1、三复发或转性乳腺癌的分子生物治疗三复发或转性乳腺癌的分子生物治疗针对乳腺癌的生物靶向药物 Her-2/neu Herceptin Pertuzumab VEGF Bevacizumab（Avastin）SU11248 EGFR gefitinib（Iressa）,erlotinib（Tarceva）,C225三三.1 Trastuzumab 治疗治疗Her2 过表达过表达的的MBCHer-2/neu 1981年，Shih在小鼠神经母细胞瘤发现了一个高表达的癌基因，命名为neu基因。以后又发现该基因与编码表皮生长因子受体的基因相关。1985年Cousens在此基础上发现了neu在人体的等位基因，
2、称之为HER2(Human EGF receptor2)。同时，其他两位学者也同时发现了该基因并给予不同的名称(c-erbB-2和erbB相关基因)。由上述可见c-erbB-2，HER2，erbB相关基因实际上是三个不同地方的研究组几乎同时发现的同一基因。后统一用HER2一词。Her-2/neu基因与乳腺癌 一种转化基因，该基因的扩增或过度表达与乳腺癌的发生、生物学行为及预后有一定关系。有淋巴结转移组病人，无论是单因素还是多因素分析都显示：Her-/neu基因扩增与预后有关。无淋巴结转移组病人，Her-/neu基因扩增与预后的关系还未定论，尚需进一步观察。在原发性乳腺癌患者中 25%to 30
3、%有 HER2 蛋白过度表达，这些患者通常具有早期复发和生存期较短的临床特征Herceptin Herceptin是美国FDA通过的第一个用于实体瘤治疗的单克隆抗体，它对Her-2/neu(+)阳性病人有效率达1621，与紫杉类合用可提高疗效。由于其有心脏毒性，故未批准与蒽环类合用。Herceptin是通过基因转化技术得到的单克隆抗体，无免疫原性，在人体内不产生人类抗鼠类抗体（HAMA）,它与P185有很好的亲和力，能有效产生抗体依赖性细胞介导的细胞毒作用。赫赛丁单药治疗的客观疗效赫赛丁单药治疗的客观疗效Study H0649g 赫赛丁单药一线治疗赫赛丁单药一线治疗MBC Study H065
4、0 Response Rate N=114 patients 2mg/kg Vs 4mg/kg Complete responses7pt Partial responses 23 pt Overall response rate30 pt(26%)Time to response 1.8mo Response duration11-22mo赫赛丁与化疗联合一线治疗赫赛丁与化疗联合一线治疗MBC ORR (HO648g)Design and enrolmentNo prior anthracyclinesPrior anthracyclinesPaclitaxel(n=96)Herceptin
5、+paclitaxel(n=92)AC(n=138)Herceptin+AC(n=143)l Metastatic breast cancerl HER2 overexpressionl No prior CT for MBCl Measurable diseasel KPS 60%Eligible patients(n=469)Comparative Study HO648gOverall ORRP-value 0.1038 0.0001Comparative Study HO648gTime-to-Disease ProgressionH+P(n=92)median=6.9 moP (n=
6、96)median=3.0 moH+AC (n=143)median=8.1 moAC (n=138)median=6.1 mop=0.0003p=0.0001Overall survivalCT patients treated withHerceptin after disease24%62%65%progression1.00.80.60.40.200515253545H+CTCTProbability of survival25.4 months(25%)20.3 monthsRR=0.76p=0.025Time(months)Mean combination index values
7、 for chemotherapeutic drug/Herceptin combinations in vitro*5-dFUrd is a metabolite of Xeloda;Herceptin plus Xeloda demonstrates additive activity in vivo31Konecny G,et al.Breast Cancer Res Treat 1999;57:114(Abstract 467)2Pegram M,et al.Oncogene 1999;18:2241513Fujimoto-Ouchi K,et al.Cancer Chemother
8、Pharmacol 2002;49:21116联合指数，在联合化疗时，对某一效应测量终点，定量测定药物相互作用的程度。CI值越小协同作用越大 Herceptin与每周与每周paclitaxel(n=95)Phase II trial of Herceptin plus weekly paclitaxel(90mg/m2)RRs in 7080%range in HER2-positive patients169%(DAKO)67%(PAb1)76%(CB11)81%(TAB250)75%(FISH)Used by Intergroup to develop adjuvant design Wi
9、dely used in the clinical setting in the USA and Australia1Seidman AD,et al.J Clin Oncol 2001;19:258795Herceptin 联合联合 docetaxel Phase II trials Herceptin was administered as a 4mg/kg initial dose followed by 2mg/kg weekly until progressionHerceptin 与与 vinorelbine联合联合1Burstein H,et al.J Clin Oncol 20
10、01;19:2722302Jahanzeb M,et al.Breast Cancer Res Treat 2001;69:284(Abstract 429)Herceptin与与 gemcitabine联合联合 Phase II study(n=59)of Herceptin plus gemcitabine(1,200mg/m2 day 1 and 8 q3-weekly)RR=33%(22/59)In patients with IHC 3+disease,RR=45%(17/38)OShaughnessy JA,et al.Breast Cancer Res Treat 2001;69
11、:302(Abstract 523)Herceptin与与 docetaxel和和platinum 联合（联合（First-line）Herceptin in combination with docetaxel and cisplatin(BCIRG 101)RR=79%(49/62)Herceptin in combination with docetaxel and carboplatin(BCIRG 102)RR=56%(31/55)This regimen is being investigated in phase III trials in the adjuvant(006)an
12、d metastatic(007)settingsNabholtz J-M,et al.Eur J Cancer 2001;37:S190(Abstract 695)Herceptin与与 Xeloda联合联合 In patients pretreated for metastatic breast cancerRR=62%(8/13)when Xeloda was administered at a dose of 1,125mg/m2 b.i.d.1RR=53%(9/17)when Xeloda was administered at a dose of 1,000mg/m2 b.i.d.
13、2 The combination was well tolerated Additional trials to further examine this combination include a randomised phase II trial of Herceptin plus docetaxel Xeloda1Bangemann N,et al.Ann Oncol 2000;11:143(Abstract 653P)2Bangemann N,et al.Breast Cancer Res Treat 2000;64:123(Abstract 530)Herceptin 与化疗联合与化疗联合小结小结 Several Herceptin combination regimens are activehigh RRsfavourable safety profiles To date,no direct comparison has been made to establish the best first-line combination strategy Optimal therapy may differ depending on patient and tumour characteristics
