATAC(Anastrozole),Trialists Group TA.Br J Cancer.2001;85:317.,RANDOM IZE,Surgery,Tamoxifen 20 mg od,Anastrozole 1 mg od,Tamoxifen 20 mg od,Anastrozole 1 mg o
10、d,5 years,DFS/OS,KaplanMeier Curves of Disease-free Survival in ITT Population,Curves truncated at 42 months,KaplanMeier Curves of Disease-free Survivalin Receptor-positive Population,Curves truncated at 42 months,Predefined adverse events*Hot flushes,A Arimidex T Tamoxifen C Combination,1060,T,C,12
11、29,1243,A,%patients,A vs TC vs TA vs C,0.791.020.78,OR,0.00010.750.0001,p value,A vs TC vs TA vs C,0.520.940.56,0.00010.50.0001,OR,p value,A,T,C,A,Arimidex;C,combination;T,tamoxifen,138,253,238,%patients,Predefined adverse eventsVaginal bleeding,The ATAC Early breast cancer trial in postmenopausal p
12、atientsEndometrial sub-protocol results,Demographics,285 women from 31 centres in 10 countriesMean age 60 yrs(44-80 yrs)Mean age at menopause 50 years80%4 years or more post menopause,Baseline Ultrasound,1,2,3,4,5,6,7,8,9,10,10,0,10,20,30,40,50,60,n,Endometrial thickness(mm),Median endometrial thick
13、ness,0,2,4,6,8,10,0,12,24,Endometrial thickness(mm),ArimidexTamoxifenCombination,Time(months),A vs TC vs TA vs C,0.230.460.50,0.020.110.51,OR,p value,A,T,C,A,Arimidex;C,combination;T,tamoxifen,3,13,6,%patients,Predefined adverse eventsEndometrial cancer,ATAC Summary,Anastrozole is superior to tamoxi
14、fen in terms of:Disease-free survival in:Overall population(HR=0.83)Receptor-positive patients(HR=0.78)Incidence of contralateral breast cancer in:Overall population(OR=0.42),Conclusions,Anastrozole is the first and only AI to show superior efficacy and improved tolerability compared with tamoxifen
15、in the treatment of EBCOverall risk-benefit assessment supports anastrozole becoming the future adjuvant treatment of choice in postmenopausal womenAnastrozole also shows promise for the chemoprevention of breast cancer,Analysis of the Incidence of New(Contralateral)Breast Primaries,Arimidex(Anastro
16、zole)in Breast cancer prevention:Design of IBIS II and data from ATAC,Why use an Aromatase Inhibitor?,At least as effective as tamoxifen in ABCATAC trial provides early warning on side effectsATAC trial provides efficacy data in early breast cancer at all endpoints;striking reduction in contralatera
17、l breast cancer eventsVery low side-effect profile,ATAC:incidence of new(contralateral)breast primaries in ITT population,9 invasive,0,5,10,15,20,25,30,35,Tamoxifen(n=3116),Arimidex(n=3125),Combination(n=3125),5 DCIS,3 DCIS,23invasive,5 DCIS,30 invasive,No.cases,Arimidex vs tamoxifen OR 0.42;95%CI 0
