乳腺癌化疗进展.ppt

乳腺癌化疗进展,徐兵河 中国医学科学院肿瘤医院内科,Worldwide Top 5 cancer incidence in 2000,Top 5 cancer incidence: Lung cancer: 1,239,000 Breast cancer: 1,053,000 Colorectal cancer: 944,000 Gastric cancer: 876,000 Liver cancer: 564,000,Parkin DM et al, Estimating the world cancer burden: Globocan 2000: int. J. Cancer:94,153-156(2001),In Thousands,我国城市乳腺癌发病率及死亡率,世界标准人口调整计算(1/10) 城市 发病率 死亡率 在女性肿瘤中位次 发病率 死亡率 上海 25.6 8.0 1 5 天津 24.6 5.2 2 4 北京 23.4 7.4 2 4 哈尔滨 23.4 6.8 2 5 武汉 16.1 6.0 2 5 ,乳腺癌的主要治疗方法,手术治疗 放射治疗 内科治疗 化学治疗 内分泌治疗 生物治疗,乳腺癌,术后5年内约30%的病人肿瘤复发和转移,典型病例,李，女，34 岁，680801 左乳癌（T1N1M0），2002.57： CAF化疗2周期，PD 2002.7.25：左乳癌改良根治术, 病理：浸润性导管癌，淋巴结转移114，ER，PR+，C-erbB2+。术后予紫杉醇顺铂化疗2周期，口服TAM 5个月 2003.2：肝左叶转移（1.2cm） 2003.2.21：双卵巢切除 2003.46：口服瑞宁得，复查肝转移进展（2.22cm）,冰山熔化？,难！难！难！,THE GOOD NEWS THERE IS A HIGH PROBABILITY THAT OUR ABILITY TO INDIVIDUALIZE CHEMOTHERAPY REGIMENS WILL MARKEDLY IMPROVE IN THE FUTURE !,28,个体化治疗,患者：身体状况、重要器官功能、免疫功能 肿瘤：病理类型、分化程度、基因表达 药物：种类、作用机制、代谢、毒性,GENE EXPRESSION PROFILING PREDICTS CLINICAL OUTCOME OF B.C. (Nature 2002),78 untreated N- primary tumors,44 w/o relapse at 8 y follow-up,34 with a relapse within 5 y,5000 genes,231 genes,70 genes = Poor prognosis signature,97,91,70,27,Poor prognosis signature,St Gallen criteria,Group with relapse,Group relapse -free,% who “need“ adjuvant therapy,23,Targets for anticancer therapy,Signal transduction to nucleus,Nucleus,Binding site,Tyrosine kinase activity,Cytoplasm,Plasma membrane,Growth factor,Gene activation,CELL DIVISION,HER2 mechanism of action,1 = gene copy number 2 = mRNA transcription 3 = cell surface receptor protein expression 4 = release of receptor extracellular domain,Normal,Amplification/Overexpression,Cytoplasm,HER2 receptor protein,Cytoplasmic membrane,Nucleus,HER2 DNA,HER2 mRNA,1,2,3,4,Indicators of increased HER2 production,Her-2/neu,Her-2/neu（C-erbB2）是一种原癌基因，该基因与乳腺癌细胞增殖有关。 大约2530%的乳腺癌病人伴有Her-2/neu的过度表达。 Her-2的过度表达的乳腺癌患者生存期短，并对某些化疗药物耐药。,Slamon et al, 1987,Shortened Median Survival HER2 overexpressing 3 yrs HER2 normal 6 - 7 yrs,Breast Cancer,Scientific Rationale,HER2 Oncoprotein Overexpression,HER2 Oncogene Amplification,Herceptin: Humanized Anti-HER2 Antibody,Targets HER2 oncoprotein High affinity (Kd = 0.1 nM) and specificity 95% human, 5% murine Decrease potential for immunogenicity Increase potential for recruiting immune-effector mechanisms,Scientific Rationale,Herceptin Mechanism of