乳腺癌内分泌治疗的新思路和临床实践

1、1乳癌内分泌治疗乳癌内分泌治疗新思路和临床实践新思路和临床实践2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31970198019902000TamoxifenTamoxifenMAAGExemestane /MATamoxifenpure A.E. ?MA4Hormone Therapy Response Rate (%) in Different Receptor Status5Survival b

2、y Response Arimidex 1 mg% Survival 6MAAG 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7Tamoxifen for 5 Years vs No TreatmentPercentYearsER+68.2%54.9%020406080100051015vsRecurrencesBreast Deaths020406080100051015ER+73.0%6

3、4.0%vsYearsPercent8Tamoxifen 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 9Tamoxifen 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10Tamoxifen 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TAMTAM11Tamoxifen 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

4、险增加子宫内膜癌的风险12Tamoxifen 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 13MAAG 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！？14

5、Survival DataAnastrozole / MAMedian time to death(months)2 year survival rate (%)P Anastrozole is = Exemestane is? Neoadjuvant Letrozole is Adjuvant ？ Anastrozole 24MilestonesActivated1996Planned accrual9366Accrual to dateClosed 1999 Ongoing AI Adjuvant Trials: ATAC (Anastrozole)Br J CancerRANDOM IZ

6、ESurgeryTamoxifen 20 mg odAnastrozole 1 mg odTamoxifen 20 mg odAnastrozole 1 mg od5 yearsDFS/OS25Curves 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)P

7、roportion event free (%)0808590951000612182430364226KaplanMeier 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 (%)TamoxifenAnastrozoleCombi

8、nation0808590951000612182430364227Predefined adverse events*Hot flushesA Arimidex T Tamoxifen C Combination 1060TC1229 1243A% patientsA vs TC vs TA vs C0.791.020.78 OR0.00010.750.0001p value28A vs TC vs TA vs C0.520.940.560.00010.5100102030405060nEndometrial thickness (mm)32Median endometrial thickn

9、ess024681001224Endometrial thickness (mm)ArimidexTamoxifenCombinationTime (months)33A vs TC vs TA vs C0.230.460.500.020.110.51 ORp valueATCA, Arimidex; C, combination; T, tamoxifen3136% patientsPredefined adverse eventsEndometrial cancer34ATAC Summary Anastrozole is superior to tamoxifen in terms of

10、: 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)35Conclusions Anastrozole is the first and only AI to show superior efficacy and improved tolerability compared with tamoxifen in the t

11、reatment 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 cancer36Analysis of the Incidence of New (Contralateral) Breast Primaries Time to first contr

12、alateral new primary (months) 0612182430364209899100Proportion without CL BCa (%)AnastrozoleTamoxifenCombinationOR95% CIp-valueAN vs TAM0.420.220.790.0068Comb vs TAM0.840.511.40 0.513237Arimidex (Anastrozole) in Breast cancer prevention: Design of IBIS II and data from ATAC38Why use an Aromatase Inh

13、ibitor? 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 side-effect profile 39ATAC: incidence of new (contralateral

14、) 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 tamoxifen OR 0.84; 95% CI 0.51, 1.40; p=0.5140Women-years of follow-

15、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 contralateral tumour reduction rate for Arimidex7/100061331441IBIS I Tamoxifen i

16、n preventionBreast cancer incidence is reduced by 32%101 ( placebo ) vs 69 ( TAM ) OR 0.68 p=0.0142IBIS II: Prevention High-risk postmenopausal women, aged 40-70 years 2-arm trial for high-risk patients 5-year treatment, placebo controlledN = 6000 high-risk patientsRandomizationArimidex1 mgPlacebo43

17、IBIS 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 mg44NSABP NSABP centres: USA and Canada Double-blind randomized study Postmenopausal (n=3000)Start date: Q

18、4 2002Randomize1:15 years anastrozole1 mg od 5 years tamoxifen20 mg od45 Prevention DCIS/ Neoadj5 yearsMetastaticDisease AI 1st2nd3rdAIAI AdjuvantTAM TAMTAMTAM1Arimidex in Breast CancerAI绝经后绝经后绝经前绝经前 ？AIAI46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47卵巢切除加口服依西美坦卵巢切除加口服依西美

19、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 48Zoladex 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49Zoladex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+P

20、R）31%27%中位缓解期6 个月4 个月中位生存期37 个月33 个月50Zoladex 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% )51Klijn 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%0.67

21、0.03PFS (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前乳癌内分泌治疗 54 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 +

22、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2002年年11月疾病依然处于缓解期月疾病依然处于缓解期 55A Randomized Trial of Zoladex + TAM vsZoladex + Arimidexin per/perimenopausal patients with hormone dependent ABC56Zoladex + TAM vs Zoladex + Arimidexin per/perimenopausal ABC patients

23、 1999.1 - 2001.12 119 cases ABC First line ER (+) Zoladex 3.6mg / 28d + TAM 20mg/d Zoladex 3.6mg / 28d + Arimidex 1mg/d57Zoladex + 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 to

24、Death 18.9 months 14.3 months58 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,Dec59Overview of LHRHa in Breast Cancer Adjuvant Therapy Benefits of Reversible Ovarian Ablation6

25、01. EBCTCG. Lancet 1996; 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61Estimation of the hazard ratio for relapse between women with drug-induced amenorrhea ( group A ) and those

26、 without ( group 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 amen

27、orrhea is associated with a 44% reduction in the rate of relapse62*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 Confer

28、ring additional benefit when added to standard treatment Potential replacement for chemotherapy64ZEBRA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65ZEBRA 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

29、乳腺癌早期乳腺癌 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66ZEBRA 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67CMF 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 1:1绝经前绝经前ER+和和/或或 PgR+ve乳腺癌乳腺癌Ja

30、kesz 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 68ABCSG 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

31、 Cancer Res Treat 1999; 57: 25, Abstr 2.Jakesz R, et al. Eur J Surg Oncol 2000; 26: 281, Abstr 110.69l2,648 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 无进一步治疗无进一步治疗 Houghton J, et

32、 al. ASCO 2000; 19: 93a, Abstr 359.Zoladex 用于绝经前患者 (ZIPP) 70ZIPP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 M. Breast Cancer Res T

33、reat 1999; 57: 30, Abstr 24.71INT-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 72INT-0101: 5-Year 结果 *CAF + Zoladex vs CAF alone#CAF + Zoladex + TAM

34、vs CAF + Zoladex 3.6mg+目前尚无统计分析发表目前尚无统计分析发表 NS = 无意义无意义CAF CAF + Zoladex CAF + Zoladex + TAM (n=494) (n=502) (n=507)DFS (%) 67 70 ( p=0.06 )* 77 ( p0.01 )# 40岁患者岁患者DFS (%) 54 65+ 72+总体生存率总体生存率 85 86 (NS) 86 (NS)Kuter I. Oncologist 1999; 4: 299308.Davidson NE, et al. Breast 1999; 8: 2323, Abstr 069.

35、73 Zoladex 辅助治疗试验结果总结 研究研究治疗治疗疾病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 +

36、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 74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

37、经前、受体阳性早期乳癌辅助治疗 75N -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 CTTAM or none1. TAM 2. CT + TAM1. CT + TAM 2. TAM ER+veOv abl, oophorectomy or GnRH analogue; CT, chemotherapyGuidelines for adjuvant therapyof breast c

38、ancerSt Gallen 2001Risk groupER-vePremenopausalPostmenopausalNACT CT 76QuestionsDoes 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 ta

39、moxifen by an aromataseinhibitor might improve optimal endocrine therapy77Study 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