早期乳腺癌辅助化疗进展中国医学科学院肿瘤医院徐兵河 .ppt

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1、早期乳腺癌辅助化疗进展早期乳腺癌辅助化疗进展中国医学科学院肿瘤医院中国医学科学院肿瘤医院 徐兵河徐兵河Breast Cancer Incidence Trends Over TimeCancer Incidence Trends in China 2005 2015 Cancer Incidence Trends in China 2005 2015 Incidence Rates Projection by Cancer TypeIncidence Rates Projection by Cancer TypePer 100,000 CAGR 2.98%CAGR 4.5%CAGR 0.65%

2、CAGR 2.35%CAGR 0.99%CAGR 2.60%Source:Estimates of Cancer Incidence in China for 2000 and Projections for 2005,Yang L,et al.中国乳腺癌发病概况中国乳腺癌发病概况v每年约有19万新发乳腺癌病例 2002年全国乳腺癌年龄标化发病率:18.7/100,000；死亡率:5.5/100,000v发病率：城市农村v高发年龄段：4550岁近近15年来乳腺癌年来乳腺癌发病率上升发病率上升死亡率下降死亡率下降死亡率下降的原因死亡率下降的原因v早期诊断 v综合治疗The benefits of

3、 chemotherapy data from clinical trailsnEarly Breast Cancer Trialists Collaborative Group(EBCTCG).194 randomised trials of adjuvant chemotherapy(CMF,CAF,CEF)or hormonal therapy(TAM)that began by 1995.Lancet 2005Placebo53.3%37.147.90102030405060Time(years)051510Recurrence(%)15-year gain 12.3%(SE 1.6)

4、Log-rank 2p0.0000115-year probabilities of recurrence in women aged 50 years,with/without polychemotherapyPolychemotherapy41.1%35.524.6Younger women,35%node-positive;older women,70%node-positive;SE=standard errorEBCTCG.Lancet 2005;365:1687-1717Placebo42.4%20.435.00102030405060Breastcancermortality(%

5、)15-year gain 10.0%(SE 1.6)Log-rank 2p0.00001Polychemotherapy32.4%Time(years)05151015.727.115-year probabilities of breast cancer mortality in women aged 50 years,with/without polychemotherapyEBCTCG.Lancet 2005;365:1687-1717Younger women,35%node-positive;older women,70%node-positive010203040506015-y

6、ear gain 4.1%(SE 1.2)Log-rank 2p0.00001Placebo57.6%Polychemotherapy53.4%48.805151035.444.129.415-year probabilities of recurrence in women aged 50-69 years,with/without polychemotherapyTime(years)EBCTCG.Lancet 2005;365:1687-1717Recurrence(%)Younger women,35%node-positive;older women,70%node-positive

7、Placebo50.4%21.338.3010203040506015-year gain 3.0%(SE 1.3)Log-rank 2p0.00001Polychemotherapy47.4%18.705151035.415-year probabilities of breast cancer mortality in women aged 50-69 years,with/without polychemotherapyTime(years)Younger women,35%node-positive;older women,70%node-positiveEBCTCG.Lancet 2

8、005;365:1687-1717Breastcancermortality(%)Placebo45.0%38.326.5010203040506015-year gain 11.8%(SE 1.3)Log-rank 2p0.0000115-year probabilities of 15-year probabilities of recurrence recurrence in women in women with ER+(or ER-unknown)disease,with ER+(or ER-unknown)disease,with/without 5 years with/with

9、out 5 years tamoxifentamoxifenAbout 5 years tamoxifen33.2%Time(years)05151015.124.7ER=oestrogen receptor;10,386 women:20%ER-unknown,30%node-positiveEBCTCG.Lancet 2005;365:1687-1717Recurrence(%)010203040506015-year gain 9.2%(SE 1.2)Log-rank 2p0.00001Placebo34.8%About 5 years tamoxifen25.6%25.70515101

10、1.98.317.815-year probabilities of breast cancer 15-year probabilities of breast cancer mortalitymortality in women with ER+(or ER-unknown)disease,in women with ER+(or ER-unknown)disease,with/without 5 years with/without 5 years tamoxifentamoxifenTime(years)10,386 women:20%ER-unknown,30%node-positiv

