1、乳腺癌内分泌治疗乳腺癌内分泌治疗王东民王东民北京大学第一医院外科北京大学第一医院外科90.779.377.277.176.873.673.372.969.368.86348.239.536.83426.826.524.322.721.4美国美国,SEER:白人白人 美国美国,SEER:黑人黑人 新西兰新西兰:非毛利人非毛利人 新西兰新西兰:毛利人毛利人 加拿大加拿大 意大利意大利,帕尔马帕尔马 丹麦丹麦 瑞典瑞典 美国美国,洛杉矶洛杉矶:菲律宾人菲律宾人 英国英国,英格兰和威尔士英格兰和威尔士 美国美国,洛杉矶洛杉矶:日本人日本人德国德国,东部洲东部洲新加坡新加坡:中国人中国人 美国美国,洛杉
2、矶洛杉矶:中国人中国人 香港香港 台湾台湾 中国中国,上海上海 日本日本,大阪大阪 日本日本,Yamagata 美国美国,洛杉矶洛杉矶:韩国人韩国人 020406080100世界女性乳腺癌发病率世界女性乳腺癌发病率,1988-1992,1988-1992 Cancer Incidence in Five Continents,Vol.VII,1988-1992Cancer Registry Annual Report Republic of China,1993-1998每每100,000 100,000 人口发病人口发病 乳腺癌发病的最关键因素乳腺癌发病的最关键因素雌激素作用雌激素作用综合治
3、疗（立体治疗）综合治疗（立体治疗）外科治疗外科治疗放疗放疗化疗化疗内分泌治疗内分泌治疗分子靶向治疗分子靶向治疗对乳腺癌认识的演变对乳腺癌认识的演变Hippocrates和和Galen的的black bile学说学说l 12世紀，William of Salicet(1210-1277)，那些發瘋的黑色膽汁是包含於乳房內的血管。當時使用caustics(浸蝕劑)，使乳房腐爛l Andeas Versalius(1514-1564)人體構造，以外科切除術來治療乳癌l 1757年Le Dran，乳癌加腋下淋巴結腫大，其預後較差，建立起乳癌是一個局部疾病的觀念l 有描述記載的乳房腫瘤切除是拿坡崙外科醫
4、師Larrey为DAblay夫人所作的手術。她描寫外科醫師使用刀子從我的胸骨上把乳房刮起來，前後只花20分鐘，Larrey醫師臉色蒼白，但被血液噴的全臉都是血，醫師的表情悲傷、害怕、恐懼到似乎要死去一樣。古代手術代表著痛苦、殘害古代手術代表著痛苦、殘害Halstedian theory l G.Morgagni 病理解剖學，Rudolf Virchow 細胞病理學 1846年William Morton乙醚全身麻醉示範成功 1867年J.Lister消毒滅菌概念的確立l Halsted 发表，The results of operations for the cure of cancer of
5、 the breast performed at Johns Hopkins hospital from June 1889 to January 1894 the efficiency of an operation is measured truer in terms of local recurrence than ultimate cure。當時局部再發率:60-82%肿瘤扩散有一定规律，由区域淋巴结到全身肿瘤扩散有一定规律，由区域淋巴结到全身Halsteds radical mastectomy 19th20th(50yrs)l William Stewart Halsted bor
6、n Sept.23,1852,New York,N.Y.,U.S.died Sept.7,1922,Baltimore,Md.l American pioneer of scientific surgery who established at Johns Hopkins University,BaltimoreFisherian theory l 肿瘤细胞扩散无固定模式肿瘤细胞扩散无固定模式，区域淋巴结对播散无，区域淋巴结对播散无屏障作用，反映肿瘤生物学行为屏障作用，反映肿瘤生物学行为l 血行播散与淋巴转移无相关性，局部复发为血行血行播散与淋巴转移无相关性，局部复发为血行播散的局部表现，是预
7、后决定因素播散的局部表现，是预后决定因素l 不同局部治疗方式对生存率无影响，不同局部治疗方式对生存率无影响，NSABP B-04 l 三期临床试验肯定保乳手术疗效：三期临床试验肯定保乳手术疗效：NSABP B-06(Bernard Fisher),Milan Cancer Institute(Umberto Veronesi)Systemic disease onsetBreast Conserving treatmentUmberto Veronesi,M.D.Bernard Fisher,M.D.Spectrum theory 1980年 Samuel Hellman（芝加哥大學）提出，s
8、pectrum意思：部份乳癌，雖然沒有局部淋巴結轉移，但確有遠處轉移，相反，有一些病灶已經很大，但卻沒有淋巴結或遠處轉移，大部份乳癌是屬於中間型 這個觀念是對淋巴結、淋巴管道、淋巴循環系統的解剖學、生理學、生物學行為以及分子生物學的瞭解所引發出來的新觀念 肿瘤的内在特性肿瘤的内在特性乳癌内分泌治疗的挑战乳癌内分泌治疗的挑战l Breast cancer-heterogeneous disease,ER+/-tumorsl Predict risk-difficultl one size fits all?l Endocrine therapy may be the best or only s
9、ystemic treatmentl Optimal endocrine therapy:Based on varied response to endocrine therapy.individuation?Endocrine pathways and the breast卵巢切除卵巢切除l George Beatson,was the first to publish a case report.He postulated an association between the hormonal action of the ovaries and the proliferation of b
10、reast cells and tested this in June 1895.A 33 year old woman had noticed a small lump on her left breast when breast feeding her first child.This lump got larger after the birth of her second baby and she went to the Glasgow Royal Infirmary.A 12 cm tumour was removed but the cancer was already far a
