Essapen Sharadah, Thomas Hilary, Green Margaret, De Vries Corrine, Cook Martin G, Marks Christopher, Topham Clare, Modjtahedi Helmout
Division of Oncology, Postgraduate Medical School, University of Surrey, Guildford, Surrey GU2 7XH, UK.
Int J Oncol. 2004 Feb;24(2):241-8.
The prognostic role of HER-2 has been established in breast cancer but remains controversial in colorectal cancer. In this study, 170 archival specimens of Dukes' B and C colorectal cancer were analysed immunohisto-chemically, using an anti-HER-2 monoclonal antibody HM64.13. Immunostaining was classified as cytoplasmic or membranous, and the intensity of the immunostaining was graded negative, weak or strong. The association between these scores and survival was estimated using Cox survival analyses. Overall, 87% of cases showed cytoplasmic HER-2 staining, with 54% exhibiting strong intensity cytoplasmic immunostaining. Membranous HER-2 was seen in 41% of cases, with most of these being of strong intensity. No correlation with clinical outcome was seen with membranous HER-2. Positive cytoplasmic immunostaining was found to be associated with a significantly better overall survival (HR 0.46, CI95 0.24-0.87) in the Dukes C cancers, but no survival benefit was seen in the Dukes' B cancers. Tumour grade, depth of tumour invasion and positive apical node were also found to be independent prognostic factors in Dukes' C cancers. We conclude that HER-2 over-expression occurs in a significant number of colorectal cancers. Since cytoplasmic HER-2 is incapable of transmitting the strong mitogenic signal via heterodimerization with other members of the Epidermal Growth Factor Receptor (EGFR) family, this may partly explain the correlation between cytoplasmic HER-2 over-expression and a better prognosis in the Dukes' C colorectal cancers. In addition, high levels of membraneous HER-2 in colorectal cancer could make HER-2 a good target for monoclonal antibody-based immunotherapy.
HER-2的预后作用在乳腺癌中已得到确立，但在结直肠癌中仍存在争议。在本研究中，使用抗HER-2单克隆抗体HM64.13对170例存档的Dukes B期和C期结直肠癌标本进行了免疫组织化学分析。免疫染色分为细胞质或细胞膜染色，免疫染色强度分为阴性、弱阳性或强阳性。使用Cox生存分析评估这些评分与生存率之间的关联。总体而言，87%的病例显示细胞质HER-2染色，其中54%表现为强强度细胞质免疫染色。41%的病例可见细胞膜HER-2，其中大多数为强强度。未发现细胞膜HER-2与临床结局相关。在Dukes C期癌症中，发现细胞质免疫染色阳性与总体生存率显著提高相关（风险比0.46，95%置信区间0.24 - 0.87），但在Dukes B期癌症中未观察到生存获益。肿瘤分级、肿瘤浸润深度和阳性顶端淋巴结也被发现是Dukes C期癌症的独立预后因素。我们得出结论，HER-2过表达在大量结直肠癌中出现。由于细胞质HER-2无法通过与表皮生长因子受体（EGFR）家族的其他成员异源二聚化来传递强烈的促有丝分裂信号，这可能部分解释了细胞质HER-2过表达与Dukes C期结直肠癌较好预后之间的相关性。此外，结直肠癌中高水平的细胞膜HER-2可能使HER-2成为基于单克隆抗体的免疫治疗的良好靶点。
