早期乳腺癌辅助化疗进展.ppt

早期乳腺癌辅助化疗进展,Breast Cancer Incidence Trends Over Time,Cancer Incidence Trends in China 2005 2015 Incidence Rates Projection by Cancer Type,Per 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 al.,中国乳腺癌发病概况,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: 5.5/100,000 发病率：城市农村 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,早期诊断 综合治疗,The benefits of chemotherapy data from clinical trails,Early Breast Cancer Trialists Collaborative Group (EBCTCG). 194 randomised trials of adjuvant chemotherapy (CMF,CAF,CEF) or hormonal therapy (TAM) that began by 1995.,Lancet 2005,Placebo 53.3%,37.1,47.9,Time (years),0,5,15,10,Recurrence (%),15-year gain 12.3% (SE 1.6) Log-rank 2p0.00001,15-year probabilities of recurrence in women aged 50 years, with / without polychemotherapy,Polychemotherapy 41.1%,35.5,24.6,Younger women, 35% node-positive; older women, 70% node-positive; SE=standard error,EBCTCG. Lancet 2005; 365: 1687-1717,Placebo 42.4%,20.4,35.0,Breast cancer mortality (%),15-year gain 10.0% (SE 1.6) Log-rank 2p0.00001,Polychemotherapy 32.4%,Time (years),0,5,15,10,15.7,27.1,15-year probabilities of breast cancer mortality in women aged 50 years, with / without polychemotherapy,EBCTCG. Lancet 2005; 365: 1687-1717,Younger women, 35% node-positive; older women, 70% node-positive,15-year gain 4.1% (SE 1.2) Log-rank 2p0.00001,Placebo 57.6%,Polychemotherapy 53.4%,48.8,0,5,15,10,35.4,44.1,29.4,15-year probabilities of recurrence in women aged 50-69 years, with / without polychemotherapy,Time (years),EBCTCG. Lancet 2005; 365: 1687-1717,Recurrence (%),Younger women, 35% node-positive; older women, 70% node-positive,Placebo 50.4%,21.3,38.3,15-year gain 3.0% (SE 1.3) Log-rank 2p0.00001,Polychemotherapy 47.4%,18.7,0,5,15,10,35.4,15-year probabilities of breast cancer mortality in women aged 50-69 years, with / without polychemotherapy,Time (years),Younger women, 35% node-positive; older women, 70% node-positive,EBCTCG. Lancet 2005; 365: 1687-1717,Breast cancer mortality (%),Placebo 45.0%,38.3,26.5,15-year gain 11.8% (SE 1.3) Log-rank 2p0.00001,15-year probabilities of recurrence in women with ER+ (or ER-unknown) disease, with / without 5 years tamoxifen,About 5 years tamoxifen 33.2%,Time (years),0,5,15,10,15.1,24.7,ER=oestrogen receptor; 10,386 women: 20% ER-unknown, 30% node-positive,EBCTCG. Lancet 2005; 365: 1687-1717,Recurrence (%),15-year gain 9.2% (SE 1.2) Log-rank 2p0.00001,Placebo 34.8%,About 5 years tamoxifen 25.6%,25.7,0,5,15,10,11.9,8.3,17.8,15-year probabilities of breast cancer mortality in women with ER+ (or ER-unknown) disease, with / without 5 years tamoxifen,Time (years),10,386 women: 20% ER-unknown, 30% node-positive,EBCTCG. Lancet 2005; 365: 1687-1717,Breast cancer mortality (%),0,1,3,5,4,Time (years),2,5-year gain 11.9% (SE 1.0) Log-rank 2p0.00001,Nil 25.8%,About 5 years tamoxifen alone 13.9%,5-year recurrence in women with ER+ (or ER-unknown) disease with no chemotherapy, with / without 5 years tamoxifen,EBCTCG. Lancet 2005; 365: 1687-1717,Recurrence (%),7056 women: 19% node-positive,0,1,3,5,4,2,5-year gain 10.6% (SE 1.5) Log-rank 2p0.00001,Chemotherapy