11、dvanced.She was referred to the Glasgow Cancer Hospital,and Beatson removed both her ovaries.The woman survived for nearly four years before dying of recurrent disease.He reported the case to the Edinburgh Medico-Chirurgical Society and published details in the Lancet in July 1896.l 这是乳腺癌作为全身性疾病治疗的开
12、始这是乳腺癌作为全身性疾病治疗的开始Sir George Thomas Beatson,He took his degree from Clare College,Cambridge,in 1869,studied medicine at Edinburgh University.He was later examiner in surgery at Edinburgh;Consulting Surgeon to Glasgow Infirmary and Chairman of the Scottish Branch of the Royal Red Cross Society end th
13、e St.Andrews Ambulance Association.He died at Glasgow in 1933SIR G.T.BEATSONHierarchy of evidence on ovarian ablation for breast cancer Continued maintenance of the reviewl 2000+Continued maintenance of the reviewl 2000 Next cycle of review by Early Breast Cancer Trialists Collaborative Groupl 1998
14、Review published as Cochrane reviewl 1996 Second full review published in Lancetl 1992 First full review is publishedl 1990 Partial review is published l 1983 Early Breast Cancer Trialists Collaborative Group is formed l 1948 First randomised trial beginsl 1900+Case series and non-randomised studies
15、 are publishedl 1896 Beatson publishes first case reportl 1889 Schinzinger suggests possible useSERMsl 1967年 Jensen发现 ER-hormonal responsive markerl Tamoxifen Golden standardTamoxifen evidence(adjuvant)l In 1986,as monotherapy for early breast cancer in node-positive,postmenopausal women.1l NATO(The
16、 Nolvadex Adjuvant Trial Organisation 1983)2 evaluate the effectiveness in early breast cancer.l The Stockholm trial(1996)3l The Scottish trialists group(2001)4l NSABP B-14 trial(1996)5l EBCTCG(1998)6 1.Jordan VC 1999 Melville,NY.PRR,Inc 2.Lancet.1983 Feb 5;1(8319):257-61.3.JNCI 1996:88;1543-9 4.JNC
17、I,Vol.93,No.6,456-462,2001 5.JNCI 1996:88;1529-42 6.Lancet.1998,vol 351,(9114):1451-1467Tamoxifen for early breast cancer:an overview of the randomised trials Early Breast Cancer Trialists Collaborative Groupl 37000 women in 55 such trials,Nearly 8000 ER-,18000 ER+,12000 untested tumours.1,2,and 5-y
18、ear of adjuvant tamoxifenl Recurrence reductions(10-yr follow-up)were 21%,29%and 47%l Mortality reductions were 12%,17%,and 26%.Similar for node+and node-disease,but the absolute mortality reductions were greater in node+women(109%vs.56%).l Contralateral breast cancer reductions were 13%,26%and 47%l
19、 Endometrial cancer was doubled(1,2 years)and quadrupled in trials of 5 years of tamoxifen.The absolute decrease in contralateral breast cancer was about twice as large as the absolute increase in endometrial cancer.The Lancet Volume 351,Issue 9114,1998,1451-1467Optimal Duration of Therapy l Two lar
20、ge European trials,with tamoxifen for five-year had fewer recurrences and deaths than for two-year.1,2l Two North American trials,compared tamoxifen lasting 5-year with 10-year 3,4,5 l Scotland trial compared 5-year with indefinite tamoxifen 6l There was no convincing evidence(5years)was beneficial.
