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1、转移性乳腺癌内科治疗进展,王中华2012.05.09讲课,Age Distribution,Data from Shanghai Cancer Institute,5-yr disease-free,5-yr recurrence,Gain from adjuvant chemotherapy,70%,30%,70%,10%,20%,Risk reduction:30%20%,10/30=33%Absolute benefit:10%70%always free 20%always recurred,超过 2/3 的乳腺癌复发为远处转移,远处转移(61%-75%)5年生存率 41.3%,对侧乳
2、腺癌(9%-11%)5年生存率83.4%,局部复发(16%-28%)5年生存率 59.3%,BIG=Breast International Group.Baum et al.Lancet.2002;359:2131.Thrlimann et al.N Engl J Med.2005;363:2747.,晚期乳腺癌治疗目的,控制疾病，缓解症状 提高患者的生活质量，延长高质量的生存期,全面评估,内分泌,化疗,乳腺癌的分子分型与内科治疗方法,Luminar A/BER（+）和/或PR（+）,Her-2 阳性,所有类型MBC受体三阴性,全身化疗 针对所有类型的晚期乳腺癌,晚期乳腺癌的化疗发展史,19
3、55,1965,1975,1985,1995,2005,2015,Cyclophosphamide1959,Methotrexate1971,Doxorubicin1974,Gemcitabine2004,Capecitabine1998,Lapatinib 2006,Accessed on-line at http:/www.fda.gov/cder/cancer/druglistframe.htm,Docetaxel1996,Paclitaxel1994,Trastuzumab2000,Approved specificallyfor first-line use in MBC,Nab p
4、aclitaxel2005,Ixabepilone 2007,Bevacizumab 2008,5-FU1962,Platinums,晚期乳腺癌化疗适应证,病变发展迅速内脏转移，如肝、肺广泛转移无病生存期（DFS）2年ER和PR阴性既往内分泌治疗无效,化疗的应用方法,联合 Vs.单药（AB Vs.A）ORRTTP OS 或 联合 Vs.序贯（AB Vs.AB）TTP、OS未显示有明显优势,联合化疗 VS.单药,优先选择联合化疗有广泛转移或有临床症状，需要快速控制病情或肿瘤进展迅速或威胁生命的转移或患者的耐受性较好优先考虑单药化疗无重要脏器转移或无临床症状或转移部位少,辅助,首选,蒽环,蒽环类联
5、合紫杉类 AT,蒽环类CAF、CEFAC、EC,未化疗,CMF,复发转移性乳腺癌化疗药物选择原则,多西他赛联合卡培他滨 TX紫杉醇吉联合吉西他滨 GP,或,蒽环类及紫杉类治疗失败,卡培他滨、长春瑞滨、吉西他滨、铂类、伊沙匹隆、ABX,First-Line Second-LineDoxorubicin 35-50%125-30%1Epirubicin52-68%28%Paclitaxel29-63%119-57%Docetaxel47-65%139-58%Capecitabine 25%120-27%1Gemcitabine 23-37%113-41%1Vinorelbine 40-44%117
6、-36%,1Esteva F et al,Oncologist 2001(6):133-146,单药治疗MBC有效率,白蛋白结合型紫杉醇III 期临床试验:试验设计,Gradishar et al.J Clin Oncol.2005;23:77947803,MBC,III 期临床试验:注射用紫杉醇（白蛋白结合型）显著延长了患者的至肿瘤进展时间,Gradishar et al.J Clin Oncol.2005;23:77947803,标准紫杉醇l(n=224),注射用紫杉醇（白蛋白结合型）(n=229),中位时间=23.0 周(19.426.1),中位时间=16.9 wks(15.120.9)
7、,无进展百分比,P=0.006风险比=0.75,周,0816243240485664 72 80 88 96,104,112,120,III 期临床试验:毒性,Gradishar et al.J Clin Oncol.2005;23:77947803,Capecitabine 1,250mg/m2 BID days 114+Docetaxel 175mg/m2 day 1,Docetaxel 100mg/m2 day 1,3-weekly cycles,n=255,n=256,OShaughnessy et al.J Clin Oncol.2002;20:2812-2823,SO14999研究
8、：多西他赛联合希罗达 vs.多西他赛,R,主要研究终点:TTP,Gemzar 1,250mg/m2 BID days 1，8+Paclitaxel 175mg/m2 day 1,Paclitaxel 175mg/m2 day 1,3-weekly cycles,n=529,OShaughnessy et al.J Clin Oncol.2002;20:2812-2823,JHQG 研究设计紫杉醇联合吉西他滨 vs.紫杉醇,R,主要研究终点:TTP,蒽环类和紫杉类均耐药乳腺癌的化疗,希罗达 伊沙匹隆(Ixabepilone)希罗达（2B）NVB GEMNVB 希罗达NVB DDP/CBPGEM