alone 28.1%,Chemotherapy + about 5 years tamoxifen 17.5%,5-year recurrence in women with ER+ (or ER-unknown) disease with chemotherapy, with / without 5 years tamoxifen,Time (years),EBCTCG. Lancet 2005; 365: 1687-1717,Recurrence (%),3330 women: 53% node-positive,Chemotherapy versus endocrine therapy in the treatment of breast cancer,In premenopausal women, polychemotherapy improves 15-year recurrence by 12.4% and survival by 10.0% In postmenopausal women, 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 years,EBCTCG. Lancet 2005; 365: 1687-1717,Chemotherapy versus endocrine therapy in the treatment of breast cancer,In 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 chemotherapy,EBCTCG. Lancet 2005; 365: 1687-1717,乳腺癌辅助化疗进展,1960s 1970s 1980s 1990s 2000 2002,手术,CMF1,蒽环类药物 AC2, CAF3,FEC4,Dose5,6,CEF1207, 15 FEC1008 EC9,Meta-analysis12,紫杉类药物10,11,13,DI14 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 2000 11 B-28 2000 12 EBCTCG 1998, 2000,13 TAC vs FAC 14 CALGB 9741 15 MA.05 10 years!,评估紫杉类乳腺癌辅助化疗的 随机临床试验,CALGB 9344 AC vs AC P NSABP B-28 AC vs AC P* ECTO A CMF vs AP CMF BCIRG 001 TAC vs FAC NSABP B-27 AC vs ACT PACS 01 FEC vs FEC T ECOG 2197 AT vs AC ECOG 1199 ACP3 vs P1 vs D3 vs D1 ,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 effective,Hudis C, Citron M, Berry D, Cirrincione C, Gradishar W, Davidson N, Martino S, Livingston R, Ingle J, Perez E, Abrams J, Schilsky R, Ellis M, Carpenter J, Muss H, Norton L, & Winer E On behalf of CALGB/ECOG/SWOG/NCCTG investigators,HER2+ Breast Cancer and Adjuvant Therapy,Her-2,Her-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;235:17782,HER2 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,高度亲和性 (Kd=0.1nM) 和特异性 95% 人源化, 5% 鼠抗，显著降低免疫原性(HAMA),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！ Trastuzumab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 cell,Macrophage,Fc receptor,Herceptin : 作用机制,Trastuzumab in adjuvant , phase III studies,赫赛汀辅助治疗循证医学证据,新英格兰杂志 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,1703,1591,1434,1127,742,383,140,1698,1535,1330,984,639,334,127,100,80,60,40,20,0,Patients(%),Months from randomisation,1 year trastuzumab,Observation,0,No. at risk,赫赛汀辅助治疗HERA研究无进展生存时间(ITT),Events,HR,95% CI,p value,0.64,0.54, 0.76,0.0001,3-year DFS,80.6,74.3,218,321,6.3%,HERA研究DFS风险(ITT) 观察组和赫赛汀一年治疗组,Months since randomisation,1703,1627,1498,1190,794,407,146,100,80,60,40,20,0,Patients(%),Months from randomisation,Observation,No. at risk,1698,1608,1453,1097,711,366,139,赫赛汀辅助治疗HERA研究总生存时间(ITT),1 year trastuzumab,Events,HR,95% CI,p value,0.66,0.47, 0.91,0.0115,3-year OS,92.4,89.7,0,59,90,Median FU 2 yrs,2.7%,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: 1673-1684,87%,85%,67%,75%,HR=0.48; p0.0001,100,90,80,70,60,50,0,1,2,3,4,5,2-year median follow-up,AC PH,n,Events,AC PH 1672 133,AC P 1679 261,Patients (%),Romond et al N Engl J Med 2005; 353: 1673-1684,0,1,2,3,4,Rate per 1000 Women /Yr,随机分组后年,ACTH,ACT,N9831/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,Patients (%),Years,100,90,80,70,0,1,2,3,4,5,93%,86%,84%,80%,80%,91%,86%,77%,73%,n 1074 1075 1073,Events 77 98 