Al Janaby Tina, Khelwatty Said, Bagwan Izhar, Abbassi-Ghadi Nima, Modjtahedi Helmout
Department of Biomolecular Science, School of Life Science, Pharmacy and Chemistry, Kingston University London, Kingston, UK.
Berkshire Surrey Pathology Services, Royal Surrey Hospital, Guildford, UK.
World J Oncol. 2025 Jun;16(3):254-268. doi: 10.14740/wjon2552. Epub 2025 Apr 4.
The heterogenous expression of human epidermal growth factor receptor (HER) family members may contribute to poor response to current therapies with HER inhibitors in cancer. This study aimed to explore the co-expression and prognostic significance of HER family members with epidermal growth factor receptor variant III (EGFRvIII), cluster of differentiation 44 (CD44), cluster of differentiation 109 (CD109), and claudin 18.2 (CLDN18.2) in patients with stomach cancer.
The relative expression and prognostic significance of these biomarkers at different cut-off values were determined in 78 patients with stomach adenocarcinoma by immunohistochemistry.
Of the 78 cases, positive tumor staining was present for wild-type EGFR (13%), HER2 (82%), HER3 (9%), HER4 (33%), EGFRvIII (33%), CD44 (41%), CD109 (60%), and CLDN18.2 (40%). Furthermore, the expression of HER2 was accompanied with the co-expression of EGFR (9%), HER3 (8%), HER4 (27%), EGFRvIII (28%), CD44 (33%), CD109 (49%), and CLDN18.2 (32%). Interestingly, at the cut-off value ≥ 5% of tumor cells with positive staining, the co-expressions of HER2/EGFRvIII, EGFRvIII/CD44, and HER2/EGFRvIII/CD44 were associated with poor overall survival. Moreover, CLDN18.2 immunostaining of intensity of 3+, membranous expression of CD109, the co-expression of CD109/CLDN18.2 and CD109/EGFRvIII/CD44 were also associated with poorer overall survival and a higher risk of poor overall survival. All these remained as independent prognostic factors for survival in multivariate analysis.
This study provides first comprehensive analysis of the novel biomarker combinations that are significantly associated with overall survival. Co-expression of HER2 with EGFRvIII, CD44, and CD109, plus membranous CD109 and high-intensity CLDN18.2, independently predicted poor survival in stomach adenocarcinoma, highlighting their potential as prognostic biomarkers. These biomarker combinations may represent potential therapeutic targets for novel combination therapies, and future studies should investigate their predictive value for the response to therapy.
人类表皮生长因子受体（HER）家族成员的异质性表达可能导致癌症患者对目前HER抑制剂治疗反应不佳。本研究旨在探讨HER家族成员与表皮生长因子受体变异体III（EGFRvIII）、分化簇44（CD44）、分化簇109（CD109）和紧密连接蛋白18.2（CLDN18.2）在胃癌患者中的共表达情况及预后意义。
通过免疫组织化学法测定78例胃腺癌患者中这些生物标志物在不同临界值下的相对表达及预后意义。
78例病例中，野生型EGFR（13%）、HER2（82%）、HER3（9%）、HER4（33%）、EGFRvIII（33%）、CD44（41%）、CD109（60%）和CLDN18.2（40%）呈肿瘤阳性染色。此外，HER2的表达伴有EGFR（9%）、HER3（8%）、HER4（27%）、EGFRvIII（28%）、CD44（33%）、CD109（49%）和CLDN18.2（32%）的共表达。有趣的是，在肿瘤细胞阳性染色≥5%的临界值时，HER2/EGFRvIII、EGFRvIII/CD44和HER2/EGFRvIII/CD44的共表达与总生存期较差相关。此外，CLDN18.2免疫染色强度为3+、CD109膜表达、CD109/CLDN18.2和CD109/EGFRvIII/CD44的共表达也与总生存期较差及总生存期不良风险较高相关。在多因素分析中，所有这些均为生存的独立预后因素。
本研究首次对与总生存期显著相关的新型生物标志物组合进行了全面分析。HER2与EGFRvIII、CD44和CD109的共表达，加上膜性CD109和高强度CLDN18.2，独立预测胃腺癌患者生存不良，突出了它们作为预后生物标志物的潜力。这些生物标志物组合可能代表新型联合治疗的潜在治疗靶点，未来研究应调查它们对治疗反应的预测价值。