9、DDP/CBP,phase III Spanish Breast Cancer Research Group(GEICAM)trial 疗效：毒副作用：GEMNVB vs.NVBG3/4 ANC下降 66 vs.44（p=0.0074）ANC减少性发热 11 vs.6（p=0.15）非血液学毒性两组无显著差异,蒽环和紫杉类治疗失败 GEMNVB vs.NVB,Lancet Oncology2007;8:219-225,gemcitabine 1200 mg/m2 days 1 and 8 vinorelbine 30 mg/m2 days 1 and 8 q21d,vinorelbine 30
10、 mg/m2 days 1 and 8 q21d,PD,252 pts MBCpretreated with anthracyclines and taxanes,Epothilone:Ixabepilone(BMS-247550)Bristol-Myers Squibb,New York,NY,Activity in multiple tumor modelsLow susceptibility to tumor resistance mechanisms MRP and P-gp efflux pumps()tubuiln overexpression tubuiln mutationsA
11、ntitumor activity in taxane resistance models,S.cellulosum,Epothilone B,Ixabepilone,59%,36%,23%,22%,35%,12%,41%,Study Design:International,Randomized,Phase III trial,BMS 046,Ixabepilone 40 mg/m2 IV over 3 hrs Day 1,every 3 wks+Capecitabine 1000 mg/m2 orally BID Days 1-14,every 3 wks,Capecitabine 125
12、0 mg/m2 orally BID Days 1-14 every 3 wks,Patients with metastatic or locally advanced breast cancerto anthracyclines PRE/RESISTANT and taxaneRESISTANT,Stratified by visceral metastases previous MBC chemotherapy anthracycline resistance study site,PD,Ixabepilone Plus Capecitabine vs Capecitabine Alon
13、e,Ixabepilone Plus Capecitabine vs Capecitabine Alone,Overall response rate*I+C vs C:35%vs 14%(P.0001)PFS benefit for combination arm*(5.8 vs 4.2 mos)辅助化疗后快速复发（5.6 vs.2.8 mos）2008 SABCS,*As determined by independent radiologic review,Months,Proportion Progression Free,4,0,8,12,16,20,24,0.0,0.2,0.4,0
14、.6,0.8,1.0,28,32,36,PFS by Independent Radiologic Review,Capecitabine,Ixabepilone+Capecitabine,HR:0.75(95%CI:0.64-0.88)P=.0003,Vahdat LT,et al.ASCO 2007.Abstract 1006.,Grade 3/4 peripheral neuropathy:23%for ixabepilone plus capecitabine vs 0%for capecitabine alone 感觉神经/累积性/可逆性中位恢复至 G1 or 基线:6 weeks,
15、More hematologic toxicity observed in ixabepilone arm,Ixabepilone Plus Capecitabine vs Capecitabine Alone,October 22,2007 FDA Approves Ixempra(ixabepilone,Bristol-Myers Squibb)for Advanced Breast Cancer PatientsThe U.S.Food and Drug Administration has approved Ixempra(ixabepilone),a new anti-cancer
