Nectin-4 as a Potential Prognostic Biomarker in Endometrial Adenocarcinoma

Background: Endometrial adenocarcinoma is the most prevalent gynecologic malignancy in developed countries. While molecular classifications such as TCGA and ProMisE have enhanced prognostic stratification by incorporating genetic alterations like p53 mutations and mismatch repair (MMR) deficiency, these systems may not fully capture tumor invasiveness and immune evasion potential. Nectin-4, a transmembrane cell adhesion molecule, has recently gained attention as a prognostic and therapeutic target in various cancers. However, its role in endometrial adenocarcinoma remains unclear. Aims: This study aims to investigate the expression pattern of Nectin-4 in endometrial adenocarcinoma and assess its correlation with tumor grade, hormone receptor status, p53 expression, and MMR protein expression, in order to evaluate its potential as a prognostic biomarker. Methods: In this retrospective study, 55 formalin-fixed, paraffin-embedded (FFPE) tissue samples collected between 2015 and 2023 were analyzed, including endometrial adenocarcinoma (n = 35), endometrial intraepithelial neoplasia (n = 10), and normal endometrial tissues (n = 10). Immunohistochemistry (IHC) was performed to assess Nectin-4, p53, estrogen/progesterone receptors, and MMR proteins (MLH1, PMS2, MSH2, MSH6). Staining was scored using the H-score method. Statistical correlations were evaluated using Chi-square or Fisher’s exact test for categorical variables, and Spearman’s correlation for continuous variables. Results: Nectin-4 expression was significantly associated with higher histological grades of endometrial adenocarcinoma (p < 0.001). All Grade III tumors showed strong Nectin-4 positivity, while Grades I and II demonstrated variable expression. No Nectin-4 expression was observed in normal endometrium, and only mild expression in intraepithelial neoplasia. Strong Nectin-4 expression was significantly correlated with p53 overexpression (p = 0.007) and PMS2 loss (p = 0.002), but not with other MMR proteins or hormone receptor status. Nectin-4 expression also showed a positive correlation with increasing patient age (p < 0.001). Conclusion: Nectin-4 expression is strongly associated with high-grade endometrial adenocarcinoma, p53 overexpression, and PMS2 loss, suggesting its potential utility as a prognostic biomarker. These findings highlight the need for further large-scale studies to validate Nectin-4’s clinical relevance and investigate its role as a potential therapeutic target in endometrial cancer.