Background/Objectives: The aberrant expression and activation of HER family members is a known major oncogenic pathway for the proliferation, progression, and metastasis of a wide range of human malignancies. In this study, our aim was to examine the relative expression and prognostic significance of all members of the HER family, the type III EGFR mutant (EGFRvIII), and the putative stem cell markers CD44 and CD109 in patients with glioblastoma. Methods: The expression levels of wild-type EGFR (wtEGFR), HER2, HER3, HER4, EGFRvIII, CD44, and CD109 were determined in tumour specimens from 80 patients by immunohistochemistry. The staining was scored based on the percentage of positive tumour cells, the intensity, and the cellular location of immunostaining. The association between the expression level of the biomarkers and patient overall survival was evaluated using Chi-squared, Kaplan–Meier survival curves, and log-rank tests. Results: At a cut-off value of ≥5% with positive staining, 46% (wtEGFR), 75% (HER2), 19% (HER3), 71% (HER4), 85% (EGFRvIII), 95% (CD44), and 16% (CD109) of the cases were positive for these biomarkers. Interestingly, at the same cut-off value, the expression of wtEGFR in these patients was accompanied by co-expression with HER2 (35%), HER3 (0%), HER4 (30%), EGFRvIII (36%), CD44 (44%), HER2/EGFRvIII (28%), HER2/CD44 (31%), and EGFRvIII/CD44 (36%). In addition, the expression of EGFRvIII was accompanied by co-expression with HER2 (65%), HER3 (15%), HER4 (63%), CD44 (83%), CD109 (16%), wtEGFR/HER2 (28%), and 55% of the cases had co-expression of EGFRvIII/HER2/HER4/CD44. With the exception of HER2 expression, at cut-off values of ≥5% of tumour cells with positive staining, which was associated with better overall survival [HR = 0.57 (p= 0.038), HR = 0.56 (p= 0.034)], there was no significant association between the expression of other members of the HER family, EGFRvIII, CD44, and CD109 on the overall survival in both univariate and multivariate analysis. Conclusions Our results suggest that the co-expression of different members of the HER family, with EGFRvIII, CD44, and CD109, occurs in patients with glioblastoma. As the results of therapy with EGFR inhibitors have not been encouraging in patients with a brain tumour, further investigation should determine whether the co-expression of such biomarkers can be of predictive value for the response to the therapy with various types of HER inhibitors and their potential as therapeutic targets for co-targeted therapy.
背景/目的：HER家族成员的异常表达与激活是多种人类恶性肿瘤增殖、进展及转移的重要致癌通路。本研究旨在探讨胶质母细胞瘤患者中HER家族所有成员、III型EGFR突变体（EGFRvIII）以及推定干细胞标志物CD44与CD109的相对表达水平及其预后意义。方法：通过免疫组织化学方法检测80例患者肿瘤标本中野生型EGFR（wtEGFR）、HER2、HER3、HER4、EGFRvIII、CD44及CD109的表达水平。染色评分基于阳性肿瘤细胞百分比、染色强度及免疫染色的细胞定位。采用卡方检验、Kaplan-Meier生存曲线和对数秩检验评估生物标志物表达水平与患者总生存期的关联性。结果：以≥5%阳性染色为截断值，各生物标志物阳性率分别为：wtEGFR 46%、HER2 75%、HER3 19%、HER4 71%、EGFRvIII 85%、CD44 95%、CD109 16%。值得注意的是，在同一截断值下，wtEGFR表达常伴随其他标志物共表达：HER2（35%）、HER3（0%）、HER4（30%）、EGFRvIII（36%）、CD44（44%）、HER2/EGFRvIII（28%）、HER2/CD44（31%）及EGFRvIII/CD44（36%）。此外，EGFRvIII表达常伴随HER2（65%）、HER3（15%）、HER4（63%）、CD44（83%）、CD109（16%）、wtEGFR/HER2（28%）共表达，55%病例存在EGFRvIII/HER2/HER4/CD44多重共表达。生存分析显示，除HER2表达（≥5%阳性肿瘤细胞截断值）与较好总生存期相关[风险比=0.57（p=0.038），风险比=0.56（p=0.034）]外，单变量与多变量分析均未发现HER家族其他成员、EGFRvIII、CD44及CD109的表达与总生存期存在显著关联。结论：本研究提示胶质母细胞瘤患者中存在HER家族不同成员与EGFRvIII、CD44及CD109的共表达现象。鉴于EGFR抑制剂在脑肿瘤患者中的疗效未达预期，未来研究需进一步验证这些生物标志物的共表达模式是否对各类HER抑制剂治疗反应具有预测价值，并探索其作为联合靶向治疗靶点的潜力。
肿瘤(癌症)患者之家