Will single-time tumor profiling and a "guilt by association" approach allow us to outsmart HER2-positive breast cancer?
Will single-time tumor profiling and a "guilt by association" approach allow us to outsmart HER2-positive breast cancer?
复制标题
一次性肿瘤分析和“关联罪”方法能否让我们智胜 HER2 阳性乳腺癌？
DOI：
10.1158/1078-0432.ccr-06-2717
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发表时间：
2007
期刊：
影响因子：
--
通讯作者：
Arteaga,CarlosL
中科院分区：
文献类型：
--
作者：
Arteaga,CarlosL
Amplification of the HER2/Neu (ERBB2) gene, the second member of the epidermal growth factor receptor (ErbB) tyrosine kinase family, occurs in f25% of invasive breast cancers and is associated with poor patient outcome (1). Trastuzumab (Herceptin), a humanized monoclonal IgG1 that binds to the extracellular domain of the HER2 receptor, induces clinical responses in HER2-overexpressing breast cancers and prolongs patient survival when combined with chemotherapy (2–8). The randomized studies that showed the clinical benefit of trastuzumab enrolled mainly or exclusively patients with breast cancer that overexpress HER2 as measured by intense membrane staining in the majority of tumor cells with HER2 antibodies (3+ by immunohistochemistry) or excess copies of the HER2 gene determined by fluorescence in situ hybridization. Patients with a single copy of the HER2 gene (so called fluorescence in situ hybridization negative) or with 2+ HER2 protein by immunohistochemistry have not been shown to benefit from therapy with trastuzumab either alone or in combination with chemotherapy. For these reasons, trastuzumab is approved for use only in patients with HER2-overexpressing breast cancer as defined above. Therefore, HER2 overexpression by immunohistochemistry and/or fluorescence in situ hybridization is the biomarker predictive of good odds of response to treatment with the antibody. However, many patients with HER2 gene–amplified metastatic breast cancers do not respond or eventually escape trastuzumab, suggesting both de novo and acquired mechanisms of therapeutic resistance.Few studies have already reported or speculated on potential mechanisms of resistance to trastuzumab. For example, overexpression of the insulin-like growth factor (IGF)-I receptor or increased levels of IGF-I receptor/HER2 heterodimers (9, 10), which potently activate phosphatidylinositol-3 kinase and its downstream effector Akt, partially abrogate trastuzumab action when transfected into antibody-sensitive human breast cancer cells. Amplification of the phosphatidylinositol-3 kinase
