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1、乳腺癌内分泌治疗,王东民北京大学第一医院外科,乳腺癌发病的最关键因素雌激素作用,综合治疗（立体治疗）,外科治疗放疗化疗内分泌治疗分子靶向治疗,对乳腺癌认识的演变,Hippocrates和Galen的black bile学说,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Andeas Versalius(1514-1564) 人體構造，以外科切除術來治療乳癌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有描述記載的乳房腫瘤切除是拿坡崙外科醫師
2、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,Halstedian theory,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Halsted 发表，The results of operations for the cure of cancer of the breast per
3、formed 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,Halsteds radical mastectomy 19th20th(50yrs),William Stewart Halsted born Sept. 23, 1852, New York, N.Y
4、., U.S.died Sept. 7, 1922, Baltimore, Md.American pioneer of scientific surgery who established at Johns Hopkins University, Baltimore,Fisherian theory,肿瘤细胞扩散无固定模式 ，区域淋巴结对播散无屏障作用，反映肿瘤生物学行为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，是预后决定因素不同局部治疗方式对生存率无影响，NSABP B-04 三期临床试验肯定保乳手术疗效： NSABP B-06 (Bernard Fisher), Mila
5、n Cancer Institute (Umberto Veronesi),Systemic disease onset,Breast Conserving treatment,Umberto Veronesi , M. D.,Bernard Fisher, M.D.,Spectrum theory,1980年 Samuel Hellman（芝加哥大學）提出， spectrum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
6、解所引發出來的新觀念,肿瘤的内在特性,乳癌内分泌治疗的挑战,Breast cancer -heterogeneous disease, ER+ /- tumorsPredict risk-difficultone size fits all ?Endocrine therapy may be the best or only systemic treatmentOptimal endocrine therapy: Based on varied response to endocrine therapy. individuation?,Endocrine pathways and the br
7、east,卵巢切除,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 breast cells and tested this in June 1895.A 33year old woman had noticed a small lump on her left breast when breast feeding her first ch
8、ild. This lump got larger after the birth of her second baby and she went to the Glasgow Royal Infirmary. A 12cm tumour was removed but the cancer was already far advanced. She was referred to the Glasgow Cancer Hospital, and Beatson removed both her ovaries. The woman survived for nearly four years
9、 before dying of recurrent disease. He reported the case to the Edinburgh Medico-Chirurgical Society and published details in the Lancet in July 1896. 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
10、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 the St. Andrews Ambulance Association. He died at Glasgow in 1933,SIR G. T. BEATSON,Hierarchy of evidence on ovarian ablation for breast cancer C
11、ontinued maintenance of the review,2000+ Continued maintenance of the review2000 Next cycle of review by Early Breast Cancer Trialists Collaborative Group1998 Review published as Cochrane review1996 Second full review published in Lancet1992 First full review is published1990 Partial review is publi
12、shed 1983 Early Breast Cancer Trialists Collaborative Group is formed 1948 First randomised trial begins1900+ Case series and non-randomised studies are published1896 Beatson publishes first case report1889 Schinzinger suggests possible use,SERMs,1967年 Jensen发现 ER-hormonal responsive markerTamoxifen
13、 Golden standard,Tamoxifen evidence (adjuvant),In 1986, as monotherapy for early breast cancer in node-positive, postmenopausal women.1NATO (The Nolvadex Adjuvant Trial Organisation 1983)2 evaluate the effectiveness in early breast cancer.The Stockholm trial (1996)3The Scottish trialists group(2001)