16、treatment,for use in patients with metastatic or locally advanced breast cancer who have not responded to certain other cancer drugs.,何时停药？治疗越长越好？,效不更方至病情进展或不可耐受的毒性选择其中一个药物用至进展或不可耐受的毒性更换其他一种化疗药希罗达，PLD更换成内分泌治疗耐受性好，作用机制不同，减少耐药停止用药（6-8周期后），观察定期复查，进展再给予处理,三种不同剂量多西他赛治疗MBC,*P 0.05,Paclitaxel(200 mg/m2）d2+
17、Epirubicin(90 mg/m2)d1 orDoxorubicin(50 mg/m2)d1,every 3 weeks 6-8cyclesN=459,CR/PR/SD,Paclitaxel 175 mg/m2,no further chemotherapy,every 3 weeks 8cycles,*HR+HT,Paclitaxel maintenance JCO,2006,R,Gennari A,et al,JCO,2006,3912-8,N=215(255),The primary end point:PFS,Gennari A,et al,JCO,2006,3912-8,MANT
18、A1 study,Possible Explanationfor MANTA1 study(Paclitaxel maintenance),Use of concurrent endocrine therapy in 60%of hormone receptor-positive patientsControl arm patients actual received maintenance hormonal therapyThe concurrent of chemo and hormonal may reduce the efficacyToxicity of paclitaxel Sen
19、sory neuropathy grade 2 occurred in 26%,grade 3 in 6%and grade 4 in 2%of the patients in maintenancegrade ANC 24%,GEICAM 2001-01 Study Phase III trial,288 pts MBC,2008 ESMO,observation,PLD 40mg/m2 q28d 6,一线,CR/PR/SD,AT（50/75）6,155 pts,78 pts,77 pts,R,A：ADMT：TXTPLD：脂质体ADM,*Statistically significant;a
20、ssessed in futility analysis.,Randomized Studies of Chemotherapy Duration in MBC,MBC的化疗,为何用？目的何时用？适应症怎么用？方法（联合、单药）用何药？三级选用（蒽环，蒽环耐药，蒽环及紫杉均耐药）何时停？五种措施,生物靶向治疗 与化疗联合,Targeted therapies for breast cancer,mTOR,Tam,AI,Her-2阳性MBC Herceptin Lapatinib,HER2阳性定义,IHC 3+,CISH+,FISH+,或,或,免疫组织化学法(IHC)色素原位杂交法(CISH)荧
21、光原位杂交法(FISH),Hercetpin单药治疗晚期乳腺癌的疗效,HO649g HO551g HO650（关键试验）（期）（关键试验）_ N(intent-to-treat)222 46 114#CR 8 1 7#PR 26 4 23 有效率 15 11 26中位缓解期（月）9.1 6.6 18.8中位生存期（月）13 14 24.4_,Herceptin联合化疗一线治疗Her-2阳性MBC,H:Herceptin,T:TXT,P:PAX,C:CBP,X:Xeloda,曲妥珠单抗联合泰索帝：同时还是序贯使用?HERTAX,Bontenbal et al.ASCO 2008.Abstract
22、 1014.,99 例 HER2+,一线 M+主要目的:PFS次要目的:RR&OS,曲妥珠单抗每周+泰索帝 100 mg/m,曲妥珠单抗 每周,随机,泰索帝 100 mg/m,序贯,PD,Lapatinib 针对Her-2阳性MBCFDA于2007.3.13批准上市规格250mg/150#,Lapatinib:Targeting EGFR and HER2,Lapatinib oral tyrosine kinase inhibitor of ErbB1 and ErbB2Blocks signaling through EGFR and HER2 homodimers and heterod
23、imersMay also prevent signaling between ErbB1/ErbB2 and other ErbB family members,Rusnak DW,et al.Mol Cancer Ther.2001;1:85-94.Xia W,et al.Oncogene.2002;21:6255-6263.,Geyer CE,et al.ASCO 2006.Clinical Science Symposium.,EGF100151:Lapatinib+Capecitabine in Advanced Breast Cancer,到疾病进展时间（ITT Populatio