11、eEBCTCG.Lancet 2005;365:1687-1717Breastcancermortality(%)010203040506001354Time(years)25-year gain 11.9%(SE 1.0)Log-rank 2p0.00001Nil25.8%About 5 years tamoxifen alone13.9%5-year recurrence in women with ER+(or 5-year recurrence in women with ER+(or ER-unknown)disease withER-unknown)disease with no

12、chemotherapyno chemotherapy,with/without 5 yearswith/without 5 years tamoxifentamoxifenEBCTCG.Lancet 2005;365:1687-1717Recurrence(%)7056 women:19%node-positive01020304050600135425-year gain 10.6%(SE 1.5)Log-rank 2p0.00001Chemotherapy alone28.1%Chemotherapy+about 5 years tamoxifen17.5%5-year recurren

13、ce in women with ER+(or 5-year recurrence in women with ER+(or ER-unknown)diseaseER-unknown)disease with chemotherapywith chemotherapy,with/without 5 yearswith/without 5 years tamoxifentamoxifenTime(years)EBCTCG.Lancet 2005;365:1687-1717Recurrence(%)3330 women:53%node-positiveChemotherapy versus end

14、ocrine therapy in the treatment of breast cancerlIn premenopausal women,polychemotherapy improves 15-year recurrence by 12.4%and survival by 10.0%lIn postmenopausal women,15-year gains in recurrence and survival are smaller(4.2%and 3.0%,respectively)lanthracycline-based polychemotherapy reduces the

15、annual death rate by 38%for women 50 years and by 20%for those of age 50-69 yearsEBCTCG.Lancet 2005;365:1687-1717Chemotherapy versus endocrine therapy in the treatment of breast cancerlIn patients with ER+disease,tamoxifen improves 15-year recurrence by 11.8%and survival by 9.2%lGains made with tamo

16、xifen treatment appear to be irrespective of adjuvant chemotherapyEBCTCG.Lancet 2005;365:1687-1717乳腺癌辅助化疗进展乳腺癌辅助化疗进展1960s 1970s 1980s 1990s 2000 20021960s 1970s 1980s 1990s 2000 2002手术手术CMF1蒽环类药物蒽环类药物AC2,CAF3,FEC4Dose5,6CEF1207,15FEC1008EC9Meta-analysis12紫杉类药物紫杉类药物10,11,13DI14 Sequene 生物治疗生物治疗 1 Bon

17、adonna 1976 2 B-15,B-23 1990,2000 3 SECSG 1994 4 Coombes 1996 5 Bonadonna 1995 6 Wood 1994 7 MA-05 1998 8 FASG 2001 9 Belgium 2001 10 CALGB 200011 B-28 200012 EBCTCG 1998,200013 TAC vs FAC14 CALGB 974115 MA.05 10 years!评估紫杉类乳腺癌辅助化疗的评估紫杉类乳腺癌辅助化疗的随机临床试验随机临床试验lCALGB 9344 AC vs AC PlNSABP B-28 AC vs AC

18、P*lECTO A CMF vs AP CMFlBCIRG 001 TAC vs FAClNSABP B-27 AC vs ACTlPACS 01 FEC vs FEC TlECOG 2197 AT vs AClECOG 1199 ACP3 vs P1 vs D3 vs D1l.T=多西他赛 P=泰素*在化疗时同时给予三苯氧胺紫杉烷辅助化疗荟萃分析紫杉烷辅助化疗荟萃分析:方法方法l目的目的:比较含紫杉烷辅助化疗方案与不含紫杉烷比较含紫杉烷辅助化疗方案与不含紫杉烷辅助化疗方案辅助化疗方案u主要结局指标主要结局指标:OSu次要结局指标次要结局指标:DFS,毒性毒性l11项随机对照试验项随机对照试验

19、,17056名患者名患者l平均中位随访平均中位随访54.6个月个月l总结果有利于紫杉烷总结果有利于紫杉烷uOS:HR 0.81(95%CI,0.75-0.88;p.00001)uDFS:HR 0.81(95%CI,0.75-0.86;p.00001)Nowak 等等.ASCO 2007.文摘号文摘号 545.Five Year follow-up of INT C9741:Five Year follow-up of INT C9741:Dose-dense chemotherapy is safe and Dose-dense chemotherapy is safe and effecti

