乳腺癌内分泌治疗的新思路和临床实践培训课件

1、乳腺癌内分泌治疗的新思路和临床实践乳腺癌内分泌治疗的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 新的治疗乳腺癌内分泌治疗的新思路和临床实践2乳癌的治疗手段Surgery 乳癌内分泌治疗的发展1970198019902000TamoxifenTamoxifenMAAG新的芳香化酶抑制剂Exemestane /MA新的芳香化酶抑制剂Tamoxifenpure A.E. ? MAIIIIIIIIIIIIIII乳腺癌内分泌治疗的

2、新思路和临床实践3乳癌内分泌治疗的发展1970198019902000TamoHormone Therapy Response Rate (%) in Different Receptor Status乳腺癌内分泌治疗的新思路和临床实践4Hormone Therapy Response Rate Survival by Response Arimidex 1 mg02040608010001234CR or PRStable 24 wksProgressionYears from Randomisation% Survival 乳腺癌内分泌治疗的新思路和临床实践5Survival by Res

3、ponse ArimidexMAAG Prevention DCIS/Neoadj 5 yearsMetastaticDisease 1st2nd3rdAdjuvant TAM TAMTAMTAMOVABL三苯氧胺 （TAM) 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6MA Prevention DCIS/5 yearsMTamoxifen for 5 Years vs No TreatmentPercentYearsER+85.276.168.273.762.754.911.5 (SE 0.9)13.4 (SE 1.1)13.4 (SE 1.4)68.2%54.9%020

4、406080100051015vsRecurrencesBreast Deaths020406080100051015ER+73.0%64.0%91.480.973.087.873.264.03.6 (SE 0.7)7.8 (SE 1.0)9.0 (SE 1.4)vsYearsPercent乳腺癌内分泌治疗的新思路和临床实践7Tamoxifen for 5 Years vs No TTamoxifen Adjuvant 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 乳腺癌内分泌治疗的新思路和临床实践8Tamoxifen Adjuvant Therapy

5、forTamoxifen Adjuvant Therapy for EBC合适的TAM服药时间为5年乳腺癌内分泌治疗的新思路和临床实践9Tamoxifen Adjuvant Therapy forTamoxifen Adjuvant Therapy for EBC ER阳性无论年龄大小都可用TAM乳腺癌内分泌治疗的新思路和临床实践10Tamoxifen Adjuvant Therapy forTamoxifen Adjuvant Therapy for EBC降低对侧乳癌发生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 forT

6、amoxifen 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 乳腺癌内分泌治疗的新思路和临床实践12Tamoxifen Adjuvant Therapy forMAAG Prevention DCIS/Neoadj 5 yearsMetastaticDisease 1st2nd3rdAdjuvant1 TAM TAMTAMTAMOVABLTamoxifenIndications in Breast Cancer三苯氧胺 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13MA Preven

7、tion DCIS/5 yearsMSurvival DataAnastrozole / MAMedian time to death(months)2 year survival rate (%)P Anastrozole is = Exemestane is? Neoadjuvant Letrozole is Adjuvant ？Anastrozole 乳腺癌内分泌治疗的新思路和临床实践23The Gold Standard TamoxifenFirMilestonesActivated1996Planned accrual9366Accrual to dateClosed 1999 On

8、going AI Adjuvant Trials: ATAC (Anastrozole)Trialists Group TA. Br J Cancer. 2001;85:317.RANDOM IZESurgeryTamoxifen 20 mg odAnastrozole 1 mg odTamoxifen 20 mg odAnastrozole 1 mg od5 yearsDFS/OS乳腺癌内分泌治疗的新思路和临床实践24MilestonesOngoing AI Adjuvant KaplanMeier Curves of Disease-free Survival in ITT Populat

9、ionCurves 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 Curves of Dis

10、easKaplanMeier Curves 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

11、26KaplanMeier Curves of DiseasePredefined adverse events*Hot flushesA Arimidex T Tamoxifen C Combination 1060TC12291243A% 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27Predefined adverse events*HotA vs TC vs TA vs C0.520.940.560.00010.50.0001ORp valueATCA, Arimid

12、ex; C, combination; T, tamoxifen138253238% patientsPredefined adverse eventsVaginal bleeding乳腺癌内分泌治疗的新思路和临床实践28A vs T0.52100102030405060nEndometrial thickness (mm)乳腺癌内分泌治疗的新思路和临床实践31Baseline Ultrasound12345678910Median endometrial thickness024681001224Endometrial thickness (mm)ArimidexTamoxifenCombi

13、nationTime (months)乳腺癌内分泌治疗的新思路和临床实践32Median endometrial thickness02A 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33A vs T0.230.02 ORp vaATAC SummaryAnastrozole is superior to

14、tamoxifen 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)乳腺癌内分泌治疗的新思路和临床实践34ATAC SummaryAnastrozole is suConclusionsAnastrozole is the first and only AI to show superior eff

15、icacy and improved tolerability compared with tamoxifen 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乳腺癌内分泌治疗的新思路和临床实践35Conclu

16、sionsAnastrozole is the Analysis of the Incidence of New (Contralateral) Breast 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

17、疗的新思路和临床实践36Analysis of the Incidence of NArimidex (Anastrozole) in Breast cancer prevention: Design of IBIS II and data from ATAC乳腺癌内分泌治疗的新思路和临床实践37Arimidex (Anastrozole) in BreWhy use an Aromatase Inhibitor?At least as effective as tamoxifen in ABCATAC trial provides early warning on side effectsA

18、TAC trial provides efficacy data in early breast cancer at all endpoints; striking reduction in contralateral breast cancer eventsVery low side-effect profile 乳腺癌内分泌治疗的新思路和临床实践38Why use an Aromatase InhibitoATAC: incidence of new (contralateral) breast primaries in ITT population9 invasive0510152025

19、3035Tamoxifen(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 tamoxifen 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39ATAC: incidence of new (contraWomen-years of follow-up per ar

20、m 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 contralateral tumour reduction rate for Arimidex7/1000613314乳腺癌内分泌治疗的新思路和临床实践40Women-year

21、s of follow-up per aIBIS 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 I Tamoxifen in preventioIBIS II: PreventionHigh-risk postmenopausal women, aged 40-70 years2-arm trial for high-risk patients5-year treatment

22、, 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: PreventionHigh-risk pIBIS II: DCISWomen, 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 = 4000Randomizat

23、ionArimidex1 mgTamoxifen20 mg乳腺癌内分泌治疗的新思路和临床实践43IBIS II: DCISWomen, aged 40-70NSABPNSABP centres: USA and Canada Double-blind randomized studyPostmenopausal (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44NSABPStart date: Q4 2002Random Pr

24、evention DCIS/ Neoadj5 yearsMetastaticDisease AI 1st2nd3rdAIAI AdjuvantTAM TAMTAMTAM1Arimidex in Breast CancerMAAI绝经后绝经前 ？AIAI乳腺癌内分泌治疗的新思路和临床实践45 Prevention DCIS/5 yearsMet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 依西美坦绝经后乳腺癌内分泌治疗的新思路和临床实践46绝经前乳癌内分泌治疗绝经前绝经后乳腺癌内分泌治疗的新思路和临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，4

25、1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47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Zoladex 诺雷得 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 诺雷得 用于绝经前乳腺癌患者的治疗乳Zoladex与卵巢切除术治疗复发转移乳癌效果比较乳腺癌内分泌治疗的新思路和临床

26、实践49Zoladex与卵巢切除术治疗复发转移乳癌效果比较乳腺癌内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%) 性欲减退 ( 47.4% )乳腺癌内分泌治疗的新思路和临床实践50Zoladex 3.6mg 用于绝经前进展期乳腺癌II期临Klijn JGM, et al. J Clin Oncol 2001; 19: 34353.变量LHRH类似物LHRH 类似物 + Tamoxifen相

27、对危险度p 值OR (CR+PR)30%39%0.670.03PFS (中位)5.4月8.7 月0.70 Zoladex Arimidex TAM Zoladex + Arimidex 诺雷得 + 瑞宁得绝经前乳癌内分泌治疗 乳腺癌内分泌治疗的新思路和临床实践53 Zoladex 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 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

28、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 乳腺癌内分泌治疗的新思路和临床实践54 诺雷德 + 瑞宁得治疗绝经前患者田XX，女，39岁，住院号A 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55A Randomized Trial of ZoladeZoladex + TAM vs Zoladex +

29、Arimidexin per/perimenopausal ABC patients 1999.1 - 2001.12119 cases ABCFirst lineER (+)Zoladex 3.6mg / 28d + TAM 20mg/dZoladex 3.6mg / 28d + Arimidex 1mg/d乳腺癌内分泌治疗的新思路和临床实践56Zoladex + TAM vs Zoladex + Zoladex + Arimidex vs Zoladex + TAM in pre/perimenopausal ABC patients Zoladex + Arimidex Zoladex

30、+ 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57Zoladex + Arimidex vs Zoladex Zoladex + Arimidex is effcient and well toleratedshould be considered for first line therapy in per/perimenopausal women with hormone depende

31、nt ABC Milla-Santos, SAB 2002,Dec乳腺癌内分泌治疗的新思路和临床实践58 Zoladex + Arimidex is effciOverview 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59Overview of LHRHa in Breast C1. EBCTCG. Lancet 1996; 348: 118996.2. Brincker H, et al. J Clin Oncol 1987; 5: 1

32、7718.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601. EBCTCG. Lancet 1996; 348: 1Estimation of the hazard ratio for relapse between women with drug-induced amenorrhea ( group A ) and those without ( group B )10 published st

33、udies (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% reduc

34、tion in the rate of relapse乳腺癌内分泌治疗的新思路和临床实践61Estimation of the hazard ratio*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 patientsDesi

35、gnConferring additional benefit when added to standard treatmentPotential replacement for chemotherapy乳腺癌内分泌治疗的新思路和临床实践63Zoladex Trials in PremenopauZEBRA试验( Zoladex Early Breast Cancer 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乳腺癌内分泌治疗的新思路和临床实践64ZEBRA试验( Zoladex Early BreZEBRA 试验设计

36、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)肿瘤复发死亡死亡乳腺癌内分泌治疗的新思路和临床实践65ZEBRA 试验设计手术 放疗Zoladex 3.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择乳腺癌内分泌治疗的新思路和临床实践66ZEBRA 临床试验结论Z

37、oladex 在受体阳性病例与 CCMF 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 乳腺癌内分泌治疗的新思路和临床实践67CMF x 6 Zoladex 3.6mg

38、/28 天xABCSG 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68ABCSG AC05临床试验结果 Zoladex 3.6m2,648 例随机化试验淋巴结 + / -无论ER 状

39、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. 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692,648 例标准治疗手术.Zoladex 3.6mg / 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

40、=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.乳腺癌内分泌治疗的新思路和临床实践70ZIPP结果乳癌术后在标准治疗中加用 Zoladex DINT-0101 ECOG / SWOG 临床试验 手术CAF x 6随机化 1:1:1CAF x 6 Zoladex x 5 年CAF x 6 Zoladex +TA

41、M 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 乳腺癌内分泌治疗的新思路和临床实践71INT-0101 ECOG / SWOG 临床试验 乳腺癌内分泌治疗的新思路和临床实践培训课件 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 + T

42、AM 较CMF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 (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 乳腺癌内分泌治疗的新思

43、路和临床实践73 Zoladex 辅助治疗试验结果总结 研究治疗疾病基本结 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 Zoladex可作为 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74结 论Zoladex对绝经前受体阳性早期乳癌辅助治N -low riskN -average/high riskN +TAM or none1. Ov abl + TAM CT2. CT + TAM Ov abl3. TAM4. Ov abl1. CT + TAM Ov a

44、bl2. 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新思路和临床实践75N -low riskTAM or noneTAM QuestionsDoes en

45、docrine 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 therapy乳腺癌内分泌治疗的新思路和临床

46、实践76QuestionsDoes endocrine therapStudy 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+ standard CT RTStratification:nodal status (N0, N1- 4, N4)age categories (40 vs 4