24、n）,70,20,40,60,80,0,100,10,20,30,40,50,60,0,Time(weeks),Patients Progression Free*(%),EGF100151,Geyer CE,et al.N Engl J Med 2006;355(26):2733-2743.,GBG-26：曲妥珠单抗加希罗达 vs.希罗达，延长TTP近3个月（8.2m vs.5.6m P0.05)EGF104900：曲妥珠单抗加拉帕替尼 vs.拉帕替尼，显著延长TTP（2.8m vs.1.9m P=0.008）,含曲妥珠单抗一线治疗Her-2阳性MBC进展后,von Minckwitz G
25、et al.J Clin Oncol 2008:26(May 20 Suppl);abs 1025.OShaughnessy J et al.J Clin Oncol 2008:26(May 20 Suppl);abs 1015.,PCH 或wPCH,贝伐单抗,Paclitaxel Bevacizumab in MBC(E2100),N=715Locally recurrentor 1st-line MBC,值得关注的是贝伐单抗组有更多感染、3/4 级的高血压、蛋白尿、头痛、心脑血管局部缺血,Miller et al.N Engl J Med.2007;357:2666-2676,Result
26、s,Paclitaxel 90 mg/m2 d 1,8,15 q4w,Paclitaxel 90 mg/m2 d 1,8,15 q4w+bevacizumab 10 mg/kg d1,15,Yellow text indicates statistically significant values.,R,Docetaxel Bevacizumab in MBC(AVADO),N=705Locally recurrentor 1st-line MBCStratification:RegionPrior taxane/time to relapse since adjuvant chemoMeas
27、urable diseaseHR status,R,Docetaxel 100mg/m2+Placebo q3w,Docetaxel+Bevacizumab 7.5mg/kg q3w,Docetaxel+Bevacizumab 15mg/kg q3w,Bevacizumab continued to disease progression;all pts given option to receive bevacizumab with 2nd-line chemo;docetaxel administered for maximum of 9 cycles,Miles et al.ASCO 2
28、008.Late-Breaking Abstract 1011.,Phase III Studies:E2100 and AVADO,*Miller et al.N Eng J Med.2007;*Miles et al.ASCO 2008(LBA#1011).,Yellow text indicates statistically significant values.,E2100 and AVADO Safety data,*Miller et al.N Eng J Med.2007;*Miles et al.ASCO 2008(LBA#1011).*VTE:no increase in
29、bevacizmab arm in either study.,Ongoing Phase III Trials Evaluating Bevacizumab in First-Line MBC,GEICAM 2006-11,AVEREL,HER2+DiseaseTrastuzumab-containingregimens,Hormonal therapy,RIBBON 1,RIBBON 1,RIBBON 1,Capecitabine,AVADO,Single-agenttaxane therapy,Anthracycline-based chemotherapy,Bevacizumab,晚期
30、乳腺癌的内分泌治疗 针对Luminal A/B 的 MBC ER（+）PR（+）ER（+）或 PR（+）,内分泌治疗与化学治疗,内分泌改变肿瘤的内环境来抑制其生长对正常细胞影响小，副作用小28周起效，缓解期长不需要升白、止吐等支持治疗治疗费用较低,化疗阻断肿瘤复制来杀死肿瘤细胞对正常细胞有杀伤，副作用大12周起效，缓解期短常需要升白、止吐等支持治疗治疗费用一般较高,晚期乳腺癌内分泌治疗适应证,患者年龄35岁无病生存期（DFS)2年骨和软组织转移；无症状的内脏转移ER和或PR阳性,晚期乳腺癌的内分泌治疗,月经状况 治疗药物 绝经前 戈舍瑞林(Goserelin，zoladex）亮丙瑞林(Leup
31、rolide acetate）绝经后 瑞宁得(Anastrozole)来曲唑(Letrozole)依西美坦 各种年龄 他莫昔芬，孕激素,阿那曲唑的一线疗效优于TAM,Arimidex(anastrozole)versus Tamoxifen for the First-line Treatment of Advanced Breast Cancer in Postmenopausal Womenfrom Trials 0030 and 0027 Known to be Receptor-positive,025试验设计:来曲唑 vs.他莫昔芬 作为晚期一线治疗,Mouridsen et al.