21、There was a trend toward a detrimental effect for 5years.4,6 On the basis of these results,it now seems reasonable to recommend that tamoxifen for five years1.The Swedish Breast Cancer Cooperative Group.J Natl Cancer Inst 1996;88:1543-1549.2.The Current Trials Working Party of the Cancer Research Ca
22、mpaign Breast Cancer Trials Group.J Natl Cancer Inst 1996;88:1834-1839.3.Fisher B,N Engl J Med 1989;320:479-484.4.Fisher B,J Natl Cancer Inst 1996;88:1529-1542.5.Tormey DC,J Natl Cancer Inst 1996;88:1828-1833.6.Steward HJ,the Scottish Cancer Trials Breast Group.Br J Cancer 1996;74:297-299.National S
23、urgical Adjuvant Breast and Bowel Project Trials B-14,B-24,and P1.A total of 8793 women received tamoxifen,and a total of 8824 received placebo.Data from Fisher et al.Tamoxifen and risk of endometrial cancer Risk and prognosis of endometrial cancer after tamoxifen for breast cancer Liesbeth Bergmanl
24、 Methods:309 endometrial cancer and 860 matched controlsl Findings:Risk of endometrial cancer increased with longer duration of tamoxifen use(p50%芳香化酶抑制剂在辅助内分泌治疗中的试验设计芳香化酶抑制剂在辅助内分泌治疗中的试验设计 试验名称试验名称 设计设计例数例数中位随访时间中位随访时间（月）（月）结果结果ATAC双盲双盲T a m v s A n a.V s Tam+Ana.936668无 病 生 存 率 延 长无 病 生 存 率 延 长（HR=
25、0.87）;复发风复发风险下降（险下降（HR=0.79）;远处转移下降远处转移下降（HR=0.86）;对侧乳对侧乳癌下降癌下降42%总生存相总生存相同同 ITA双盲双盲Tam 23年后年后Ana vs Tam 32年年42624复发下降（复发下降（HR=0.36）;无病生存率延长；无病生存率延长；总生存相同总生存相同A R N O/ABCSG8 Tam 2年后年后Ana vs Tam 3年年962/226228无 病 生 存 率 延 长无 病 生 存 率 延 长（HR=0.60）;远处转远处转移下降（移下降（HR=0.60）；）；总生存相同总生存相同BIG1-98双盲双盲Tam vs Letr
26、o.T a m+L e t r o v s Letro+Tam802825.8无 病 生 存 率 延 长无 病 生 存 率 延 长（HR=0.81）;远处转远处转移下降移下降27%；复发风险下降复发风险下降17%；总生存相同总生存相同MA.17 双盲双盲T a m 5 年 后年 后 L e t r o.V s placebo518726.8无病生存率延长无病生存率延长;复发下降（复发下降（HR=0.57）总生存总生存N+组延长组延长 IES 031 双盲双盲Tam 23年后年后Exe.vs Tam 32年年474230.6无病生存率延长无病生存率延长4.7%;复发下降（复发下降（HR=0.68
27、）；）；对侧乳癌下降对侧乳癌下降(HR=0.44)王东民.中国医学论坛报 31卷11期 2005.3.24ClassificationlInitial adjuvant therapy ATAC,BIG1-98lSequential therapy ITA,ARNO/ABCSG8,IES 031lExtending therapy MA.17EfficacyDisease-free survival-YESOverall survival?ATAC:Disease-free survival(HR-positive population)A261825402448235522682014830
28、T2598251623982304218919327740123456At risk:Follow-up time(years)0510152025Absolute difference:1.6%2.6%2.5%3.3%HR=hormone receptor;ITT=intent-to-treatEvents(%)Anastrozole(A)Tamoxifen(T)HR0.830.87HR+95%CI(0.730.94)(0.780.97)p-value0.0050.01ITTbenefitBIG1-98:benefitMA.17:Disease-Free Survival0204060801
29、00Disease-Free Survival10.02308229820.01327129530.062461040.018318050.091160.0000.025752582MonthsFEMARA PlaceboFEMARAPlaceboGoss et al.N Engl J Med.2003;349:TBD.Number at risk:Women surviving free of breast cancer(%)Coombes RC et al.N Engl J Med.2004;350:10811092IES:disease-free survival 0Exemestane
30、 Tamoxifen Hazard ratio=0.68(95%CI:0.560.82)Log rank test:p-value 0.00112340255075100Proportiondisease-free(%)52/216878/217360/169690/168244/75776/73020+6/2010/23620/2380ExemestaneTamoxifenNo.of events/at risk:18+4/185Years from randomisationevents occurring more than 4 years after randomisationABCS