18、.22,0.79;p=0.007Combination vs tamoxifen OR 0.84;95%CI 0.51,1.40;p=0.51,Women-years of follow-up per arm 3100 x 2.8=8600 Rate of contralateral tumours in womennot treated with tamoxifen(women-years)Expected contralateral tumoursObserved on tamoxifen46%reductionObserved on Arimidex77%REDUCTION,ATAC:p
19、rojected contralateral tumour reduction rate for Arimidex,7/1000613314,IBIS I Tamoxifen in prevention,Breast cancer incidence is reduced by 32%,101(placebo)vs 69(TAM)OR 0.68 p=0.01,IBIS II:Prevention,High-risk postmenopausal women,aged 40-70 years2-arm trial for high-risk patients5-year treatment,pl
20、acebo controlled,N=6000 high-risk patients,IBIS II:DCIS,Women,aged 40-70 years,who have had DCIS diagnosed within the previous 6 months2-arm trial(no placebo arm)5-year treatment,2 tablets/day,N=4000,NSABP,NSABP centres:USA and Canada Double-blind randomized studyPostmenopausal(n=3000),Start date:Q4
21、 2002,Randomize1:1,5 years anastrozole1 mg od,5 years tamoxifen20 mg od,Prevention DCIS/Neoadj,5 years,MetastaticDisease,AI,1st,2nd,3rd,AI,AI,Adjuvant,TAM,TAM,TAM,TAM,1,Arimidex in Breast Cancer,MA,AI,绝经后绝经前？,AI,AI,绝经前乳癌内分泌治疗,卵巢去势,绝经前,抗芳香化酶 瑞宁得（阿那曲唑）氟隆 依西美坦,绝经后,卵巢切除加口服依西美坦治疗绝经前乳腺癌骨转移长期缓解,霍秀兰，女，41岁，住
22、院号50982 2001.2 多发骨转移，左锁上淋巴结转移，穿刺活检ER(+)PR(+)Her-2(+)因患者未停经，予以双侧卵巢切除术，1月后骨痛症状改善，骨质修复；2001.5.11口服依西美坦，2001.6.6 骨痛进一步减轻，疗效评价：PR,Zoladex 诺雷得 用于绝经前乳腺癌患者的治疗,Zoladex与卵巢切除术治疗复发转移乳癌效果比较,Zoladex 3.6mg 用于绝经前进展期乳腺癌II期临床试验,资料来源于 29 个 II期临床试验(n=228)CR+PR=36.4%中位缓解间期=22 周耐受性好，未出现因不良反应退出抑制雌激素的药理作用是常见的面部潮红(75.9%)性欲减
23、退(47.4%),Klijn JGM,et al.J Clin Oncol 2001;19:34353.,变量,LHRH类似物,LHRH 类似物,+Tamoxifen,相对危险度,p 值,OR(CR+PR),30%,39%,0.67,0.03,PFS(中位),5.4月,8.7 月,0.70,0.001,OS(中位),2.5 年,2.9 年,0.78,0.02,绝经前晚期乳腺癌的治疗中LHRHa+tamoxifen 优于单用 LHRHa EORTC Meta分析资料,OR=客观反应PFS=无疾病进展生存OS=总生存,Overall logrank test:p=0.0114,Time(years
24、),0,2,4,6,8,10,0,10,20,30,40,50,60,70,80,90,100,%patients,Overall survivalAll patients,LHRH agonist+tamoxifen,LHRH agonist,Tamoxifen,Zoladex=卵巢切除术 Zoladex+TAM Zoladex Arimidex TAM Zoladex+Arimidex 诺雷得+瑞宁得,绝经前乳癌内分泌治疗,诺雷德+瑞宁得治疗绝经前患者,田XX，女，39岁，住院号53056 2001.10 多发骨转移、肝转移ER(+)PR(+)Her-2(+)2001.11.2002.1
25、Herceptin治疗 PD 2002.01.2002.3.TA化疗2周期 SD 2 mo 2002.3.28 诺雷德+瑞宁得 PR 症状明显改善，生活自理，KPS 90分 B超示肝脏病灶明显缩小 X光片示骨病灶好转 至2002年11月疾病依然处于缓解期,A Randomized Trial of Zoladex+TAM vsZoladex+Arimidexin per/perimenopausal patients with hormone dependent ABC,Zoladex+TAM vs Zoladex+Arimidexin per/perimenopausal ABC patie
26、nts,1999.1-2001.12119 cases ABCFirst lineER(+)Zoladex 3.6mg/28d+TAM 20mg/dZoladex 3.6mg/28d+Arimidex 1mg/d,Zoladex+Arimidex vs Zoladex+TAM in pre/perimenopausal ABC patients,Zoladex+Arimidex Zoladex+TAM CR+PR 80%53%Median durationof CB 12.1 months 8.3 months Median time toDeath 18.9 months 14.3 mont
