Evaluation of human epidermal growth factor receptor 2 (HER2)-related genes revealed that HER2-antibody-drug conjugate (ADC) drugs confer clinical benefits to Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle invasive bladder cancer patients.

BACKGROUND

Current guidelines recommend intravesical Bacillus Calmette-Guérin (BCG) instillation as the first-line treatment for high-risk non-muscle invasive bladder cancer (HR-NMIBC). However, a substantial proportion of BCG-refractory patients progress to muscle-invasive bladder cancer (BCa), and effective bladder-sparing therapeutic options remain scarce for this population. This study aims to develop a transcriptome-based predictive model for identifying HR-NMIBC patients who may benefit from human epidermal growth factor receptor 2 (HER2)-targeted therapy following BCG treatment failure, and to validate its clinical feasibility.

METHODS

We conducted a retrospective analysis of HR-NMIBC cases treated with BCG over the past decade at our institution to investigate the association between HER2 expression and clinical outcomes. Public databases were interrogated to elucidate the mechanisms underlying BCG failure in HER2-overexpressing NMIBC. A HER2-related prognostic score (HRS) model was developed using bioinformatics approaches, with subsequent exploration of transcriptomic disparities between high-risk and low-risk subgroups. The therapeutic potential of HER2-targeted agents was further validated through in vitro experiments using human BCa cell lines and in vivo murine orthotopic BCa models.

RESULTS

Real-world retrospective analysis revealed HER2 overexpression as an independent predictor of BCG failure in NMIBC patients. The HRS prognostic model, constructed through Least Absolute Shrinkage and Selection Operator (LASSO)-Cox regression analysis of HER2-high versus HER2-low subgroups, demonstrated superior clinical outcomes for low-risk patients via Kaplan-Meier analysis. Progression-free survival-time-dependent-receiver operating characteristic (PFS-time-dependent-ROC) curves exhibited robust sensitivity and specificity at 1-, 3-, and 5-year intervals. Preclinical validations in cellular and animal models showed promising therapeutic efficacy of HER2-targeted interventions.

CONCLUSIONS

HER2 overexpression serves as an independent prognostic biomarker for BCG failure in HR-NMIBC. The HRS prognostic model effectively stratifies high-risk patients who may derive clinical benefit from HER2-targeted therapeutic strategies.