1、乳腺癌内分泌治疗的乳腺癌内分泌治疗的新思路和临床实践新思路和临床实践乳癌的治疗手段乳癌的治疗手段 Surgery 手术 Radiation therapy 放疗 Chemotherapy 化疗 Hormone therapy 内分泌治疗 Biotherapy 生物治疗 New therapies 新的治疗乳腺癌内分泌治疗的新思路和临床实践21970198019902000TamoxifenTamoxifenMAAGExemestane/MATamoxifenpure A.E.?MA乳腺癌内分泌治疗的新思路和临床实践3Hormone Therapy Response Rate(%)in Diff
2、erent Receptor Status乳腺癌内分泌治疗的新思路和临床实践4Survival by Response Arimidex 1 mg%Survival 乳腺癌内分泌治疗的新思路和临床实践5MAAG Prevention DCIS/Neoadj 5 yearsMetastaticDisease 1st2nd3rdAdjuvant TAM TAMTAMTAMOVABL三苯氧胺三苯氧胺（TAM)最重要的乳癌内分泌治疗药物最重要的乳癌内分泌治疗药物乳腺癌内分泌治疗的新思路和临床实践6Tamoxifen for 5 Years vs No TreatmentPercentYearsER+6
3、8.2%54.9%020406080100051015vsRecurrencesBreast Deaths020406080100051015ER+73.0%64.0%vsYearsPercent乳腺癌内分泌治疗的新思路和临床实践7Tamoxifen Adjuvant Therapy for EBC辅助内分泌治疗的辅助内分泌治疗的决定因素决定因素是激素受体状况是激素受体状况ERER阳性阳性效果最好效果最好 乳腺癌内分泌治疗的新思路和临床实践8Tamoxifen Adjuvant Therapy for EBC合适的合适的TAMTAM服药时间服药时间为为5 5年年乳腺癌内分泌治疗的新思路和临床实
4、践9Tamoxifen Adjuvant Therapy for EBC ERER阳性阳性无论年龄大小都可用无论年龄大小都可用TAMTAM乳腺癌内分泌治疗的新思路和临床实践10Tamoxifen Adjuvant Therapy for EBC降低对侧乳癌发生降低对侧乳癌发生增加子宫内膜癌的风险增加子宫内膜癌的风险乳腺癌内分泌治疗的新思路和临床实践11Tamoxifen Adjuvant Therapy for EBC ERER阳性阳性TAMTAM和化疗合用和化疗合用比单用比单用TAMTAM更有效更有效CAFCAF与与TAMTAM 序贯合用序贯合用比比同时效果同时效果更好更好 乳腺癌内分泌治疗
5、的新思路和临床实践12MAAG Prevention DCIS/Neoadj 5 yearsMetastaticDisease 1st2nd3rdAdjuvant1 TAM TAMTAMTAMOVABLTamoxifenIndications in Breast Cancer三苯氧胺三苯氧胺 乳癌内分泌治疗不可动摇的地位！？乳癌内分泌治疗不可动摇的地位！？乳腺癌内分泌治疗的新思路和临床实践13Survival DataAnastrozole/MAMedian time to death(months)2 year survival rate(%)P Anastrozole is=Exemest
6、ane is?Neoadjuvant Letrozole is Adjuvant？Anastrozole 乳腺癌内分泌治疗的新思路和临床实践23MilestonesActivated1996Planned accrual9366Accrual to dateClosed 1999 Ongoing AI Adjuvant Trials:ATAC(Anastrozole)Br J CancerRANDOM IZESurgeryTamoxifen 20 mg odAnastrozole 1 mg odTamoxifen 20 mg odAnastrozole 1 mg od5 yearsDFS/OS
7、乳腺癌内分泌治疗的新思路和临床实践24Curves truncated at 42 monthsHR95.2%CIp-valueAN vs TAM0.830.710.960.0129Comb vs TAM1.020.881.180.7718TamoxifenAnastrozoleCombinationTime to event(months)Proportion event free(%)Time to event(months)Proportion event free(%)08085909510006121824303642乳腺癌内分泌治疗的新思路和临床实践25KaplanMeier Cu
8、rves of Disease-free Survivalin Receptor-positive PopulationCurves truncated at 42 monthsHR95.2%CIp-valueAN vs TAM0.780.650.930.0054Comb vs TAM1.020.871.210.7786Time to event(months)Proportion event free(%)TamoxifenAnastrozoleCombination08085909510006121824303642乳腺癌内分泌治疗的新思路和临床实践26Predefined adverse