14、4NSABP B-14 trial (1996)5EBCTCG (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.JNCI, Vol. 93, No. 6, 456-462, 2001 5.JNCI 1996:88;1529-42 6.Lancet. 1998,vol 351,(9114):1451-1467,Tamoxifen for early breast cancer: an overview of the randomis
15、ed trials Early Breast Cancer Trialists Collaborative Group,37000 women in 55 such trials, Nearly 8000 ER- ,18000 ER+, 12000 untested tumours. 1, 2, and 5-year of adjuvant tamoxifenRecurrence reductions(10-yr follow-up)were 21%,29% and 47%Mortality reductions were 12% , 17%, and 26%. Similar for nod
16、e+ and node- disease, but the absolute mortality reductions were greater in node+ women (109% vs. 56%). Contralateral breast cancer reductions were 13%, 26% and 47% Endometrial cancer was doubled (1 , 2 years) and quadrupled in trials of 5 years of tamoxifen .The absolute decrease in contralateral b
17、reast cancer was about twice as large as the absolute increase in endometrial cancer.,The Lancet Volume 351, Issue 9114 , 1998, 1451-1467,Optimal Duration of Therapy,Two large European trials, with tamoxifen for five-year had fewer recurrences and deaths than for two-year.1,2Two North American trial
18、s, compared tamoxifen lasting 5-year with 10-year 3,4,5 Scotland trial compared 5-year with indefinite tamoxifen 6There was no convincing evidence (5years) was beneficial. There was a trend toward a detrimental effect for 5years.4,6 On the basis of these results, it now seems reasonable to recommend
19、 that tamoxifen for five years,1.The Swedish Breast Cancer Cooperative Group. J Natl Cancer Inst 1996;88:1543-1549.2.The Current Trials Working Party of the Cancer Research Campaign 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
20、,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 Surgical Adjuvant Breast and Bowel Project Trials B-14, B-24, and P1. A total of 8793 women received tamoxifen, and a t
21、otal 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 Bergman,Methods : 309 endometrial cancer and 860 matched controlsFindings: Risk of endometrial cancer increased with lon
22、ger duration of tamoxifen use (p0001), with relative risks of 20 (12-32) for 2-5 yrs and 69 (24-194) for 5 yrs vs. no users. Endometrial cancers of stage III and IV occurred more frequently in long-term tamoxifen users ( 2 years) than in non-users (174% vs 54%, p=0006). 3-year endometrial-cancer-spe
23、cific survival was significantly worse for long-term tamoxifen users than for non-users (76% for 5 years, 85% for 2-5 years vs 94% for non-users, p=002). time-dependent and dose-dependent poor differentiation ,poor survival,Lancet 2000; 356: 881-87,The risk of venous thromboembolic disease associate
24、d with adjuvant hormone therapy for breast carcinomaSteven R. Deitcher, M.D. *, Marcelo P. V. Gomes, M.D.,METHODSThe authors conducted a computerized PubMed literature search for English-language articles published between January 1966 and December 2003. RESULTSThe risk of VTE was increased twofold
25、to threefold during tamoxifen or raloxifene use for breast carcinoma chemoprevention. In the setting of early-stage breast carcinoma, the risk of VTE is increased both with tamoxifen use and anastrozole use. Such risk appeared to be lower with anastrozole. CONCLUSIONSAll agents appear to increase th
26、e risk of VTE. Available data were insufficient to support any assumptions that newer hormonal forms are safer than tamoxifen in women with advanced breast carcinoma.,Cancer 2004,肾上腺切除,1952年 Huggins发表 Inhibition of human mammary and prostatic cancers by adrenalectomy 7例为ABC中6例为绝经前并已行卵巢切除术。结果：2例 部分缓解