20、veeffectiveHudis C,Citron M,Berry D,Cirrincione C,Gradishar W,Davidson N,Martino S,LivingstonR,Ingle J,Perez E,Abrams J,Schilsky R,EllisM,Carpenter J,Muss H,Norton L,&Winer EOn behalf of CALGB/ECOG/SWOG/NCCTGinvestigatorsHER2+Breast Cancer HER2+Breast Cancer and Adjuvant Therapyand Adjuvant TherapyH

21、er-2lHer-2是一种原癌基因，该基因与乳腺癌细胞增殖有关。l约2530%的乳腺癌Her-2过度表达。lHer-2的过度表达的乳腺癌患者生存期短，预后差。l成为乳腺癌治疗的理想靶点。HER2HER2阳性对生存期的影响阳性对生存期的影响HER2HER2阳性的乳腺癌患者的生存率降低！阳性的乳腺癌患者的生存率降低！中位生存期中位生存期HER2 HER2 阳性阳性3 3 年年HER2 阴性阴性67 年年Slamon DJ et al.Science 1987;235:17782HER2 HER2 状态状态:预示肿瘤对治疗的反应预示肿瘤对治疗的反应 内分泌治疗内分泌治疗 HER2HER2阳性患者相对

22、耐药阳性患者相对耐药 CMFCMF方案方案 HER2HER2阳性患者相对耐药阳性患者相对耐药 蒽环类蒽环类 对蒽环类相对敏感对蒽环类相对敏感 紫杉类药物紫杉类药物相对敏感相对敏感赫赛汀赫赛汀 (曲妥珠单抗曲妥珠单抗):):人源化抗人源化抗HER2HER2单克隆抗体单克隆抗体l l高度亲和性高度亲和性(K Kd d=0.1nM)=0.1nM)和特异性和特异性l l95%95%人源化人源化,5%,5%鼠抗，显鼠抗，显著降低免疫原性著降低免疫原性(HAMA)HAMA)l全球第一种治疗实体瘤的单克隆抗体，为全球第一种治疗实体瘤的单克隆抗体，为HER2HER2癌基因癌基因阳性的肿瘤患者带来了新的希望！阳

23、性的肿瘤患者带来了新的希望！lTrastuzumab是包含了完整的muMAB 4D5抗原决定簇的人类IgG1的人体球蛋白Killer cellKiller cellMacrophageMacrophageHerceptinHerceptin stimulates ADCCstimulates ADCC(antibody-dependent cell-mediated cytotoxicity)(antibody-dependent cell-mediated cytotoxicity)Fc receptorFc receptorHerceptin :作用机制作用机制Trastuzumab in

24、 adjuvant,phase III studies赫赛汀赫赛汀辅助治疗循证医学证据辅助治疗循证医学证据新英格兰杂志新英格兰杂志20052005年年1010月月北美研究结果发表北美研究结果发表新英格兰杂志新英格兰杂志20052005年年1010月月HERAHERA研究结果发表研究结果发表新英格兰杂志新英格兰杂志20062006年年2 2月月FinHERFinHER结果发表结果发表1703159114341127742383140169815351330984639334127100806040200Patients(%)Months from randomisation12361 year

25、trastuzumabObservation0186No.at risk 赫赛汀辅助治疗赫赛汀辅助治疗HERA研究无进展生存时间研究无进展生存时间(ITT)2430EventsHR95%CIp value0.640.54,0.76 0.00013-yearDFS80.674.32183216.3%HERA研究研究DFS风险风险(ITT)观察组和赫赛汀一年治疗组观察组和赫赛汀一年治疗组观察组和赫赛汀一年治疗组观察组和赫赛汀一年治疗组Months since randomisation1703162714981190794407146100806040200Patients(%)Months fr

26、om randomisationObservationNo.at risk 1698160814531097711366139赫赛汀辅助治疗赫赛汀辅助治疗HERA研究总生存时间研究总生存时间(ITT)1 year trastuzumabEventsHR95%CIp value0.660.47,0.910.01153-yearOS92.489.71236018624305990Median FU 2 yrs2.7%赫赛汀辅助治疗北美临床赫赛汀辅助治疗北美临床N9831/B31无进展生存时间无进展生存时间随机分组后年随机分组后年Romond et al N Engl J Med 2005;353:

27、1673-1684Romond et al N Engl J Med 2005;353:1673-168487%85%67%75%HR=0.48;p0.000110090807060500123452-year median follow-up AC PAC PHnEventsACPH1672133ACP1679261Patients(%)18%Romond et al N Engl J Med 2005;353:1673-1684Romond et al N Engl J Med 2005;353:1673-168401234020406080100120Rate per 1000 Wome

28、n/Yr随机分组后年随机分组后年ACACTHTHACTN9831/B31N9831/B31远处转移风险远处转移风险赫赛汀辅助治疗北美临床赫赛汀辅助治疗北美临床N9831/B31总生存时间总生存时间ACACTHTH94%94%91%91%87%92%ACTNDeathsACT167992ACTH 167262HR=0.67,2P=0.015Years From RandomizationPatients(%)Years10090807001234593%86%84%80%80%91%86%77%73%n107410751073Events7798147ACDHDCarboHACD6050HR=0

29、.49HR=0.61BCIRG 006研究研究DFSSlamon et al 2005 SABCS(abstract#1)无病生存率无病生存率总生存率总生存率HR(95%CI)P值值HR(95%CI)P值值N9831/B-310.48(0.410.57)0.000010.65(0.510.84)0.0007HERA 0.54(0.430.67)0.00010.76(0.471.23)0.26FinHER0.42(0.210.83)0.010.41(0.161.08)0.07BCIRG AC-TH TCH0.61(0.480.86)0.67(0.540.83)1 cm辅助内分泌治疗辅助内分泌治疗

30、+辅助化疗辅助化疗+曲妥珠单抗（曲妥珠单抗（1类）类）淋巴结阳性（指淋巴结阳性（指1个或多个个或多个同侧腋窝淋巴结有同侧腋窝淋巴结有1个或多个或多个转移灶个转移灶2 mm）辅助内分泌治疗辅助内分泌治疗+辅助化疗辅助化疗+曲妥珠单抗（曲妥珠单抗（1类）类）BINV-5辅助化疗辅助化疗不含曲妥珠单抗的化疗方案（均为不含曲妥珠单抗的化疗方案（均为1类）类）lFAC/CAF（氟尿嘧啶氟尿嘧啶/多柔比星多柔比星/环磷酰胺）或环磷酰胺）或FEC/CEF（环磷酰胺（环磷酰胺/表柔比星表柔比星/氟尿嘧啶氟尿嘧啶）lAC（多柔比星（多柔比星/环磷酰胺）环磷酰胺）序贯紫杉醇序贯紫杉醇lEC（表柔比星（表柔比星/环

31、磷酰胺）环磷酰胺）lTAC（多西他赛（多西他赛/多柔比星多柔比星/环磷酰胺环磷酰胺）联合）联合非格司亭非格司亭支持支持lACMF（多柔比星序贯环磷酰胺（多柔比星序贯环磷酰胺/甲氨喋呤甲氨喋呤/氟尿嘧啶）氟尿嘧啶）lECMF（表表柔比星序贯环磷酰胺柔比星序贯环磷酰胺/甲氨喋呤甲氨喋呤/氟尿嘧啶）氟尿嘧啶）lCMF（环磷酰胺（环磷酰胺/甲氨喋呤甲氨喋呤/氟尿嘧啶）氟尿嘧啶）lAC4（多柔比星（多柔比星/环磷酰胺）序贯环磷酰胺）序贯紫杉醇紫杉醇4，每，每2周周1次，联合非格司亭支持次，联合非格司亭支持lATC（多柔比星序贯紫杉醇再序贯环磷酰胺）（多柔比星序贯紫杉醇再序贯环磷酰胺）每每2周周1次，联合

32、非格司亭支持次，联合非格司亭支持lFECT（氟尿嘧啶氟尿嘧啶/表表柔比星柔比星/环磷酰胺环磷酰胺序贯多西他赛）序贯多西他赛）lTC（多西他赛和环磷酰胺）（多西他赛和环磷酰胺）含曲妥珠单抗的化疗方案（均为含曲妥珠单抗的化疗方案（均为1类）类）首选的辅助方案：首选的辅助方案：lACT同步曲妥珠单抗（多柔比星同步曲妥珠单抗（多柔比星/环磷酰胺环磷酰胺序贯紫杉醇曲妥珠单抗序贯紫杉醇曲妥珠单抗)l其他辅助方案：其他辅助方案：l多西他赛曲妥珠单抗多西他赛曲妥珠单抗 FEClTCH（多西他赛、卡铂、曲妥珠单抗）（多西他赛、卡铂、曲妥珠单抗）l化疗后序贯曲妥珠单抗化疗后序贯曲妥珠单抗lAC多西他赛曲妥珠单抗多

33、西他赛曲妥珠单抗新辅助化疗：新辅助化疗：lT曲妥珠单抗曲妥珠单抗CEF+曲妥珠单抗曲妥珠单抗（紫杉醇曲妥珠单抗序贯（紫杉醇曲妥珠单抗序贯环磷酰胺环磷酰胺/表柔比星表柔比星/氟尿嘧啶曲妥珠氟尿嘧啶曲妥珠单抗）单抗）BINV-JAdverse event profiles of chemotherapy vs tamoxifenTamoxifenChemotherapy(CMF/FAC/FEC)Hot flushesVaginal drynessVaginal dischargeThromboembolic eventsEndometrial cancerNauseaVomitingFatigue

34、Hair lossPainCNS problemsImmune system problemsEBCTCG.Lancet 2005;365:1687-1717CMF=cyclophosphamide,methotrexate and fluorouracilFAC=fluorouracil,doxorubicin and cyclophosphamideFEC=fluorouracil,epirubicin and cyclophosphamideThe rise of AIs in the treatment of breast cancerlThe adjuvant treatment o

35、f HR+early breast cancer has been revolutionised in the last 5 yearslAIs have challenged 5 years tamoxifen use as the optimum adjuvant treatment for postmenopausal women in this setting lAIs have been investigated inunewly diagnosed patientsupatients who have started adjuvant tamoxifenupatients who

36、have completed 5 years tamoxifen treatmentAI=aromatase inhibitor;HR+=hormone receptor-positive芳香化酶抑制剂用于乳腺癌术后芳香化酶抑制剂用于乳腺癌术后辅助治疗辅助治疗lMA17试验：三苯氧胺试验：三苯氧胺5年来曲唑年来曲唑5年年 vs 三苯氧胺三苯氧胺5年年lIES031试验：三苯氧胺依西美试验：三苯氧胺依西美5年年 vs 三苯氧胺三苯氧胺5年年lATAC试验：阿那曲唑试验：阿那曲唑5年年 vs 三苯氧胺三苯氧胺5年年lBig-198试验：试验：三苯氧胺三苯氧胺5年年 vs 来曲唑来曲唑5年年 vs

37、三苯氧三苯氧胺胺2年年来曲唑来曲唑3年年 vs 来曲唑来曲唑2年年三苯氧胺三苯氧胺3年年辅助内分泌治疗辅助内分泌治疗辅助内分泌治疗辅助内分泌治疗绝经后绝经后芳香化酶抑制剂芳香化酶抑制剂5年（年（1类）类）他莫昔芬他莫昔芬23年年芳香化酶抑制剂芳香化酶抑制剂直至直至5年（年（1类）类）或更久或更久(2B类）类）他莫昔芬他莫昔芬4.56年年芳香化酶抑制剂芳香化酶抑制剂5年（年（1类）类）患者有芳香化酶抑制剂禁忌证或不能接受芳香化酶抑制剂，患者有芳香化酶抑制剂禁忌证或不能接受芳香化酶抑制剂，或不能耐受芳香化酶抑制剂，可以服用他莫昔芬或不能耐受芳香化酶抑制剂，可以服用他莫昔芬5年（年（1类）类）BIN

38、V-1辅助内分泌治疗辅助内分泌治疗辅助内分泌治疗辅助内分泌治疗绝经前绝经前他莫昔芬他莫昔芬23年（年（1类）类）卵巢抑制卵巢抑制/切除（切除（2B类）类）绝经后绝经后绝经前绝经前BINV-I辅助内分泌治疗辅助内分泌治疗绝经后绝经后他莫昔芬直至他莫昔芬直至5年（年（1类）类）芳香化酶抑制剂芳香化酶抑制剂直至直至5年（年（1类）类）或更久或更久（2B类）类）芳香化酶抑制剂芳香化酶抑制剂5年（年（1类）类）绝经前绝经前绝经后绝经后芳香化酶抑制剂芳香化酶抑制剂5年（年（1类）类）绝经前绝经前不进行进一步内分泌治疗不进行进一步内分泌治疗BINV-I 他莫昔芬直至他莫昔芬直至5年（年（1类）类）Concl