9、 events*Hot flushesA Arimidex T Tamoxifen C Combination 1060TC1229 1243A%patientsA vs TC vs TA vs C0.791.020.78 OR0.00010.750.0001p value乳腺癌内分泌治疗的新思路和临床实践27A vs TC vs TA vs C0.520.940.560.00010.5100102030405060nEndometrial thickness(mm)乳腺癌内分泌治疗的新思路和临床实践31Median endometrial thickness024681001224Endom
10、etrial thickness(mm)ArimidexTamoxifenCombinationTime(months)乳腺癌内分泌治疗的新思路和临床实践32A vs TC vs TA vs C0.230.460.500.020.110.51 ORp valueATCA,Arimidex;C,combination;T,tamoxifen3136%patientsPredefined adverse eventsEndometrial cancer乳腺癌内分泌治疗的新思路和临床实践33ATAC Summary Anastrozole is superior to tamoxifen in te
11、rms 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)乳腺癌内分泌治疗的新思路和临床实践34Conclusions Anastrozole is the first and only AI to show superior efficacy and improved tolerability compared with t
12、amoxifen in the treatment of EBC Overall risk-benefit assessment supports anastrozole becoming the future adjuvant treatment of choice in postmenopausal women Anastrozole also shows promise for the chemoprevention of breast cancer乳腺癌内分泌治疗的新思路和临床实践35Analysis of the Incidence of New(Contralateral)Brea
13、st Primaries Time to first contralateral new primary(months)0612182430364209899100Proportion without CL BCa(%)AnastrozoleTamoxifenCombinationOR95%CIp-valueAN vs TAM0.420.220.790.0068Comb vs TAM0.840.511.40 0.5132乳腺癌内分泌治疗的新思路和临床实践36Arimidex(Anastrozole)in Breast cancer prevention:Design of IBIS II an
14、d data from ATAC乳腺癌内分泌治疗的新思路和临床实践37Why use an Aromatase Inhibitor?At least as effective as tamoxifen in ABC ATAC trial provides early warning on side effects ATAC trial provides efficacy data in early breast cancer at all endpoints;striking reduction in contralateral breast cancer events Very low si
15、de-effect profile 乳腺癌内分泌治疗的新思路和临床实践38ATAC:incidence of new(contralateral)breast primaries in ITT population9 invasive05101520253035Tamoxifen(n=3116)Arimidex(n=3125)Combination(n=3125)5 DCIS3 DCIS23invasive5 DCIS30 invasiveNo.casesArimidex vs tamoxifen OR 0.42;95%CI 0.22,0.79;p=0.007Combination vs ta
16、moxifen OR 0.84;95%CI 0.51,1.40;p=0.51乳腺癌内分泌治疗的新思路和临床实践39Women-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%REDUCTIONATAC:projected contral
17、ateral tumour reduction rate for Arimidex7/1000613314乳腺癌内分泌治疗的新思路和临床实践40IBIS I Tamoxifen in preventionBreast cancer incidence is reduced by 32%101(placebo)vs 69(TAM)OR 0.68 p=0.01乳腺癌内分泌治疗的新思路和临床实践41IBIS II:Prevention High-risk postmenopausal women,aged 40-70 years 2-arm trial for high-risk patients
18、5-year treatment,placebo controlledN=6000 high-risk patientsRandomizationArimidex1 mgPlacebo乳腺癌内分泌治疗的新思路和临床实践42IBIS II:DCIS Women,aged 40-70 years,who have had DCIS diagnosed within the previous 6 months 2-arm trial(no placebo arm)5-year treatment,2 tablets/day RandomizationArimidex1 mgTamoxifen20 m
19、g乳腺癌内分泌治疗的新思路和临床实践43NSABP NSABP centres:USA and Canada Double-blind randomized study Postmenopausal (n=3000)Start date:Q4 2002Randomize1:15 years anastrozole1 mg od 5 years tamoxifen20 mg od乳腺癌内分泌治疗的新思路和临床实践44 Prevention DCIS/Neoadj5 yearsMetastaticDisease AI 1st2nd3rdAIAI AdjuvantTAM TAMTAMTAM1Arim
20、idex in Breast CancerAI绝经后绝经后绝经前绝经前？AIAI乳腺癌内分泌治疗的新思路和临床实践45绝经前乳癌内分泌治疗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）瑞宁得（阿那曲唑）氟隆氟隆 依西美坦依西美坦绝经后乳腺癌内分泌治疗的新思路和临床实践46卵巢切除加口服依西美坦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治疗绝经前乳腺癌骨转移长期缓解 霍秀兰，女，41岁，住院号50982 2001.2 多发骨转移，左锁上淋巴结转移，穿刺活检ER(+)PR(+)Her-2(+)2001.4.6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
21、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 乳腺癌内分泌治疗的新思路和临床实践47Zoladex 诺雷得诺雷得 用于绝经前乳腺癌患者的治疗用于绝经前乳腺癌患者的治疗乳腺癌内分泌治疗的新思路和临床实践48Zoladex与卵巢切除术与卵巢切除术治疗复发转移乳癌效果比较治疗复发转移乳癌效果比较Zoladex(n=67)卵巢切除（n=69）有效率（CR+PR）31%27%中位缓解期6 个月4 个月中位生存期37 个月33 个月乳腺癌内分泌治疗的新思路和临床实践49Zoladex 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
22、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%)性欲减退(47.4%)乳腺癌内分泌治疗的新思路和临床实践50Klijn JGM,et al.J Clin Oncol 2001;19:34353.变量变量LHRH类似物类似物LHRH 类似物类似物+Tamoxifen相对相对危险度危险度p 值值OR(CR+PR)30%39%0.670.03PFS(中位中位)5.4月月8.7 月月0.70 Zoladex Arimidex TAM Zoladex+Arimidex 诺雷得+瑞宁得绝经前乳癌内分泌治疗绝经
23、前乳癌内分泌治疗 乳腺癌内分泌治疗的新思路和临床实践53 诺雷德诺雷德+瑞宁得治疗绝经前患者瑞宁得治疗绝经前患者 田田XX，女，女，39岁，住院号岁，住院号53056 2001.10 多发骨转移、肝转移多发骨转移、肝转移 ER(+)PR(+)Her-2(+)2001.11.2002.1 Herceptin治疗治疗 PD 2002.01.2002.3.TA化疗化疗2周期周期 SD 2 mo 2002.3.28 诺雷德诺雷德+瑞宁得瑞宁得 PR 症状明显改善，生活自理，症状明显改善，生活自理，KPS 90分分 B超示肝脏病灶明显缩小超示肝脏病灶明显缩小 X光片示骨病灶好转光片示骨病灶好转 至至20
24、02年年11月疾病依然处于缓解期月疾病依然处于缓解期 乳腺癌内分泌治疗的新思路和临床实践54A Randomized Trial of Zoladex+TAM vsZoladex+Arimidexin per/perimenopausal patients with hormone dependent ABC乳腺癌内分泌治疗的新思路和临床实践55Zoladex+TAM vs Zoladex+Arimidexin per/perimenopausal ABC patients 1999.1-2001.12 119 cases ABC First line ER(+)Zoladex 3.6mg/2
25、8d +TAM 20mg/d Zoladex 3.6mg/28d +Arimidex 1mg/d乳腺癌内分泌治疗的新思路和临床实践56Zoladex+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 months乳腺癌内分泌治疗的新思路和临床实践57 Zoladex+Arimidex i