27、，1例稳定，3例进展。 证实雌激素存在卵巢外合成途径1973年Griffiths在Cancer上报道第一个阻断肾上腺激素合 成药物Aminoglutethemide 治疗转移性乳腺癌。药物去势 达到了与手术去势相同OR(objective response)。但减少 了手术去势的风险。,New Stars in the Sky of Treatment for Early Breast CancerMartine J. Piccart-Gebhart, M.D., Ph.D.,AI,Cumulative distribution of breast cancer diagnoses by ag
28、e,Hankey BF, et al. J Natl Cancer Inst Monogr 1994;16:714.,绝经后受体阳性50%,芳香化酶抑制剂在辅助内分泌治疗中的试验设计,王东民.中国医学论坛报 31卷11期 2005.3.24,Classification,Initial adjuvant therapy ATAC, BIG1-98Sequential therapy ITA, ARNO/ABCSG8, IES 031Extending therapy MA.17,Efficacy,Disease-free survival-YESOverall survival?,ATAC:D
29、isease-free survival (HR-positive population),A,2618,2540,2448,2355,2268,2014,830,T,2598,2516,2398,2304,2189,1932,774,0,1,2,3,4,5,6,At risk:,Follow-up time (years),0,5,10,15,20,25,Absolute difference:,1.6%,2.6%,2.5%,3.3%,HR=hormone receptor; ITT=intent-to-treat,Events(%),Anastrozole (A),Tamoxifen (T
30、),HR0.830.87,HR+,95% CI(0.730.94)(0.780.97),p-value0.0050.01,ITT,benefit,BIG1-98:,benefit,MA.17 : Disease-Free Survival,0,20,40,60,80,100,Disease-Free Survival,Months,FEMARA,Placebo,FEMARA,Placebo,Goss et al. N Engl J Med. 2003;349:TBD.,Number at risk:,Women surviving free of breast cancer (%),Coomb
31、es RC et al. N Engl J Med. 2004; 350: 10811092,IES: disease-free survival,0,Exemestane Tamoxifen,Hazard ratio = 0.68 (95% CI: 0.560.82)Log rank test: p-value 0.001,1,2,3,4,0,25,50,75,100,Proportiondisease-free (%),52/2168,78/2173,60/1696,90/1682,44/757,76/730,20+6/201,0/2362,0/2380,Exemestane,Tamoxi
32、fen,No. of events/at risk:,18+4/185,Years from randomisation,events occurring more than 4 years after randomisation,ABCSG/ARNO:Event-free survival,Zero point = 2 years after surgery,0,75,80,85,90,95,100,0,1,2,3,4,5,Event-free survival (%),ANA vs TAM p=0.0009 HR 0.60 95% CI 0.440.81,EFS time in years
33、*,ANA,TAM,At risk:,1606,343,176,TAM,ANA,1618,1217,1243,858,874,593,623,375,178,ITA: disease-free survival,AnastrozoleTamoxifen,No. of pts223225,Obs1745,p-value0.0002,Years,Boccardo F et al. Breast Cancer Res Treat 2003; 82 (Suppl 1): S6S7 (abs 3),Proportion disease-free,Why approved AIadjuvant?,The
34、Food and Drug Administration1 approved tamoxifen and anastrozole for use as adjuvant therapy on the basis of data on disease-free survivalEarly Breast Cancer Trialists Collaborative Group2 indicates that differences in disease-free survival regularly predict differences in overall survival,1.Johnson
35、 JR, Williams G, Pazdur R. J Clin Oncol 2003;21:1404-1411. 2.Early Breast Cancer Trialists Collaborative Group. Lancet 1998;351:1451-1467,When to use AIs? -problem Initial vs.Sequential,No dataCost (2-year Tam treatment period) argument Recurrence, serious thromboembolic events, endometrial cancers,
36、 gynaecological screening interventions, the four-fold hysterectomies.Side-effects 1. No new safety concerns (three analyses, full 5-year treatment period) 2. Side-effects with anastrozole are predictable and manageable 3. The peak in early hazard rates (Tam) is not seen with anast. early benefit in
37、 reduced recurrences (AI), the higher rates of adverse events (Tam), the benefit of starting treatment with anastrozole is evident,The Lancet.Volume365,Number9466,2005,Smoothed hazard rates for recurrence,0.5,1.0,1.5,2.0,2.5,3.0,0,1,2,3,4,5,6,Follow-up time (years),Annualhazardrates(%),0,ITT = inten