32、J Clin Oncol.2001;19:2596.,试验人群:绝经后;局部晚期或局部复发或转移的乳腺癌;ER 和/或 PgR阳性或未知,来曲唑的一线疗效优于TAM,非甾体类 AI 失败后的内分泌治疗MBC,芳香化酶抑制剂作用机理:非甾体 VS 甾体,雄激素,非甾体类（抑制剂）(eg,anastrozole,letrozole),芳香化酶,甾体类（灭活剂）(eg,exemestane),Geisler et al.Clin Cancer Res.1998;4:2089-93.,EFECT:Evaluation of Treatment Options Following AI Failure,
33、Fulvestrant IM injection loading-dose regimen*(n=351),Exemestane25 mg/day orally(n=342),Postmenopausal women with hormone receptorpositive,progressing/recurring advanced breast cancer after nonsteroidal AI(N=693),Progression,death,or withdrawal,*Fulvestrant loading-dose regimen comprised 500 mg on D
34、ay 0,250 mg on Days 14 and 28,and 250 mg monthly thereafter.,Gradishar W,et al.SABCS 2006.Abstract 12.,EFECT:Similar TTP in Patients Treated With Fulvestrant or Exemestane,Gradishar W,et al.SABCS 2006.Abstract 12.,Exemestane：3.7 monthsFulvestrant：3.7 months P=.65,绝经后MBC的内分泌治疗,一线,二线,三线,TAM,孕激素,雄激素,AI
35、,TAM,孕激素,辅助,AI,孕激素?,氟维司群?,TAM?,1985,2002,新方向 靶向联合内分泌,2008 SABCS,EGF30008：拉帕替尼联合来曲唑 随机期临床,2008 SABCS,PFS,P：拉帕替尼，L:来曲唑 T：TAM,绝经后 ER/PR阳性 MBC一线,受体三阴性乳腺癌,Triple-Negative BC and PARP Inhibition,BRCA1BRCA2,1.DNA damage via platinum adducts and DNA crosslinking,2.PARP1 up-regulation Base-excision repair,3.
36、PARP1 inhibition,4.Replication fork collapseDouble strand DNA break,CELL SURVIVAL,CELL DEATH,PARP1,PARP1,BSI-201,Pt,Pt,Pt,Pt,Pt,PARP1,PARP:聚腺苷二磷酸核糖聚合酶,Phase II Trial of BSI-201:Schema,Patients receiving gemcitabine/carboplatin could cross-over to the other treatment arm upon documented disease progr
37、ession.,RANDOMIZE,21-DayCycle,BSI-201(5.6 mg/kg,IV,d 1,4,8,11)Gemcitabine(1000 mg/m2,IV,d 1,8)Carboplatin(AUC 2,IV,d 1,8)N=61,Gemcitabine(1000 mg/m2,IV,d 1,8)Carboplatin(AUC 2,IV,d 1,8)N=62,RESTAGINGPost-Cycle 2&every 6-8 wks,Metastatic TNBCN=120,Phase II Trial of BSI-201 Results:Efficacy,OShaughnes
38、sy et al.ASCO 2009;Abstract 3.,Phase II Trial of BSI-201 Results:Safety,No differences in hematologic or non-hematologic toxicitiesNo differences in GC dose reductions between arms,转移性乳腺癌内科治疗共识,晚期乳腺癌的主要治疗目的是提高患者的生活质量，延长高质量的生存期由于新药的不断问世以及合理使用，晚期乳腺癌治疗的疗效不断提高化疗与内分泌治疗是治疗晚期乳腺癌的两种同用有效地治疗方法，但分别有各自的适应证对Her-2neu阳性的患者，化疗联合生物治疗能显著提高疗效通过合理的内科治疗，能显著延长患者的生存期，部分患者甚至能够长期生存,THANK YOU FOR YOUR ATTENTION,
