Brand Francois-Xavier, Ravanel Nadia, Gauchez Anne-Sophie, Pasquier Dominique, Payan Raoul, Fagret Daniel, Mousseau Mireille
Département de Biologie Intégrée, CHU Grenoble, France.
Anticancer Res. 2006 Jan-Feb;26(1B):463-70.
The carcinogenesis process is characterized, in part, by the dysfunction of cellular communication pathways, such as the one involving HER2. HER2 is a member of the EGF receptor family, which participates in cell growth and proliferation. HER2 may be overexpressed in 15 to 30% of breast cancer cases and is associated with poor prognosis, shortened overall survival and shorter time to disease progression. Furthermore, an increasing number of studies have demonstrated the relevance of HER2 serum concentrations (sHER2, extracellular domain released into blood by proteolysis) as a predictive marker of resistance to chemotherapy in HER2-overexpressing metastatic breast cancer. The determination of HER2 overexpression/ amplification in the diagnosis of relapse of breast cancer is currently a routine procedure. Immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH) techniques, which are used to detect HER2 expression in the tumor, are improving constantly, and other parallel techniques such as chromogenic in situ hybridization (CISH) are starting to emerge. sHER2 concentrations can be measured using ELISA techniques, which can be automated. All of these procedures still need to be standardized. The discovery of a monoclonal antibody (4D5) that can inhibit the growth and proliferation of cells overexpressing HER2 led to the development of trastuzumab. Like 4D5, trastuzumab recognizes an epitope on the extracellular domain of HER2. Moreover, trastuzumab is also able to stimulate antibody-dependent cellular toxicity (ADCC). It is administered alone or in combination (with navelbine, taxol, carboplatin...) in patients with metastatic breast cancer overexpressing HER2. Other active antibodies have since been discovered, as well as other specific molecules, such as tyrosine kinase inhibitors which will undoubtedly find a place in the therapeutic arsenal used in breast cancer, especially to avoid the emergence of resistance to treatment.
致癌过程部分特征在于细胞通讯通路功能障碍，例如涉及HER2的通路。HER2是表皮生长因子受体（EGF）家族成员，参与细胞生长和增殖。在15%至30%的乳腺癌病例中，HER2可能过度表达，并与预后不良、总生存期缩短和疾病进展时间缩短相关。此外，越来越多的研究表明，HER2血清浓度（sHER2，通过蛋白水解释放到血液中的细胞外结构域）作为HER2过表达转移性乳腺癌化疗耐药的预测标志物具有相关性。在乳腺癌复发诊断中测定HER2过表达/扩增目前是常规程序。用于检测肿瘤中HER2表达的免疫组织化学（IHC）和荧光原位杂交（FISH）技术在不断改进，其他并行技术如显色原位杂交（CISH）也开始出现。sHER2浓度可以使用可自动化的ELISA技术进行测量。所有这些程序仍需标准化。一种能够抑制过表达HER2的细胞生长和增殖的单克隆抗体（4D5）的发现导致了曲妥珠单抗的研发。与4D5一样，曲妥珠单抗识别HER2细胞外结构域上的一个表位。此外，曲妥珠单抗还能够刺激抗体依赖性细胞毒性（ADCC）。它单独给药或与（长春瑞滨、紫杉醇、卡铂……）联合给药于HER2过表达的转移性乳腺癌患者。此后还发现了其他活性抗体以及其他特异性分子，如酪氨酸激酶抑制剂，它们无疑将在乳腺癌治疗药库中占有一席之地，特别是用于避免出现治疗耐药性。
