Dual molecular axis of resistance and immunoresponsiveness to BCG in pT1 non-muscle invasive bladder cancer: Insights from HER-2, SERBP1, HABP4, and IFN-γ profiling.

Bacillus Calmette-Guérin (BCG) immunotherapy remains the cornerstone of adjuvant treatment for high-risk non-muscle invasive bladder cancer (NMIBC); however, therapeutic failure is particularly frequent in pT1 disease, resulting in early recurrence and progression to muscle-invasive cancer. Identifying biomarkers to anticipate BCG failure is a current clinical priority to improve patient stratification and enable risk-adapted, bladder-sparing interventions. We retrospectively analyzed a cohort of 48 patients with histologically confirmed pT1 NMIBC treated with standard intravesical BCG at two tertiary centers. The median age was 67 years (range: 41-93), 79.2 % were male, 81.2 % had high-grade tumors, 70.8 % had multifocal lesions, and 75.0 % presented tumors > 3 cm. Formalin-fixed, paraffin-embedded tumor samples were obtained prior to BCG and, when available, at recurrence or progression. Immunohistochemical expression of HER-2, SERBP1, HABP4, and IFN-γ was quantified using semi-quantitative scoring and H-scores. Associations with recurrence-free survival (RFS) and progression-free survival (PFS) were evaluated using Kaplan-Meier survival analysis and Cox regression. HER-2 and SERBP1 were significantly overexpressed in BCG-refractory tumors, with high immunorectivities conferring markedly reduced RFS (HER-2: 7.78 vs. 11.71 months, p < 0.001; SERBP1: 7.64 vs. 11.52 months, p < 0.0001) and inferior PFS (p < 0.05). In contrast, high HABP4 and IFN-γ immunorectivities were strongly associated with sustained recurrence- and progression-free survival (both p < 0.0001). Hazard ratios for recurrence and progression exceeded 5.0 for HER-2/SERBP1-high and IFN-γ/HABP4-low profiles. These findings define two molecular phenotypes-immune-evasive versus immune-active-that may inform precision risk stratification, early intervention, and personalized therapeutic decision-making in high-risk NMIBC.