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1、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 VEGFBevacizumab(Avastin) SU11248 EGFRgefitinib(Iressa) , erlotinib (Tarceva) ,C225三.1 Trastuzumab 治疗Her2 过表达 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,称之为HER2(Human
2、 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 3
3、0%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 Study H0649g赫赛丁单药一线治疗MBC Study H0650 Response
4、 RateN=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MBC ORR (HO648g)Design and enrolmentNo prior anthracyclinesPrior anthracyclinesPaclitaxel (n=96)Herceptin + paclitaxel(n=92)A
5、C (n=138)Herceptin + AC(n=143)l Metastatic breast cancer l HER2 overexpression l No prior CT for MBC l Measurable disease l KPS 60%Eligible patients (n=469)Comparative Study HO648g Overall ORRP - value 0.1038 0.0001Comparative Study HO648g Time-to-Disease ProgressionH + P (n = 92) median = 6.9 moP (
6、n = 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 with Herceptin after disease24%62%65% progression1.00.80.60.40.20 0515253545H + CT CTProbability of survival25.4 months (25%)20.3 monthsRR=0.76 p=0.025Time (mont
7、hs)Mean combination index values 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;18:2241513Fu
8、jimoto-Ouchi K, et al. Cancer Chemother 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%
9、(FISH) Used by Intergroup to develop adjuvant design Widely used in the clinical setting in the USA and Australia1Seidman AD, et al. J Clin Oncol 2001;19:258795Herceptin联合 docetaxel Phase II trials Herceptin was administered as a 4mg/kg initial dose followed by 2mg/kg weekly until progressionHercept
10、in 与 vinorelbine联合1Burstein H, et al. J Clin Oncol 2001;19:2722302Jahanzeb M, et al. Breast Cancer Res Treat 2001;69:284 (Abstract 429)Herceptin与 gemcitabine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
11、= 45% (17/38)OShaughnessy JA, et al. Breast Cancer Res Treat 2001;69:302 (Abstract 523)Herceptin与 docetaxel和 platinum 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) T
12、his regimen is being investigated in phase III trials in the adjuvant (006) and metastatic (007) settingsNabholtz J-M, et al. Eur J Cancer 2001;37:S190 (Abstract 695)Herceptin与 Xeloda联合 In patients pretreated for metastatic breast cancerRR = 62% (8/13) when Xeloda was administered at a dose of 1,125
13、mg/m2 b.i.d.1RR = 53% (9/17) when Xeloda was administered at a dose of 1,000mg/m2 b.i.d.2 The combination was well tolerated Additional trials to further examine this combination include a randomised phase II trial of Herceptin plus docetaxel Xeloda 1Bangemann N, et al. Ann Oncol 2000;11:143 (Abstra
14、ct 653P)2Bangemann N, et al. Breast Cancer Res Treat 2000;64:123 (Abstract 530)Herceptin 与化疗联合 小结 Several Herceptin combination regimens are activehigh RRs favourable 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