Action,Preclinical: Efficacy,Single Agent in Murine Xenograft Model,Serum assays: target trough serum concentration 10 - 20 g/ml,Tumor Volume (mm)3,Treatment Day,Control IgG1,Herceptin,100 mg/kg,3 mg/kg,30 mg/kg,100 mg/kg,10 mg/kg,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 _,晚期乳腺癌应用化疗Herceptin的结果（Slamon et al. Proc ASCO, 1998),典型病例,年轻女性，病变发展快，Her2+，对蒽环类和紫杉类药耐药，内分泌治疗无效 选择抗Her2单抗以及与上述药物无交叉耐药、且两者有协同作用的药物 长春瑞滨Herceptin化疗,李，35岁， 680801 左乳癌术后7个月肝转移,肝转移（1.2cm),2003年2月,李，34岁，乳癌肝转移，680801 （卵巢切除口服阿那曲唑2个月）,肝转移（2.22.0cm),2003年 6月,李，34岁，乳癌肝转移，680801 （NVBHerceptin 3周期治疗后）,肝转移结节基本消失,2003年8月27日,Tumor-activated Xeloda,Intestine,Liver,Xeloda,5-DFCR,5-DFUR,CyD,5-DFCR,5-DFUR,5-FU,Tumor healthy tissue,Xeloda,Thymidine phosphorylase (TP),CyD,CE,5-DFCR = 5-deoxy-5-fluorocytidine; 5-DFUR = 5-deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase,TP is significantly more active in human tumor tissue,TP activity (g 5-FU/mg protein/hour),0 100 200 300 400 500,115 115,16 20,Colorectal Gastric Breast Liver (metastasis),No. patients,Healthy tissue Tumor tissue,*,*,*p0.05,Adapted from Miwa M et al. Eur J Cancer 1998;34:127481,291 351,*,309 309,*,肿瘤移植物内TP活性的上调,0 5 10 15 20,mg/kg) 对照 紫杉醇 100 多西紫杉醇 15 长春新碱 1.5 长春花碱 3 长春地辛 5 丝裂霉素C 5 阿霉素 7.5 顺铂 10 对照 氨甲喋呤 50 环磷酰胺 200,TP 活性 （unit/mg 蛋白）,吉西它滨和长春瑞宾对TP活性也有上调作用,Ishitsuka H. Invest New Drugs 2000;18:34354,304 trial Taxotere (n=203)1 304 trial Mitomycin C + vinblastine (n=189)1,Median (months) 11.4 8.7,Evolution of breast cancer therapy: superior survival with Xeloda plus Taxotere (XT),1.0 0.8 0.6 0.4 0.2 0.0,Estimated probability,Time (months),0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34,1Nabholtz J-M et al. J Clin Oncol 1999;17:141324,Mabthera，Rituximab),抗 CD20单克隆抗体 CD 20 见于正常和恶性B淋巴细胞，在非霍奇金淋巴瘤（NHL）CD20高表达 CD 20的功能与细胞周期调节有关,Mabthera (Rituximab),对低度恶性NHL有效率50%以上,主要毒性 发热 / 寒战 过敏反应 (少见),Limitations of chemotherapy in aggressive NHL,CHOP is the Gold Standard for DLCL,100 80 60 40 20 0,0 5 10 15,CHOP MACOP-B ProMACE-CytaBOM m-BACOD,Years,Fisher N Engl J Med 1993;328:10026,Overall survival (%),MabThera plus CHOP in previously untreated DLCL patients,Progression during Treat. 22% vs 9% p=0.002 CR rate 76% vs 63% p=0.005 Relapse 25% vs 14% p=0.002 Event-free survival 57% vs 38% p0.001 Overall survival 70% vs 57% p=0.007,No clinically relevant increase in adverse events,肿瘤内科治疗趋势,传统治疗: 直接攻击快速增值的肿瘤细胞 作用特点：非特异性、针对所有细胞 现代治疗: