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1、早期乳腺癌辅助化疗进展Breast Cancer Incidence Trends Over TimeCancer Incidence Trends in China 2005 2015 Incidence Rates Projection by Cancer TypePer 100,000 CAGR 2.98%CAGR 4.5%CAGR 0.65%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
2、al.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15年来乳腺癌发病率上升死亡率下降死亡率下降的原因v早期诊断 v综合治疗The benefits of chemotherapy data from clinical trailsEarly Breast Cancer Trialists Collaborative Group (EBCTCG).194 randomised trials of adjuvant chemotherapy (CMF,CA
3、F,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)Log-rank 2p0.0000115-year probabilities of recurrence in women aged 50 years, with / without polychemotherapyPolychemotherapy41.1%35.524.6Younger
4、women, 35% node-positive; older women, 70% node-positive;SE=standard errorEBCTCG. Lancet 2005; 365: 1687-1717Placebo42.4%20.435.00102030405060Breastcancermortality(%)15-year gain 10.0% (SE 1.6)Log-rank 2p0.00001Polychemotherapy32.4%Time (years)05151015.727.115-year probabilities of breast cancer mor
5、tality in women aged 50 years, with / without polychemotherapyEBCTCG. Lancet 2005; 365: 1687-1717Younger women, 35% node-positive; older women, 70% node-positive010203040506015-year gain 4.1% (SE 1.2)Log-rank 2p0.00001Placebo57.6%Polychemotherapy53.4%48.805151035.444.129.415-year probabilities of re
6、currence 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-positivePlacebo50.4%21.338.3010203040506015-year gain 3.0% (SE 1.3)Log-rank 2p0.00001Polychemotherapy47.4%18.70515103
7、5.415-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 2005; 365: 1687-1717Breastcancermortality(%)Placebo45.0%38.326.5010203040506015-year gain 11.8% (SE
8、 1.3)Log-rank 2p0.0000115-year probabilities of recurrence in women with ER+ (or ER-unknown) disease, with / without 5 years tamoxifenAbout 5 years tamoxifen33.2%Time (years)05151015.124.7ER=oestrogen receptor; 10,386 women: 20% ER-unknown, 30% node-positiveEBCTCG. Lancet 2005; 365: 1687-1717Recurre
9、nce(%)010203040506015-year gain 9.2% (SE 1.2)Log-rank 2p0.00001Placebo34.8%About 5 years tamoxifen25.6%25.705151011.98.317.815-year probabilities of breast cancer mortality in women with ER+ (or ER-unknown) disease, with / without 5 years tamoxifenTime (years) 10,386 women: 20% ER-unknown, 30% node-
10、positiveEBCTCG. 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 ER-unknown) disease with no chemotherapy, with / without 5 years tamoxifenEB
11、CTCG. 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 recurrence in women with ER+ (or ER-unknown) disease with chemotherapy, with / without 5
12、 years tamoxifenTime (years)EBCTCG. Lancet 2005; 365: 1687-1717Recurrence(%) 3330 women: 53% node-positiveChemotherapy versus endocrine therapy in the treatment of breast cancerIn premenopausal women, polychemotherapy improves 15-year recurrence by 12.4% and survival by 10.0%In postmenopausal women,
13、 15-year gains in recurrence and survival are smaller (4.2% and 3.0%, respectively) anthracycline-based polychemotherapy reduces the 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 trea
14、tment of breast cancerIn patients with ER+ disease, tamoxifen improves 15-year recurrence by 11.8% and survival by 9.2%Gains made with tamoxifen treatment appear to be irrespective of adjuvant chemotherapyEBCTCG. Lancet 2005; 365: 1687-1717乳腺癌辅助化疗进展1960s 1970s 1980s 1990s 2000 20021960s 1970s 1980s
15、1990s 2000 2002手术CMF1蒽环类药物AC2, CAF3,FEC4Dose5,6CEF1207, 15FEC1008EC9Meta-analysis12紫杉类药物10,11,13DI14 Sequene 生物治疗 1 Bonadonna 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
16、TAC vs FAC14 CALGB 974115 MA.05 10 years!评估紫杉类乳腺癌辅助化疗的随机临床试验lCALGB 9344 AC vs AC PlNSABP B-28 AC vs AC 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:方法目的: 比较含紫杉烷辅助化疗方案与不
17、含紫杉烷辅助化疗方案主要结局指标: OS次要结局指标: DFS, 毒性11项随机对照试验, 17056名患者平均中位随访54.6个月总结果有利于紫杉烷OS: HR 0.81 (95% CI, 0.75-0.88; p.00001)DFS: HR 0.81 (95% CI, 0.75-0.86; p.00001)Nowak 等. ASCO 2007. 文摘号 545. Five Year follow-up of INT C9741: Dose-dense chemotherapy is safe and effectiveHudis C, Citron M, Berry D, Cirrinci
18、one 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 and Adjuvant TherapyHer-2Her-2是一种原癌基因，该基因与乳腺癌细胞增殖有关。 约2530%的乳腺癌Her-2过度表达。 Her-2的过度表达的乳腺癌患
19、者生存期短，预后差。成为乳腺癌治疗的理想靶点。 HER2阳性对生存期的影响HER2阳性的乳腺癌患者的生存率降低！中位生存期HER2 阳性3 年HER2 阴性67 年Slamon DJ et al. Science 1987;235:17782HER2 状态: 预示肿瘤对治疗的反应 内分泌治疗 HER2阳性患者相对耐药 CMF方案 HER2阳性患者相对耐药 蒽环类 对蒽环类相对敏感 紫杉类药物相对敏感赫赛汀 (曲妥珠单抗): 人源化抗HER2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%
20、 鼠抗，显著降低鼠抗，显著降低免疫原性免疫原性( (HAMA)HAMA)l全球第一种治疗实体瘤的单克隆抗体，为HER2癌基因阳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 cellMacrophageHerceptin stimulates ADCC(antibody-dependent cell-mediated cytotoxicity)Fc receptorHerceptin : 作用机制Trastuzumab in adjuvant , phase III studies赫赛汀辅助治疗循证医学证据新
21、英格兰杂志2005年10月北美研究结果发表新英格兰杂志2005年10月HERA研究结果发表新英格兰杂志2006年2月FinHER结果发表1703159114341127742383140169815351330984639334127100806040200Patients(%)Months from randomisation12361 year trastuzumabObservation0186No. at risk 赫赛汀辅助治疗HERA研究无进展生存时间(ITT)2430EventsHR95% CIp value0.640.54, 0.76 0.00013-yearDFS80.674
22、.32183216.3%HERA研究DFS风险(ITT)观察组和赫赛汀一年治疗组Months since randomisation1703162714981190794407146100806040200Patients(%)Months from randomisationObservationNo. at risk 1698160814531097711366139赫赛汀辅助治疗HERA研究总生存时间(ITT)1 year trastuzumabEventsHR95% CIp value0.660.47, 0.910.01153-yearOS92.489.7123601862430599
23、0Median FU 2 yrs2.7%赫赛汀辅助治疗北美临床N9831/B31无进展生存时间随机分组后年Romond 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: 1673-168401234020406080100120Rate per 100
24、0 Women /Yr随机分组后年ACACTHTHACTN9831/B31远处转移风险赫赛汀辅助治疗北美临床N9831/B31总生存时间ACACTHTH94%94%91%91%87%92%ACTNDeathsACT167992ACTH167262HR=0.67, 2P=0.015Years From RandomizationPatients (%)Years10090807001234593%86%84%80%80%91%86%77%73%n107410751073Events7798147ACDHDCarboHACD6050HR=0.49HR=0.61BCIRG 006研究DFSSlamo
25、n 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+辅助化疗+曲妥珠单抗（1类）淋巴结阳性（指1
26、个或多个同侧腋窝淋巴结有1个或多个转移灶2 mm）辅助内分泌治疗+辅助化疗+曲妥珠单抗（1类）BINV-5辅助化疗不含曲妥珠单抗的化疗方案（均为1类）lFAC/CAF（氟尿嘧啶/多柔比星/环磷酰胺）或FEC/CEF（环磷酰胺/表柔比星/ 氟尿嘧啶）lAC（多柔比星/环磷酰胺）序贯紫杉醇lEC（表柔比星/环磷酰胺）lTAC（多西他赛/多柔比星/环磷酰胺）联合非格司亭支持lACMF（多柔比星序贯环磷酰胺/甲氨喋呤/氟尿嘧啶）lECMF（表柔比星序贯环磷酰胺/甲氨喋呤/氟尿嘧啶）lCMF（环磷酰胺/甲氨喋呤/ 氟尿嘧啶）lAC4 （多柔比星/环磷酰胺）序贯紫杉醇4，每2周1次，联合非格司亭支持lAT
27、C（多柔比星序贯紫杉醇再序贯环磷酰胺）每2周1次，联合非格司亭支持lFECT（ 氟尿嘧啶/表柔比星/环磷酰胺序贯多西他赛）lTC（多西他赛和环磷酰胺）含曲妥珠单抗的化疗方案（均为1类）首选的辅助方案：lACT同步曲妥珠单抗（多柔比星/环磷酰胺序贯紫杉醇曲妥珠单抗)l其他辅助方案：l多西他赛曲妥珠单抗 FEClTCH（多西他赛、卡铂、曲妥珠单抗）l化疗后序贯曲妥珠单抗lAC多西他赛曲妥珠单抗新辅助化疗：lT曲妥珠单抗CEF+曲妥珠单抗（紫杉醇曲妥珠单抗序贯环磷酰胺/表柔比星/ 氟尿嘧啶曲妥珠单抗）BINV-JAdverse event profiles of chemotherapy vs ta
28、moxifenTamoxifenChemotherapy(CMF / FAC / FEC)Hot flushesVaginal drynessVaginal dischargeThromboembolic eventsEndometrial cancerNauseaVomitingFatigueHair lossPainCNS problemsImmune system problemsEBCTCG. Lancet 2005; 365: 1687-1717CMF=cyclophosphamide, methotrexate and fluorouracilFAC=fluorouracil, d
29、oxorubicin and cyclophosphamideFEC=fluorouracil, epirubicin and cyclophosphamideThe rise of AIs in the treatment of breast cancerThe adjuvant treatment of HR+ early breast cancer has been revolutionised in the last 5 yearsAIs have challenged 5 years tamoxifen use as the optimum adjuvant treatment fo
30、r postmenopausal women in this setting AIs have been investigated innewly diagnosed patientspatients who have started adjuvant tamoxifenpatients who 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辅助治疗MA17试验：三苯氧胺5年来曲唑5年 vs 三苯氧胺5年IES031试验：三苯
31、氧胺依西美5年 vs 三苯氧胺5年ATAC试验：阿那曲唑5年 vs 三苯氧胺5年Big-198试验：三苯氧胺5年 vs 来曲唑5年 vs 三苯氧胺2年来曲唑3年 vs 来曲唑2年三苯氧胺3年辅助内分泌治疗辅助内分泌治疗绝经后芳香化酶抑制剂5年（1类）他莫昔芬23年芳香化酶抑制剂直至5年（1类）或更久(2B类）他莫昔芬4.56年芳香化酶抑制剂5年（1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，或不能耐受芳香化酶抑制剂，可以服用他莫昔芬5年（1类）BINV-1辅助内分泌治疗辅助内分泌治疗绝经前他莫昔芬23年（1类）卵巢抑制/切除（2B类）绝经后绝经前BINV-I辅助内分泌治疗绝经后他莫
32、昔芬直至5年（1类）芳香化酶抑制剂直至5年（1类）或更久（2B类）芳香化酶抑制剂5年（1类）绝经前绝经后芳香化酶抑制剂5年（1类）绝经前不进行进一步内分泌治疗BINV-I 他莫昔芬直至5年（1类）ConclusionsEndocrine therapy is an effective and well-tolerated long-term treatment strategy in reducing the risk of recurrence after primary surgeryThird-generation AIs are becoming the new gold standa
33、rd in endocrine therapyNovel Treatments The erbB familyTargeting Her2 and EGFR in breast cancerAnti-angiogenesisTargeting VEGF signaling pathways with monoclonal antibodies and TKIsOther important pathways Potential benefits through inhibition of PARP, SRC and other pathwaysTailored therapy个体化治疗（Tai
34、lored Therapy)化疗化疗化疗Three Breast Cancer Studies Used To Select 21 Gene PanelPROLIFERATIONPROLIFERATIONKi-67Ki-67STK15STK15SurvivinSurvivinCyclin B1Cyclin B1MYBL2MYBL2ESTROGENESTROGENERERPRPRBcl2Bcl2SCUBE2SCUBE2INVASIONINVASIONStromolysin 3Stromolysin 3Cathepsin L2Cathepsin L2HER2HER2GRB7GRB7HER2HER2
35、BAG1BAG1GSTM1GSTM1REFERENCEREFERENCEBeta-actinBeta-actinGAPDHGAPDHRPLPORPLPOGUSGUSTFRCTFRCCD68CD6816 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0.5 cm或l微浸润或l肿瘤0
36、.61.0 cm，且高分化，无不良预后因素pN0 不进行辅助治疗pN1mi 考虑进行辅助内分泌治疗l肿瘤0.61.0 cm，中/低分化或伴不良预后因素l肿瘤1cm考虑21-基因RT-PCR分析（2B类）未做复发评分为低危（1cm考虑21-基因RT-PCR分析（2B类）未做复发评分为低危（18）复发评分为中危（1830）复发评分为高危（31)辅助内分泌治疗辅助化疗（1类）辅助内分泌治疗（2B类）辅助内分泌治疗辅助化疗（2B类）辅助内分泌治疗+辅助化疗（2B类）Sensitivity ( + )Sensitivity ( - )Responder Probable survival benefit
37、Non-RespondersToxicity without survival benefitDelay in effectivetreatment Anti-cancer agentToday - One Size Fits All TherapySensitivity ( + )Sensitivity ( - )ResponderSurvival benefitNon-RespondersToxicity without survival benefitDelay in effectivetreatment The Future - Tailored TherapyMolecular profiling 1 2 2Right therapy for right patient 3乳腺癌辅助化疗（结论）化疗改善无病生存和总生存率联合化疗优于单药化疗化疗时间6个月以上不能增加疗效蒽环类联合方案优于CMF方案紫杉类联合方案对一些病人疗效更好。对HER-2阳性乳腺癌，应考虑化疗联合曲妥珠单抗对受体阳性的患者要给予内分泌治疗