26、s effcient and well toleratedshould be considered for first line therapy in per/perimenopausal women with hormone dependent ABC Milla-Santos,SAB 2002,Dec乳腺癌内分泌治疗的新思路和临床实践58Overview of LHRHa in Breast Cancer Adjuvant Therapy Benefits of Reversible Ovarian Ablation乳腺癌内分泌治疗的新思路和临床实践591.EBCTCG.Lancet 19
27、96;348:118996.2.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乳腺癌内分泌治疗的新思路和临床实践60Estimation of the hazard ratio for relapse between women with drug-induced amenorrhea(group A)and those without(group
28、B)10 published studies(1995)Results: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;333:596-597Conclusion:Drug-induced amenorrhea is associated with a 44%r
29、eduction in the rate of relapse乳腺癌内分泌治疗的新思路和临床实践61*Aebi et al.Lancet 2000;355:1869-1874Impact of chemotherapy-induced amenorrhea(AM+)in the adjuvant setting by age*IBCSG studies I,II,V,VII:treatment with chemotherapy onlyER+AM-ER+AM+ER-AM-ER-AM+8000 patients Design Conferring additional benefit when
30、 added to standard treatment Potential replacement for chemotherapy乳腺癌内分泌治疗的新思路和临床实践63ZEBRA试验试验(Zoladex Early Breast Cancer Research Association)“诺雷德诺雷德”（戈舍瑞林）（戈舍瑞林）与与CMF辅助治疗辅助治疗绝经期前和更年期妇女乳腺癌的疗效比较绝经期前和更年期妇女乳腺癌的疗效比较乳腺癌内分泌治疗的新思路和临床实践64ZEBRA 试验设计手术手术 放疗放疗Zoladex 3.6mg 1/28天天 2年年绝经前绝经前/围绝经期围绝经期 LNM()早期乳
31、腺癌早期乳腺癌 年龄年龄 50 岁岁随访随访CMF 1/28天天 x 6程程随机化随机化1:1 (开放开放 多中心多中心)肿瘤复发肿瘤复发死亡死亡死亡死亡乳腺癌内分泌治疗的新思路和临床实践65ZEBRA 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择乳腺癌内分泌治疗的新思路和临床实践66CMF x 6 Zoladex 3.6mg/28 天天x 3年年+TAM 20mg/天天x 5 年年随机分组随机分组 1:
32、1绝经前绝经前ER+和和/或或 PgR+ve乳腺癌乳腺癌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.l1,045 可评估病例可评估病例l淋巴结淋巴结+/ABCSG AC05 临床试验奥地利乳腺癌辅助治疗试验 乳腺癌内分泌治疗的新思路和临床实践67ABCSG 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 3.6mg加用TAM较CMF 对绝经前受体阳性
33、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.乳腺癌内分泌治疗的新思路和临床实践68l2,648 例例l随机化试验随机化试验l淋巴结淋巴结+/-l无论无论ER 状态状态l标准治疗标准治疗=放疗放疗 化疗化疗 tamoxifen标准治疗标准治疗手术手术.Zoladex 3.6mg/28 天天 2 年年Tamoxifen 20mg/天天 2 年年Zoladex 3.6mg/28 天天+TAM 2 年年
34、 无进一步治疗无进一步治疗 Houghton J,et al.ASCO 2000;19:93a,Abstr 359.Zoladex 用于绝经前患者(ZIPP)乳腺癌内分泌治疗的新思路和临床实践69ZIPP结果乳癌术后在标准治疗中加用 Zoladex DFS显著改善显著改善(HR=0.77 p0.001)提高生存的趋势提高生存的趋势(HR=0.78 p=0.08)对侧乳腺癌发生率降低对侧乳腺癌发生率降低(HR=0.60 p=0.05)ER+ve患者较患者较ERve 或不详的患者更有益或不详的患者更有益Houghton J,et al.ASCO 2000;19:93a,Abstr 359.Baum
35、 M.Breast Cancer Res Treat 1999;57:30,Abstr 24.乳腺癌内分泌治疗的新思路和临床实践70INT-0101 ECOG/SWOG 临床试验 手术手术CAF x 6随机化随机化 1:1:1CAF x 6 Zoladex x 5 年年CAF x 6 Zoladex+TAM x 5 年年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 乳腺癌内分泌治疗的新思路和临床实践71 Zoladex 辅助治疗试验结果总结 研究研究治疗治疗疾病