31、G/ARNO:Event-free survivalZero point=2 years after surgery07580859095100012345Event-free survival(%)ANA vs TAM p=0.0009 HR 0.60 95%CI 0.440.81EFS time in years*ANATAMAt risk:1606343176TAMANA161812171243858874593623375178ITA:disease-free survival0.00.20.40.60.81.00123456AnastrozoleTamoxifenNo.of pts2
32、23225Obs1745p-value0.0002YearsBoccardo F et al.Breast Cancer Res Treat 2003;82(Suppl 1):S6S7(abs 3)Proportion disease-freeWhy approved AIadjuvant?l The Food and Drug Administration1 approved tamoxifen and anastrozole for use as adjuvant therapy on the basis of data on disease-free survivall Early Br
33、east Cancer Trialists Collaborative Group2 indicates that differences in disease-free survival regularly predict differences in overall survival1.Johnson JR,Williams G,Pazdur R.J Clin Oncol 2003;21:1404-1411.2.Early Breast Cancer Trialists Collaborative Group.Lancet 1998;351:1451-1467When to use AIs
34、?-problem Initial vs.Sequentiall No datal Cost(2-year Tam treatment period)argument Recurrence,serious thromboembolic events,endometrial cancers,gynaecological screening interventions,the four-fold hysterectomies.l Side-effects 1.No new safety concerns(three analyses,full 5-year treatment period)2.S
35、ide-effects with anastrozole are predictable and manageable 3.The peak in early hazard rates(Tam)is not seen with anast.early benefit in reduced recurrences(AI),the higher rates of adverse events(Tam),the benefit of starting treatment with anastrozole is evidentThe Lancet.Volume 365,Number 9466,2005
36、Smoothed hazard rates for recurrence0.51.01.52.02.50123456Follow-up time(years)Annualhazardrates(%)Anastrozole Tamoxifen 0ITT=intent-to-treat ATAC Trialists Group.Lancet 2005;365:6062;Howell A.Breast Cancer Res Treat 2004;88(Suppl 1):S7,abs 1ER+PR-与与HER2Choice AIs marker？-May beDowsett,M.San Antonio
37、 2003BIG1-98:A comparison of the proportional risk reduction of adjuvant tamoxifen therapy based on PgR status in populations of ER-positive patients ER+PgR-(n=2000)ER+PgR+(n=7000)%Reduction in recurrence rates(SD)32 637 3%Reduction in death rates(SD)18 716 4Early Breast Cancer Trialists Collaborati
38、ve Group.Lancet 351:14511467 ASCO Technology Assessment on the use of AIs as adjuvant therapy ER+PR-Although this subset analysis was retrospective,the number of events considered was relatively large.Some Panel members felt the results should be factored into the decision-making process,while other
39、 Panel members did not favor using this information in clinical decisions.The clinical significance of epidermal growth factor receptor(EGF-R)in human breast cancer:a review on 5232 patientsJG Klijn,PM Berns,PI Schmitz and JA Foekens l EGF-R positivity was present in 2500(48%)of 5232 breast tumors i
40、n 40 different series of patients Immunological methods tends to be lowerl Nearly all studies indicate a negative relationship between EGF-R and steroid receptor status.EGF-R positive is twice as high in ER or PR-negative tumors compared to ER or PR-positive tumorsl EGF-R-positive tumors have poor p
