1、乳腺癌內(nèi)分泌治療乳腺癌內(nèi)分泌治療的新思路和臨床實(shí)的新思路和臨床實(shí)踐踐1970198019902000TamoxifenTamoxifenMAAGExemestane /MATamoxifenpure A.E. ?MAHormone Therapy Response Rate (%) in Different Receptor StatusSurvival by Response Arimidex 1 mg% Survival MAAG Prevention DCIS/Neoadj 5 yearsMetastaticDisease 1st2nd3rdAdjuvant TAM TAMTAMTAMO

2、VABL三苯氧胺三苯氧胺 （TAM) 最重要的乳癌內(nèi)分泌治療藥物最重要的乳癌內(nèi)分泌治療藥物Tamoxifen for 5 Years vs No TreatmentPercentYearsER+68.2%54.9%020406080100051015vsRecurrencesBreast Deaths020406080100051015ER+73.0%64.0%vsYearsPercent7Tamoxifen Adjuvant Therapy for EBC輔助內(nèi)分泌治療的輔助內(nèi)分泌治療的決定因素決定因素是激素受體狀況是激素受體狀況ERER陽性陽性效果最好效果最好 8Tamoxifen Adj

3、uvant Therapy for EBC合適的合適的TAMTAM服藥時間服藥時間為為5 5年年9Tamoxifen Adjuvant Therapy for EBC ERER陽性陽性無論年齡大小都可用無論年齡大小都可用TAMTAM10Tamoxifen Adjuvant Therapy for EBC降低對側(cè)乳癌發(fā)生降低對側(cè)乳癌發(fā)生增加子宮內(nèi)膜癌的風(fēng)險增加子宮內(nèi)膜癌的風(fēng)險Tamoxifen Adjuvant Therapy for EBC ERER陽性陽性TAMTAM和化療合用和化療合用比單用比單用TAMTAM更有效更有效CAFCAF與與TAMTAM 序貫合用序貫合用比比同時效果同時效果更好

4、更好 MAAG Prevention DCIS/Neoadj 5 yearsMetastaticDisease 1st2nd3rdAdjuvant1 TAM TAMTAMTAMOVABLTamoxifenIndications in Breast Cancer三苯氧胺三苯氧胺 乳癌內(nèi)分泌治療不可動搖的地位?。咳榘﹥?nèi)分泌治療不可動搖的地位??？Survival DataAnastrozole / MAMedian time to death(months)2 year survival rate (%)Arimidex 10 mg (n = 92)瑞寧得用藥瑞寧得用藥9個月沒有明顯的體重變化個月沒

5、有明顯的體重變化 瑞寧得瑞寧得 (Arimidex)比 MA更有效、更安全 瑞寧得瑞寧得 (Arimidex) 1 mg 在復(fù)發(fā)轉(zhuǎn)移乳癌治療中緩解率 / 臨床獲益率相當(dāng)生存期更長耐受性更好 Prevention DCIS/ Neoadj5 yearsMetastaticDisease 1st2nd3rdAIAI AdjuvantTAM TAMTAMTAM1Arimidex in Breast CancerAnastrozole is Superior to Tamoxifen in First Line Therapy（0030）JCO 2000;18:3748* Hazard ratio (

6、tam : Arimidex) 1.44, lower CL 1.16. Study powered for equivalence. Median follow-up of 18 months. 71% progressedTrial 0030: Kaplan-Meier Curve of Probability of Time to ProgressionArimidex (n=171)Tamoxifen (n=182)Median TTP*: Arimidex 11.1 monthstamoxifen 5.6 months p=0.005 (2-sided) 01020304050607

7、0809010006121824303642Time to progression (months)Percentage not progressedAIs is Superior to Tamoxifenas First-line Therapy for Advanced Breast Cancer芳香化酶抑制劑芳香化酶抑制劑取代三苯氧胺取代三苯氧胺成為標(biāo)準(zhǔn)的一線內(nèi)分泌治療成為標(biāo)準(zhǔn)的一線內(nèi)分泌治療 Prevention DCIS/ Neoadj5 yearsMetastaticDisease AI 1st2nd3rdAIAI AdjuvantTAM TAMTAMTAM1Arimidex in

