Targeting Human Epidermal Growth Factor Receptor 2 in Bladder Cancer: Evaluating Its Role as a More Robust Clinicopathological Biomarker Compared to Programmed Death Ligand 1 Expression

Abstract

Objective: This retrospective cross-sectional analytical study evaluated the clinicopathological associations of programmed death ligand 1 (PD-L1) and human epidermal growth factor receptor 2 (HER2/neu) expression in 250 patients with urothelial carcinoma of the urinary bladder, with particular emphasis on their relationship to tumor stage and lymph node involvement.

Methods: A retrospective observational study was conducted on 250 patients with urothelial carcinoma who underwent immunohistochemical evaluation of PD-L1, using a tumor proportion score (TPS) of ≥1%, and HER2/neu with 3+ considered positive. Formalin-fixed paraffin-embedded tissue from transurethral resection of bladder tumor and cystectomy specimens was analyzed by immunohistochemistry. The HER2/ neu was scored using a standard 0-3+ system, and PD-L1 expression was assessed by TPS. Associations were tested using chi-square or Fisher’s exact tests. Multivariable logistic regression evaluated whether HER2/neu independently predicted nodal involvement after adjustment for age, sex, tumor stage, and morphology. Statistical significance was set at P < .05.

Results: The HER2/neu 3+ positivity was present in 100/250 patients (40%) and was significantly associated with nodal involvement (P = .019). On multivariable logistic regression, HER2/neu is independently associated with nodal involvement, reflecting aggressive tumor biology (adjusted OR 2.41; 95% CI 1.33-4.36; P = .004). Among node-negative patients (N0, n = 200), 35.5% were HER2/neu positive, rising stepwise to 50.0% in N1, 54.5% in N2, and 71.4% in N3 disease, supporting a relationship between HER2/ neu overexpression and nodal progression. In contrast, PD-L1 positivity (TPS ≥1%) was observed in 129/250 patients (51.6%) and was not significantly associated with age, sex, tumor stage, nodal status, grade, multiplicity, or morphology (all P > .05).

Conclusion: The HER2/neu was an independent clinicopathological biomarker associated with nodal involvement and aggressive tumor biology in urothelial carcinoma. PD-L1 showed limited clinicopathological utility in this cohort, though it retains predictive value for immune checkpoint inhibitor therapy.

Cite this article as: Mittal A, Malhotra K, Panwar V, Kishore S, Taher M, Singhal A. Targeting human epidermal growth factor receptor 2 in bladder cancer: evaluating its role as a more robust clinicopathological biomarker compared to programmed death ligand 1 expression. Urol Res Pract. 2026, 52, 0061, doi: 10.5152/tud.2026.25061.