38、t-to-treat,ATAC Trialists Group. Lancet 2005; 365: 6062; Howell A. Breast Cancer Res Treat 2004; 88 (Suppl 1): S7, abs 1,ER+ PR-与HER2,Choice AIs marker？-May be,Dowsett, M. San Antonio 2003,BIG1-98:,A comparison of the proportional risk reduction of adjuvant tamoxifen therapy based on PgR status in p
39、opulations of ER-positive patients,Early Breast Cancer Trialists Collaborative 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
40、felt the results should be factored into the decision-making process, while other 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 Sc
41、hmitz and JA Foekens,EGF-R positivity was present in 2500 (48%) of 5232 breast tumors in 40 different series of patients Immunological methods tends to be lowerNearly all studies indicate a negative relationship between EGF-R and steroid receptor status . EGF-R positive is twice as high in ER or PR-
42、 negative tumors compared to ER or PR- positive tumorsEGF-R-positive tumors have poor prognosis significant correlation with tumor grade,Endocrine Reviews, Vol 13, 3-17,ASCO Technology Assessment on the use of AIs as adjuvant therapy,HER2 over expressionFor postmenopausal women with breast cancer ov
43、erexpressing HER-2, higher response rates have been reported for aromatase inhibitors as compared with tamoxifen in two randomized neoadjuvant trials 1,2Based on the available clinical evidence, the Panel would generally recommend that HER-2 status not be considered when making choices about adjuvan
44、t hormonal therapy.However, that some Panel members are more inclined to recommend initial 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, 2001
45、,Efficacy,Side effect,ATAC:adverse events,T40.910.213.20.83.44.52.429.47.7,A35.75.43.50.24.12.81.635.611.0,Completion analysis,Hot flushesVaginal bleedingVaginal dischargeEndometrial cancer*Ischaemic cardiovascular diseaseVenous thromboembolic eventsDeep venous thromboembolic eventsJoint symptomsTot
46、al fractures*,T38.16.616.2 9.5 2.42.61.18.34.119.2,L33.63.3148.8 1.02.71.2 8.75.843.6,Primary core analysis (%),Hot flushesVaginal bleedingNight sweatsNausea Thromboembolic eventsVomitingCVA/TIAOther cardiovascularBone fractureHypercholesterolemia,BIG 1-98: adverse events,Thrlimann B. St Gallen pres
47、entation 2005,Fracture rate comparison(Direct),ATAC(68mon)， Anast. 11.0% vs. Tam. 7.7%（pATAC(47mon)ATAC(33mon)2. TAM后使用AI，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？,Fracture rate comparison(Indirect),HRT = 1.48Placebo = 1.91,Healthy womenAge = 63,WHI(n=16,608),Tamoxifen = 1.80Placeb
48、o = 1.84,Breast cancer preventionAge 50 (61%),PI(n=13,175),Anastrozole = 2.26Tamoxifen = 1.56,Early breast cancer (adjuvant)Age = 64,ATAC(n=6,186),Annual Fracture rate(%),SettingAverage age (years),Clinical study,ATAC Trialists Group. Lancet 2005; 365: 6062Fisher et al. J Natl Cancer Inst 1998; 90:
49、13711388 Womens Health Initiative Writing Group. JAMA 2002; 288: 321333,ATAC:Serious adverse events,Serious adverse events leading to deathDrug-related serious adverse events leading to death,p-value0.60.5,Tamoxifen (%)(n=3094) 3.6 0.3,Anastrozole (%)(n=3092) 3.3 0.2,BIG 1-98:,乳癌,乳癌,AI？,TAM？,Guideli
50、nes & Consensus,St. Gallen 2005NCCN 2005ASCO Technology Assessment on the use of AIs as adjuvant therapy 2004,St.Gallen 2005 Recommendations,Treatment According to Responsiveness to Endocrine Therapies,Endocrine Resp.,Endocrine Resp.Doubt,St.Gallen 2005 Recommendations,Treatment According to Respons