41、rognosis significant correlation with tumor gradeEndocrine Reviews,Vol 13,3-17ASCO Technology Assessment on the use of AIs as adjuvant therapyHER2 over expressionl For postmenopausal women with breast cancer overexpressing HER-2,higher response rates have been reported for aromatase inhibitors as co
42、mpared with tamoxifen in two randomized neoadjuvant trials 1,2l Based on the available clinical evidence,the Panel would generally recommend that HER-2 status not be considered when making choices about adjuvant hormonal therapy.l However,that some Panel members are more inclined to recommend initia
43、l therapy with an aromatase inhibitor in postmenopausal women with HER-2positive tumors.1.Smith I,Dowsett M:Breast Cancer Res Treat 82,2003 2.Ellis MJ,Coop A,Singh B,et al:J Clin Oncol 19:3808-3816,2001EfficacySide effectATAC:adverse eventsT40.910.213.20.83.44.52.429.47.7A35.75.43.50.24.12.81.635.61
44、1.0Completion analysisp-value0.00010.00010.00010.020.10.00040.020.00010.0001Hot flushesVaginal bleedingVaginal dischargeEndometrial cancer*Ischaemic cardiovascular diseaseVenous thromboembolic eventsDeep venous thromboembolic eventsJoint symptomsTotal fractures*T38.16.616.2 9.5 2.42.61.18.34.119.2L3
45、3.63.3148.8 1.02.71.2 8.75.843.6Primary core analysis(%)Hot flushesVaginal bleedingNight sweatsNausea Thromboembolic eventsVomitingCVA/TIAOther cardiovascularBone fractureHypercholesterolemiaBIG 1-98:adverse events Thrlimann B.St Gallen presentation 2005Fracture rate comparison(Direct)l ATAC(68mon)，
46、Anast.11.0%vs.Tam.7.7%（p0.0001）l ATAC(47mon)，Anast.7.1%vs.Tam.4.4%（p0.001）l ATAC(33mon)，Anast.5.9%vs.Tam.3.7%（pATAC(47mon)ATAC(33mon)2.TAM后使用后使用AI，骨折较低骨折较低?BIG1-98(25.8mon)MA.17(26.8mon)3.正常人群中发生骨折的基线水准？骨盐预防？正常人群中发生骨折的基线水准？骨盐预防？Fracture rate comparison(Indirect)HRT=1.48Placebo=1.91Healthy womenAge=6
47、3WHI(n=16,608)Tamoxifen=1.80Placebo=1.84Breast cancer preventionAge 50(61%)PI(n=13,175)Anastrozole=2.26Tamoxifen=1.56Early breast cancer(adjuvant)Age=64 ATAC(n=6,186)Annual Fracture rate(%)SettingAverage age(years)Clinical studyATAC Trialists Group.Lancet 2005;365:6062Fisher et al.J Natl Cancer Inst
48、 1998;90:13711388 Womens Health Initiative Writing Group.JAMA 2002;288:321333ATAC:Serious adverse eventsSerious adverse events leading to deathDrug-related serious adverse events leading to death p-value0.60.5Tamoxifen(%)(n=3094)3.6 0.3Anastrozole(%)(n=3092)3.3 0.2BIG 1-98:乳癌乳癌乳癌乳癌AI？TAM？Guidelines&
49、Consensusl St.Gallen 2005l NCCN 2005l ASCO Technology Assessment on the use of AIs as adjuvant therapy 2004Risk groupPre.Post.Pre.Post.Node-negLower RiskTam.or NilTam.or AI,or NilTam.or NilTam.or Nil;AI?ER-AI无效无效Node-neg Node-posAverage RiskET(Tam OFS)or CTTam OFS(AI OFS?)Tam.or AI,CTTamCTAICTTam OF
50、S,or CT alone CT(AI OFS?)CTTamCTAISt.Gallen 2005 RecommendationsTreatment According to Responsiveness to Endocrine TherapiesEndocrine Resp.Endocrine Resp.DoubtRisk groupPre.Post.Pre.Post.Node-posHigher RiskCTTam OFS,OR(AI+OFS instead of Tam out trial)?CTTam,ORCTAI,Exe.or Anast.after 2-3 yrs TamLetro