27、hs,Zoladex+Arimidex is effcient and well toleratedshould be considered for first line therapy in per/perimenopausal women with hormone dependent ABC Milla-Santos,SAB 2002,Dec,Overview of LHRHa in Breast Cancer Adjuvant Therapy Benefits of Reversible Ovarian Ablation,1.EBCTCG.Lancet 1996;348:118996.2
28、.Brincker H,et al.J Clin Oncol 1987;5:17718.,Zoladex 用于辅助治疗,Zoladex 3.6mg单用或与 tamoxifen合用在晚期乳腺癌治疗中显示其良好的疗效和耐受性EBCTCG 1996年资料明确了绝经前早期乳腺癌治疗中卵巢去势延长生存的作用,Estimation of the hazard ratio for relapse between women with drug-induced amenorrhea(group A)and those without(group B),10 published studies(1995)Res
29、ults:1.In 9/10 studies RFS longer in group A than in group B NB Bonadonnas CMF study:20-year RFS=39%vs 30%(=22%reduction;p=NS)2.Mean hazard ratio:0.56(0.39-0.86),*del Mastro et al.N Engl J Med 1995;333:596-597,Conclusion:Drug-induced amenorrhea is associated with a 44%reduction in the rate of relaps
30、e,*Aebi et al.Lancet 2000;355:1869-1874,Impact of chemotherapy-induced amenorrhea(AM+)in the adjuvant setting by age*,IBCSG studies I,II,V,VII:treatment with chemotherapy only,ER+AM-ER+AM+ER-AM-ER-AM+,35 years(n=169)37%47%59%50%,35 years(n=1714)57%64%65%58%,10-year overall survival,Zoladex Trials in
31、 Premenopausal Women with Early BC,7 Trials using ZoladexZEBRA Austrian(AC05)INT 101(ECOG/SWOG)ZEBRA-NO ZIPP(combined analysis)GROCTA 02 IBCSG VIII 8000 patientsDesignConferring additional benefit when added to standard treatmentPotential replacement for chemotherapy,ZEBRA试验(Zoladex Early Breast Can
32、cer Research Association),“诺雷德”（戈舍瑞林）与CMF辅助治疗绝经期前和更年期妇女乳腺癌的疗效比较,ZEBRA 试验设计,手术 放疗,Zoladex 3.6mg 1/28天 2年,绝经前/围绝经期 LNM()早期乳腺癌 年龄 50 岁,随访,CMF 1/28天 x 6程,随机化1:1(开放 多中心),肿瘤复发,死亡,死亡,ZEBRA 临床试验结论,Zoladex 在受体阳性病例与 CMF 疗效相等ER水平检测对治疗起关键作用Zoladex较之CMF 有更小的不良反应Zoladex单药治疗 是对ER+、淋巴结阳性、绝经前/围绝经期早期乳腺癌 CMF化疗之外的又一治疗选
33、择,CMF x 6,Zoladex 3.6mg/28 天x 3年+TAM 20mg/天x 5 年,随机分组 1:1,绝经前ER+和/或 PgR+ve乳腺癌,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 可评估病例淋巴结+/,ABCSG AC05 临床试验奥地利乳腺癌辅助治疗试验,ABCSG AC05临床试验结果,Zoladex 3.6mg 加用TAM组DFS显著提高总生存率亦有提高趋势 Zoladex 3
34、.6mg加用TAM较CMF 对绝经前受体阳性乳腺癌辅助治疗更为有效,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.,2,648 例随机化试验淋巴结+/-无论ER 状态标准治疗=放疗 化疗 tamoxifen,标准治疗,手术,.,Zoladex 3.6mg/28 天 2 年,Tamoxifen 20mg/天2 年,Zoladex 3.6mg/28 天+TAM 2 年,无进一步治疗,Houghton J,et al.ASC
35、O 2000;19:93a,Abstr 359.,Zoladex 用于绝经前患者(ZIPP),ZIPP结果乳癌术后在标准治疗中加用 Zoladex,DFS显著改善(HR=0.77 p0.001)提高生存的趋势(HR=0.78 p=0.08)对侧乳腺癌发生率降低(HR=0.60 p=0.05)ER+ve患者较ERve 或不详的患者更有益,Houghton J,et al.ASCO 2000;19:93a,Abstr 359.Baum M.Breast Cancer Res Treat 1999;57:30,Abstr 24.,INT-0101 ECOG/SWOG 临床试验,手术,CAF x 6,
36、随机化 1:1:1,CAF x 6 Zoladex x 5 年,CAF x 6 Zoladex+TAM x 5 年,Davidson NE,et al.Breast 1999;8:2323,Abstr 069.,多中心试验1,504 例合格病例绝经前淋巴结+、受体+比较局部复发率/DFS/生存率,INT-0101:5-Year 结果,*CAF+Zoladex vs CAF alone#CAF+Zoladex+TAM vs CAF+Zoladex 3.6mg+目前尚无统计分析发表 NS=无意义,CAF CAF+Zoladex CAF+Zoladex+TAM(n=494)(n=502)(n=507