8、 Breast CancerRationale 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? Neoadjuvant Letrozole is Adju

9、vant ？ Anastrozole MilestonesActivated1996Planned 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/OSCurves truncated at 42 monthsHR95.2% CIp-valueAN vs

10、 TAM0.830.710.960.0129Comb vs TAM1.020.881.180.7718TamoxifenAnastrozoleCombinationTime to event (months)Proportion event free (%)Time to event (months)Proportion event free (%)08085909510006121824303642KaplanMeier Curves of Disease-free Survivalin Receptor-positive PopulationCurves truncated at 42 m

11、onthsHR95.2% CIp-valueAN vs TAM0.780.650.930.0054Comb vs TAM1.020.871.210.7786Time to event (months)Proportion event free (%)TamoxifenAnastrozoleCombination08085909510006121824303642Predefined adverse events*Hot flushesA Arimidex T Tamoxifen C Combination 1060TC1229 1243A% patientsA vs TC vs TA vs C

12、 ORp valueA vs TC vs TA vs CORp valueATCA, Arimidex; C, combination; T, tamoxifen138253238% patientsPredefined adverse eventsVaginal bleedingThe ATAC Early breast cancer trial in postmenopausal patientsEndometrial sub-protocol resultsDemographics 285 women from 31 centres in 10 countries Mean age 60

13、 yrs ( 44 - 80 yrs ) Mean age at menopause 50 years 80% 4 years or more post menopauseBaseline Ultrasound12345678910100102030405060nEndometrial thickness (mm)Median endometrial thickness024681001224Endometrial thickness (mm)ArimidexTamoxifenCombinationTime (months)A vs TC vs TA vs C ORp valueATCA, A

14、rimidex; C, combination; T, tamoxifen3136% patientsPredefined adverse eventsEndometrial cancerATAC Summary Anastrozole is superior to 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

15、population (OR=0.42)Conclusions Anastrozole is the first and only AI to show superior efficacy and improved tolerability compared with tamoxifen in the treatment of EBC Overall risk-benefit assessment supports anastrozole becoming the future adjuvant treatment of choice in postmenopausal women Anast

16、rozole also shows promise for the chemoprevention of breast cancerAnalysis 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

17、.0068Comb vs TAM0.840.511.40 0.5132Arimidex (Anastrozole) in Breast cancer prevention: Design of IBIS II and data from ATACWhy 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 can

18、cer at all endpoints; striking reduction in contralateral breast cancer events Very low side-effect profile ATAC: incidence of new (contralateral) breast primaries in ITT population9 invasive05101520253035Tamoxifen(n=3116)Arimidex(n=3125)Combination(n=3125)5 DCIS3 DCIS23invasive5 DCIS30 invasiveNo.

19、casesWomen-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 contralateral tumour reduction rate for Arimidex7/100

20、0613314IBIS I Tamoxifen in preventionBreast cancer incidence is reduced by 32%101 ( IBIS 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 mgPlaceboIBIS II: DCIS Wom

21、en, 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 mgNSABP NSABP centres: USA and Canada Double-blind randomized study Postmenopausal (n=3000)Start date: Q4 2002Randomize1:15

22、 years anastrozole1 mg od 5 years tamoxifen20 mg od Prevention DCIS/ Neoadj5 yearsMetastaticDisease AI 1st2nd3rdAIAI AdjuvantTAM TAMTAMTAM1Arimidex in Breast CancerAI絕經(jīng)后絕經(jīng)后絕經(jīng)前絕經(jīng)前 ？AIAI絕經(jīng)前乳癌內(nèi)分泌治療絕經(jīng)前乳癌內(nèi)分泌治療 卵巢去勢 絕經(jīng)前 抗芳香化酶 瑞寧得（阿那曲唑）瑞寧得（阿那曲唑）氟隆氟隆 依西美坦依西美坦絕經(jīng)后卵巢切除加口服依西美坦卵巢切除加口服依西美坦治療絕經(jīng)前乳腺癌骨轉(zhuǎn)移長期緩解治療絕經(jīng)前乳腺癌骨