39、usionslEndocrine therapy is an effective and well-tolerated long-term treatment strategy in reducing the risk of recurrence after primary surgerylThird-generation AIs are becoming the new gold standard in endocrine therapyNovel Treatments lThe erbB familyuTargeting Her2 and EGFR in breast cancerlAnt

40、i-angiogenesisuTargeting VEGF signaling pathways with monoclonal antibodies and TKIslOther important pathways Potential benefits through inhibition of PARP,SRC and other pathwayslTailored therapy个体化治疗（个体化治疗（Tailored Therapy)化疗化疗化疗化疗化疗化疗Three Breast Cancer Studies Used To Select 21 Gene PanelPROLIFER

41、ATIONPROLIFERATIONKi-67Ki-67STK15STK15SurvivinSurvivinCyclin B1Cyclin B1MYBL2MYBL2ESTROGENESTROGENERERPRPRBcl2Bcl2SCUBE2SCUBE2INVASIONINVASIONStromolysin 3Stromolysin 3Cathepsin L2Cathepsin L2HER2HER2GRB7GRB7HER2HER2BAG1BAG1GSTM1GSTM1REFERENCEREFERENCEBeta-actinBeta-actinGAPDHGAPDHRPLPORPLPOGUSGUSTF

42、RCTFRCCD68CD6816 Cancer and 5 Reference Genes Best RT-PCR performance and most robust predictionsPaik S,et al:NEJM 2004Recurrence Score(RS)Algorithm 31High risk 18 and 31Intermediate risk 2 mm）l肿瘤肿瘤0.5 cm或或l微浸润或微浸润或l肿瘤肿瘤0.61.0 cm，且高分化，无不良且高分化，无不良预后因素预后因素pN0 不进行辅助治疗不进行辅助治疗pN1mi 考虑进行辅助内分泌治疗考虑进行辅助内分泌治疗

43、l肿瘤肿瘤0.61.0 cm，中中/低分化或伴低分化或伴不良预后因素不良预后因素l肿瘤肿瘤1cm考虑考虑21-基因基因RT-PCR分析分析（2B类）类）未做未做复发评分为复发评分为低危（低危（1cm考虑考虑21-基因基因RT-PCR分析分析（2B类）类）未做未做复发评分为复发评分为低危低危（18）复发评分为复发评分为中危中危（1830）复发评分为复发评分为高危（高危（31)辅助内分泌治疗辅助内分泌治疗辅助化疗（辅助化疗（1类）类）辅助内分泌治疗辅助内分泌治疗（2B类）类）辅助内分泌治疗辅助内分泌治疗辅助化疗（辅助化疗（2B类）类）辅助内分泌治疗辅助内分泌治疗+辅助化疗（辅助化疗（2B类）类）S

44、ensitivity(+)Sensitivity(-)Responder Probable survival benefitNon-RespondersToxicity without survival benefitDelay in effectivetreatment Anti-cancer agentToday-One Size Fits All TherapySensitivity(+)Sensitivity(-)ResponderSurvival benefitNon-RespondersToxicity without survival benefitDelay in effect

45、ivetreatment The Future-Tailored TherapyMolecular profiling 1 2 2Right therapy for right patient 3乳腺癌辅助化疗（结论）乳腺癌辅助化疗（结论）l化疗改善无病生存和总生存率化疗改善无病生存和总生存率l联合化疗优于单药化疗联合化疗优于单药化疗l化疗时间化疗时间6个月以上不能增加疗效个月以上不能增加疗效l蒽环类联合方案优于蒽环类联合方案优于CMF方案方案l紫杉类联合方案对一些病人疗效更好。紫杉类联合方案对一些病人疗效更好。l对对HER-2阳性乳腺癌，应考虑化疗联合曲妥阳性乳腺癌，应考虑化疗联合曲妥珠单抗珠单抗l对受体阳性的患者要给予内分泌治疗对受体阳性的患者要给予内分泌治疗