37、)DFS(%)67 70(p=0.06)*77(p0.01)#40岁患者DFS(%)54 65+72+总体生存率 85 86(NS)86(NS),Kuter I.Oncologist 1999;4:299308.Davidson NE,et al.Breast 1999;8:2323,Abstr 069.,Zoladex 辅助治疗试验结果总结,研究治疗疾病基本情况DFS 结果 ZEBRAZOL vs.CMFLNM+ZOL对 ER+患者与 CMF等效(n=1,640)74%ER+AC05ZOL+TAMER/PR+ZOL+TAM 较CMF更有效(n=1,045)vs.CMF GROCTATAM+O
38、v.Supp.ER+NS(n=244)vs.CMFINT-0101CAF vs.LNM+CAFZT vs.CAFZ更有效(n=1,504)CAF+ZOL vs.ER/PR+CAF+ZOL+TAM CAFZ vs.CAF更有效趋势 但无统计学差异(p=0.06)ZIPP ZOL+标准治疗 70%ER+标准治疗 ZOL(n=2,648)vs.较单用标准治疗更有效 标准治疗*标准治疗=+/-放疗+/-化疗+/-tamoxifen,结 论,Zoladex对绝经前受体阳性早期乳癌辅助治疗有效 Zoladex单药或联合TAM疗效不比化疗效果差在标准化疗的基础上加 ZoladexTAM的效果更好 Zolad
39、ex可作为 绝经前、受体阳性早期乳癌辅助治疗,N-low riskN-average/high riskN+,TAM or none1.Ov abl+TAM CT2.CT+TAM Ov abl3.TAM4.Ov abl1.CT+TAM Ov abl2.Ov abl+TAM CT,TAM or none1.TAM 2.CT+TAM1.CT+TAM 2.TAM,ER+ve,Ov abl,oophorectomy or GnRH analogue;CT,chemotherapy,Guidelines for adjuvant therapyof breast cancerSt Gallen 2001
40、,Risk group,ER-ve,Premenopausal,Postmenopausal,NACT CT,Questions,Does endocrine therapy add to chemotherapy?Answer:yesDoes chemotherapy add to optimal endocrine therapy?Answer:,In premenopausal ER-positive breast cancer:,unknownprobably no or only minor extra benefitreplacement of tamoxifen by an ar
41、omataseinhibitor might improve optimal endocrine therapy,Study design BOOG1,Multicentre,open,randomized trial in high-risk ER-positive primary breast cancerMain question:does chemotherapy(CT)add to optimal endocrine therapy in steroid receptor-positive patients?Randomizationoptimal endocrine therapy
42、 RToptimal endocrine therapy+standard CT RTStratification:nodal status(N0,N1-4,N4)age categories(40 vs 40 years)cDNA microarray profileBCT vs mastectomy,Study design BOOG1(2),Zoladex+Arimidex(5 yrs),Zoladex+Arimidex(5 yrs)+CT(5 x FEC),R,Ongoing International Clinical Trial,ArimidexvsArimidex+Hercept
43、infor ER/PR positive and Her-2 overexpression Advanced Breast Cancer,瑞宁得用于绝经后复发转移乳癌,79 岁 女性1996年左乳癌 T2N1M0 术后CMF化疗1998年右乳癌 T2N0M0 ER(+)PR(+)TAM 10mg/d2000年11月肺部结节影（M?）ECT示第六肋浓聚但X片未见骨质破坏Next:瑞宁得 1mg 1/d 2001.10-,瑞宁得用于复发转移乳癌+诺雷得 用于绝经前患者,34 yrs 女性CAF辅助治疗后肝转移、骨转移ER(+)PR(+)Her-2(+)Herceptin PDTaxotere+Ca
44、rboplatin 2 周期 SDER(+)PR(+)2002.1-Zoladex+Arimidex疗效：PR 治疗中（2002.12）,瑞宁得用于高危乳癌术后辅助治疗,65 岁 女性2001年 左乳改良根治术 T3N2M0 LNM 10/10 ER(+)PR(+)Her-2(+)因冠心病、糖尿病等术后3个月未化疗辅助治疗:芳香化酶抑制剂,瑞宁得+诺雷得绝经前乳癌辅助治疗,绝经前T2N1M0 LNM 2/5 ER(+)PR(+)Her-2(+)CAF 辅助化疗 2 个周期化疗期间肺结核加重下步治疗：停化疗抗结核治疗诺雷得+瑞宁得 辅助内分泌治疗,Prevention DCIS/Neoadj,5 years,MetastaticDisease,AI,1st,2nd,3rd,AI,AI,Adjuvant,AI,AI,TAM,TAM,TAM,TAM,?,1,芳香化酶抑制剂的现状和未来,绝经前 诺雷得 诺雷得+瑞宁得,乳癌内分泌治疗的方向,新的药物新的指征（解救-新辅助-辅助-预防）新的联合内分泌药物联合（LHRHa+Ais）辅助治疗与化疗(CAF-T)序贯联合 与生物治疗（Herceptin）的联合,乳癌全身治疗科学合理应用,内分泌治疗,化 疗,生物治疗,