23、轉(zhuǎn)移長期緩解 霍秀蘭，女，41歲，住院號50982 2001.2 多發(fā)骨轉(zhuǎn)移，左鎖上淋巴結(jié)轉(zhuǎn)移， 穿刺活檢ER(+) PR(+) Her-2(+) 因患者未停經(jīng)，予以雙側(cè)卵巢切除術(shù)，1月后骨痛癥狀改善，骨質(zhì)修復(fù)； 2001.5.11口服依西美坦，2001.6.6 骨痛進(jìn)一步減輕，療效評價：PR Zoladex 諾雷得諾雷得 用于絕經(jīng)前乳腺癌患者的治療用于絕經(jīng)前乳腺癌患者的治療Zoladex與卵巢切除術(shù)與卵巢切除術(shù)治療復(fù)發(fā)轉(zhuǎn)移乳癌效果比較治療復(fù)發(fā)轉(zhuǎn)移乳癌效果比較Zoladex(n=67)卵巢切除（n=69）有效率（CR+PR）31%27%中位緩解期6 個月4 個月中位生存期37 個月33 個月Z

24、oladex 3.6mg 用于絕經(jīng)前進(jìn)展期乳腺癌II期臨床試驗(yàn)資料來源于 29 個 II期臨床試驗(yàn) (n=228 )CR+PR = 36.4%中位緩解間期 = 22 周耐受性好，未出現(xiàn)因不良反應(yīng)退出抑制雌激素的藥理作用是常見的面部潮紅 ( 75.9%) 性欲減退 ( 47.4% )Klijn JGM, et al. J Clin Oncol 2001; 19: 34353.變量變量LHRH類似物類似物L(fēng)HRH 類似物類似物 + Tamoxifen相對相對危險度危險度p 值值OR (CR+PR)30%39%PFS (中位中位)8.7 月月OS (中位中位)2.5 年年2.9 年年絕經(jīng)前晚期乳腺癌

25、的治療中LHRHa + tamoxifen 優(yōu)于單用 LHRHa EORTC Meta分析資料分析資料OR= 客觀反應(yīng)客觀反應(yīng)PFS = 無疾病進(jìn)展生存無疾病進(jìn)展生存OS= 總生存總生存Time (years)02468100102030405060708090100% patientsOverall survivalAll patientsLHRH agonist + tamoxifenLHRH agonistTamoxifen Zoladex = 卵巢切除術(shù)卵巢切除術(shù) Zoladex + TAM Zoladex Arimidex TAM Zoladex + Arimidex 諾雷得 + 瑞

26、寧得絕經(jīng)前乳癌內(nèi)分泌治療絕經(jīng)前乳癌內(nèi)分泌治療 諾雷德諾雷德 + 瑞寧得治療絕經(jīng)前患者瑞寧得治療絕經(jīng)前患者 田田XX，女，女，39歲，住院號歲，住院號53056 2001.10 多發(fā)骨轉(zhuǎn)移、肝轉(zhuǎn)移多發(fā)骨轉(zhuǎn)移、肝轉(zhuǎn)移 ER (+) PR (+) Her-2 (+) 2001.11.2002.1 Herceptin治療治療 PD 2002.01. 2002.3. TA化療化療2周期周期 SD 2 mo 諾雷德諾雷德 + 瑞寧得瑞寧得 PR 癥狀明顯改善，生活自理，癥狀明顯改善，生活自理，KPS 90分分 B超示肝臟病灶明顯縮小超示肝臟病灶明顯縮小 X光片示骨病灶好轉(zhuǎn)光片示骨病灶好轉(zhuǎn) 至至2002年年

27、11月疾病依然處于緩解期月疾病依然處于緩解期 A Randomized Trial of Zoladex + TAM vsZoladex + Arimidexin per/perimenopausal patients with hormone dependent ABCZoladex + TAM vs Zoladex + Arimidexin per/perimenopausal ABC patients 119 cases ABC First line ER (+) Zoladex 3.6mg / 28d + TAM 20mg/d Zoladex 3.6mg / 28d + Arimide