147,ACDH DCarboH ACD,60,50,HR=0.49,HR=0.61,BCIRG 006研究DFS,Slamon et al 2005 SABCS (abstract #1),曲妥珠单抗辅助治疗,Trastuzumab: Adjuvant Breast Cancer,All trials demonstrated an important benefit in disease free survival in the trastuzumab-treated group Some trials also demonstrated a striking benefit in overall survival However some concerns exist for cardiac safety,激素受体阳性、HER-2阳性乳腺癌的全身辅助治疗,组织学类型： 导管癌 小叶癌 混合型癌 化生性癌,pT1、pT2或pT3； 和pN0或pN1mi（腋窝淋巴结转移灶2 mm）,肿瘤0.5 cm或 微浸润或 肿瘤0.61.0 cm，且高分化,pN0 不进行辅助治疗 pN1mi 考虑辅助内分泌治疗,肿瘤0.61.0 cm，且中/低分化或伴预后不良因素,辅助内分泌治疗 辅助化疗（1类）,肿瘤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） FAC/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） AC（多柔比星/环磷酰胺）序贯紫杉醇 EC（表柔比星/环磷酰胺） TAC（多西他赛/多柔比星/环磷酰胺）联合非格司亭支持 ACMF（多柔比星序贯环磷酰胺/甲氨喋呤/氟尿嘧啶） ECMF（表柔比星序贯环磷酰胺/甲氨喋呤/氟尿嘧啶） CMF（环磷酰胺/甲氨喋呤/ 氟尿嘧啶） AC4 （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 ATC（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 FECT（ 氟尿嘧啶/表柔比星/环磷酰胺序贯多西他赛） TC（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： ACT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) 其他辅助方案： 多西他赛曲妥珠单抗 FEC TCH（多西他赛、卡铂、曲妥珠单抗） 化疗后序贯曲妥珠单抗 AC多西他赛曲妥珠单抗 新辅助化疗： T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-J,Adverse event profiles of chemotherapy vs tamoxifen,Tamoxifen,Chemotherapy (CMF / FAC / FEC),Hot flushes Vaginal dryness Vaginal discharge Thromboembolic events Endometrial cancer,Nausea Vomiting Fatigue Hair loss Pain CNS problems Immune system problems,EBCTCG. Lancet 2005; 365: 1687-1717,CMF=cyclophosphamide, methotrexate and fluorouracil FAC=fluorouracil, doxorubicin and cyclophosphamide FEC=fluorouracil, epirubicin and cyclophosphamide,The rise of AIs in the treatment of breast cancer,The adjuvant treatment of HR+ early breast cancer has been revolutionised in the last 5 years AIs have challenged 5 years tamoxifen use as the optimum adjuvant treatment for postmenopausal women in this setting AIs have been investigated in newly diagnosed patients patients who have started adjuvant tamoxifen patients who have completed 5 years tamoxifen treatment,AI=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）,Conclusions,Endocrine therapy is an effective and well-tolerated long-term treatment strategy in reducing the risk of recurrence after primary surgery Third-generation AIs are becoming the new gold standard in endocrine therapy,Novel Treatments,The erbB family Targeting Her2 and EGFR in breast cancer Anti-angiogenesis Targeting VEGF signaling pathways with monoclonal antibodies and TKIs Other important pathways Potential benefits through inhibition of PARP, SRC and other pathways Tailored therapy,个体化治疗（Tailored Therapy),化疗,化疗,化疗,Three Breast Cancer Studies Used To Select 21 Gene Panel,PROLIFERATION Ki-67 STK15 Survivin Cyclin B1 MYBL2,ESTROGEN ER PR Bcl2 SCUBE2,INVASION Stromolysin 3 Cathepsin L2,HER2 GRB7 HER2,BAG1,GSTM1,REFERENCE Beta-actin GAPDH RPLPO GUS TFRC,CD68,16 Cancer and 5 Reference Genes,Best RT-PCR performance and most robust predictions,Paik S, et al: NEJM 2004,Recurrence Score (RS) Algorithm,Scale: 0 to 100,Paik S, et al: SABCS 2003,21-基因 RT-PCR 检测的应用,限于ER+、淋巴结阴性肿瘤 仅对接受初次化疗和他莫昔芬治疗的患者有效