36、基本情况疾病基本情况DFS 结果结果 ZEBRAZOL vs.CMFLNM+ZOL对对 ER+患者与患者与 CMF等效等效(n=1,640)74%ER+AC05ZOL+TAMER/PR+ZOL+TAM 较较CMF更有效更有效(n=1,045)vs.CMF GROCTATAM+Ov.Supp.ER+NS(n=244)vs.CMFINT-0101CAF vs.LNM+CAFZT vs.CAFZ更有效更有效(n=1,504)CAF+ZOL vs.ER/PR+CAF+ZOL+TAM CAFZ vs.CAF更有效趋势更有效趋势 但无统计学差异但无统计学差异(p=0.06)ZIPP ZOL+标准治疗标准治
37、疗 70%ER+标准治疗标准治疗 ZOL (n=2,648)vs.较单用标准治疗更有效较单用标准治疗更有效 标准治疗标准治疗*标准治疗标准治疗=+/-放疗放疗+/-化疗化疗+/-tamoxifen 乳腺癌内分泌治疗的新思路和临床实践73结结 论论 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 Zoladex可作为可作为 绝经前、受体阳性早期乳癌辅助治疗绝经前、受体阳性早期乳癌辅助治疗 乳腺癌内分泌治疗的新思路和临床实践74N-low riskN-average/high riskN+T
38、AM or none1.Ov abl+TAM CT2.CT+TAM Ov abl3.TAM4.Ov abl1.CT+TAM Ov abl2.Ov abl+TAM CTTAM or none1.TAM 2.CT+TAM1.CT+TAM 2.TAM ER+veOv abl,oophorectomy or GnRH analogue;CT,chemotherapyGuidelines for adjuvant therapyof breast cancerSt Gallen 2001Risk groupER-vePremenopausalPostmenopausalNACT CT 乳腺癌内分泌治疗的
39、新思路和临床实践75QuestionsDoes 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 aromataseinhibitor might improve optimal endocrine
40、 therapy乳腺癌内分泌治疗的新思路和临床实践76Study 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 RToptimal endocrine therapy+s
41、tandard CT RTStratification:nodal status(N0,N1-4,N4)age categories(40 vs 40 years)cDNA microarray profile BCT vs mastectomy乳腺癌内分泌治疗的新思路和临床实践77Study design BOOG1(2)Zoladex+Arimidex(5 yrs)Zoladex+Arimidex(5 yrs)+CT (5 x FEC)R乳腺癌内分泌治疗的新思路和临床实践78Ongoing International Clinical TrialArimidexvsArimidex+Her
42、ceptinfor ER/PR positive and Her-2 overexpression Advanced Breast Cancer乳腺癌内分泌治疗的新思路和临床实践79瑞宁得用于瑞宁得用于绝经后绝经后复发转移乳癌复发转移乳癌 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/d 2000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-乳腺癌内分泌治疗的新思路和临床实践80瑞宁得用于复发转移乳癌瑞宁得用于复发转移乳癌+诺雷得诺雷得 用
43、于用于绝经前患者绝经前患者 34 yrs 女性 CAF辅助治疗后肝转移、骨转移 ER(+)PR(+)Her-2(+)Herceptin PD Taxotere+Carboplatin 2 周期 SD ER(+)PR(+)2002.1-Zoladex+Arimidex 疗效：PR 治疗中（2002.12）乳腺癌内分泌治疗的新思路和临床实践81瑞宁得用于高危乳癌术后辅助治疗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 乳腺癌内分泌治疗的新
44、思路和临床实践82瑞宁得瑞宁得+诺雷得诺雷得绝经前乳癌辅助治疗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：停化疗停化疗 抗结核治疗抗结核治疗 诺雷得诺雷得+瑞宁得瑞宁得 辅助内分泌治疗辅助内分泌治疗乳腺癌内分泌治疗的新思路和临床实践83 Prevention DCIS/Neoadj5 yearsMetastaticDisease AI 1st2nd3rdAIAI AdjuvantAI AITAM TAMTAMTAM?1AI 芳香化酶抑制剂的现状和未来芳香化酶抑制剂的现状和未来绝经前绝经前 诺雷得诺雷得 诺雷得诺雷得+瑞宁得瑞宁得乳腺癌内分泌治疗的新思路和临床实践84乳癌内分泌治疗的方向乳癌内分泌治疗的方向 新的药物新的药物 新的指征新的指征（解救解救-新辅助新辅助-辅助辅助-预防预防）新的联合新的联合 内分泌药物联合（内分泌药物联合（LHRHa+Ais）辅助治疗与化疗辅助治疗与化疗(CAF-T)序贯联合序贯联合 与生物治疗（与生物治疗（Herceptin）的联合的联合乳腺癌内分泌治疗的新思路和临床实践85内分泌治疗内分泌治疗生物治疗生物治疗乳腺癌内分泌治疗的新思路和临床实践86