28、x 1mg/dZoladex + 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 Zoladex + Arimidex is effcient and well toleratedshould be considered for first line

29、 therapy in per/perimenopausal women with hormone dependent ABC Milla-Santos, SAB 2002,DecOverview of LHRHa in Breast Cancer Adjuvant Therapy Benefits of Reversible Ovarian Ablation1. EBCTCG. Lancet 1996; 348: 118996.2. Brincker H, et al. J Clin Oncol 1987; 5: 17718.Zoladex 用于輔助治療 Zoladex 3.6mg單用或與

30、tamoxifen合用在晚期乳腺癌治療中顯示其良好的療效和耐受性EBCTCG 1996年資料明確了絕經(jīng)前早期乳腺癌治療中卵巢去勢延長生存的作用Estimation of the hazard ratio for relapse between women with drug-induced amenorrhea ( group A ) and those without ( group B )10 published studies (1995)Results:1. In 9/10 studies RFS longer in group A than in group B NB Bonadon

31、nas 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% reduction in the rate of relapse*Aebi et al. Lancet 2000;355:1869-1874Impact of chemothera

32、py-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 added to standard treatment Potential replacement for chemotherapyZEBRA試驗(yàn)試驗(yàn)( Zoladex Early Brea

33、st Cancer Research Association )“諾雷德諾雷德”（戈舍瑞林）（戈舍瑞林）與與CMF輔助治療輔助治療絕經(jīng)期前和更年期婦女乳腺癌的療效比較絕經(jīng)期前和更年期婦女乳腺癌的療效比較ZEBRA 試驗(yàn)設(shè)計手術(shù)手術(shù) 放療放療Zoladex 3.6mg 1 / 28天天 2年年絕經(jīng)前絕經(jīng)前 / 圍絕經(jīng)期圍絕經(jīng)期 LNM() 早期乳腺癌早期乳腺癌 年齡年齡 50 歲歲隨訪隨訪CMF 1 / 28天天 x 6程程隨機(jī)化隨機(jī)化1:1 (開放開放 多中心多中心)腫瘤復(fù)發(fā)腫瘤復(fù)發(fā)死亡死亡死亡死亡ZEBRA 臨床試驗(yàn)結(jié)論Zoladex 在受體陽性病例與 CMF 療效相等ER水平檢測對治療起關(guān)

34、鍵作用Zoladex較之CMF 有更小的不良反應(yīng)Zoladex單藥治療 是對ER+、淋巴結(jié)陽性、絕經(jīng)前/圍絕經(jīng)期早期乳腺癌 CMF化療之外的又一治療選擇CMF x 6 Zoladex 3.6mg/28 天天x 3年年 +TAM 20mg/天天x 5 年年隨機(jī)分組隨機(jī)分組 1:1絕經(jīng)前絕經(jīng)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 可評估病例

35、可評估病例l淋巴結(jié)淋巴結(jié) + / ABCSG AC05 臨床試驗(yàn)奧地利乳腺癌輔助治療試驗(yàn) ABCSG AC05臨床試驗(yàn)結(jié)果 Zoladex 3.6mg 加用TAM組DFS顯著提高 總生存率亦有提高趨勢 加用TAM較CMF 對絕經(jīng)前受體陽性乳腺癌輔助治療更為有效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.l2,648 例例l隨機(jī)化試驗(yàn)隨機(jī)化試驗(yàn)l淋巴結(jié)淋巴結(jié) + / -l無論無論ER 狀態(tài)狀態(tài)l標(biāo)準(zhǔn)

36、治療標(biāo)準(zhǔn)治療 = 放療放療 化療化療 tamoxifen標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療手術(shù)手術(shù).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 無進(jìn)一步治療無進(jìn)一步治療 Houghton J, et al. ASCO 2000; 19: 93a, Abstr 359.Zoladex 用于絕經(jīng)前患者 (ZIPP) ZIPP結(jié)果乳癌術(shù)后在標(biāo)準(zhǔn)治療中加用 Zoladex DFS顯著改善顯著改善 ( HR = 0.77 p0.001)提高生存的趨勢提高生存的趨勢 ( HR=0.78 p=0.08 )

37、對側(cè)乳腺癌發(fā)生率降低對側(cè)乳腺癌發(fā)生率降低 ( HR=0.60 p=0.05 )ER+ve患者較患者較ERve 或不詳?shù)幕颊吒幸婊虿辉數(shù)幕颊吒幸鍴oughton J, et al. ASCO 2000; 19: 93a, Abstr 359.Baum M. Breast Cancer Res Treat 1999; 57: 30, Abstr 24.INT-0101 ECOG / SWOG 臨床試驗(yàn) 手術(shù)手術(shù)CAF x 6隨機(jī)化隨機(jī)化 1:1:1CAF x 6 Zoladex x 5 年年CAF x 6 Zoladex +TAM x 5 年年Davidson NE, et al. Breas

38、t 1999; 8: 2323, Abstr 069. 多中心試驗(yàn)1,504 例合格病例絕經(jīng)前淋巴結(jié)+ 、受體+ 比較局部復(fù)發(fā)率 / DFS / 生存率 INT-0101: 5-Year 結(jié)果 *CAF + Zoladex vs CAF alone#+目前尚無統(tǒng)計分析發(fā)表目前尚無統(tǒng)計分析發(fā)表 NS = 無意義無意義CAF CAF + Zoladex CAF + Zoladex + TAM (n=494) (n=502) (n=507)DFS (%) 67 70 ( p=0.06 )* 77 ( p0.01 )# 40歲患者歲患者DFS (%) 54 65+ 72+總體生存率總體生存率 85 8

39、6 (NS) 86 (NS)Kuter I. Oncologist 1999; 4: 299308.Davidson NE, et al. Breast 1999; 8: 2323, Abstr 069. Zoladex 輔助治療試驗(yàn)結(jié)果總結(jié) 研究研究治療治療疾病基本情況疾病基本情況DFS 結(jié)果結(jié)果 ZEBRAZOL vs. CMFLNM + ZOL對對 ER+ 患者與患者與 CMF等效等效(n=1,640)74% ER + AC05ZOL + TAMER / PR + ZOL + TAM 較較CMF更有效更有效(n=1,045)vs. CMF GROCTATAM + Ov. Supp. ER

40、 + 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更有效趨勢更有效趨勢 但無統(tǒng)計學(xué)差異但無統(tǒng)計學(xué)差異 (p=0.06)ZIPP ZOL + 標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療 70% ER + 標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療 ZOL (n=2,648) vs. 較單用標(biāo)準(zhǔn)治療更有效較單用標(biāo)準(zhǔn)治療更有效 標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療* 標(biāo)準(zhǔn)治療標(biāo)準(zhǔn)治療 = +/-放療放療 +/-化療化療 +/- tamoxifen 結(jié)結(jié) 論論 Zoladex對絕經(jīng)前

41、受體陽性早期乳癌輔助治療有效 Zoladex單藥或聯(lián)合TAM療效不比化療效果差 在標(biāo)準(zhǔn)化療的基礎(chǔ)上加 ZoladexTAM的效果更好 Zoladex可作為可作為 絕經(jīng)前、受體陽性早期乳癌輔助治療絕經(jīng)前、受體陽性早期乳癌輔助治療 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 CTTAM or none1. TAM 2. CT + TAM1. CT + TAM 2. TAM ER+veO

42、v abl, oophorectomy or GnRH analogue; CT, chemotherapyGuidelines for adjuvant therapyof breast cancerSt Gallen 2001Risk groupER-vePremenopausalPostmenopausalNACT CT QuestionsDoes endocrine therapy add to chemotherapy? Answer: yesDoes chemotherapy add to optimal endocrine therapy? Answer:In premenopa

43、usal ER-positive breast cancer:unknownprobably no or only minor extra benefitreplacement of tamoxifen by an aromataseinhibitor might improve optimal endocrine therapyStudy design BOOG1 Multicentre, open, randomized trial in high-risk ER-positive primary breast cancerMain question: does chemotherapy (CT) add to optimal endocrine th