Introduction: Human epidermal growth factor receptor type 2 (HER2) overexpression is a prognostic factor and a therapeutic target for breast cancer; however, anti-HER2 therapies are ineffective in patients with bladder cancer. The authors investigated the effect of HER2 overexpression (HER2⁺) on the prognosis of muscle-invasive bladder cancer (MIBC). Materials and methods: This retrospective cohort study included patients who underwent initial transurethral resection of bladder tumors between 2005 and 2013 and were registered in the Korea National Health Insurance Database, which provides data on overall survival (OS). Sixty-one patients with clinically nonmetastatic de novo MIBC were included in this study. As a subgroup, 33 patients who underwent immediate radical cystectomy (RC) were analyzed. Univariate and multivariate Cox proportional hazards models were used to identify prognostic factors for survival. A multivariable binary logistic regression model was used to identify the favorable T stage. Results: Among the 61 patients with d-MIBC, 14 were HER2⁺ and 47 HER2^-. Age less than 70 years [hazard ratio (HR): 0.312, CI: 0.16–0.59, P<0.001] and HER2⁺ status (HR: 0.40, CI: 0.19–0.85, P=0.02) were favorable prognostic factors for OS after adjusting for clinical variables. In the RC subgroup, HER2⁺ status was a significant predictive factor for the pT2 stage (HR): 36.8, CI: 4.83–797.41, P<0.01). Age less than 70 years (HR: 0.15, CI: 0.05–0.42, P<0.001) and HER2⁺ status (HR: 0.11, CI: 0.02–0.54, P=0.01) were favorable prognostic factors for OS after adjusting for RC pathological variables. Conclusions: HER2⁺ status could be a marker for an indolent subset of MIBC and could predict favorable survival regardless of RC status. Moreover, HER2⁺ status not only consistently predicted a favorable T stage after RC, but also predicted better survival than pathological outcomes.

Introduction: Predicting the response to Bacillus Calmette–Guérin (BCG) therapy in high-risk patients with non-muscle invasive bladder cancer (NMIBC) is crucial, as failure may necessitate interventions, such as radical cystectomy or salvage therapy. With the recent classification of genetic class 2a (which has HER2 protein abundance as its signature mutation of ERBB2), evaluating its prognostic role and relationship with BCG response could yield important results.Methods: This retrospective study included 160 patients with NMIBC who underwent transurethral resection of bladder tumors at Gangneung Asan Hospital between 2000 and 2013 and were stratified based on the European Organization for Research and Treatment of Cancer (EORTC) risk criteria. In addition, we analyzed a subset of 67 patients who had received BCG induction therapy to identify factors predictive of BCG treatment response. Univariate and multivariate analyses were used to assess the impact of clinicopathological factors, HER2 positivity, and EORTC risk on recurrence, progression, survival, and BCG response. Each variable’s prognostic significance was determined using the Kaplan–Meier analysis. The tumor microenvironments (TMEs) were evaluated in relation to HER2 and EORTC risk.Results: Patients with HER2+ had a higher median age, a greater prevalence of high-grade tumors, and more frequent recurrences. The univariate analysis demonstrated that the HER2+, intermediate (vs. low-risk) high (vs. low-risk), and EORTC recurrence risk groups were significantly associated with recurrence. In patients treated with BCG, only the HER2+ status predicted recurrence. In the univariate analysis for progression, age, high EORTC progression risk (vs. low-to-intermediate), HER2+, and programmed death-ligand 1 positive (PD-L1+) were significant factors. In multivariate analyses for progression, age, high EORTC progression risk, and PD-L1+ were significant factors for progression. HER2 expression was associated with the TME, influencing the proportion of PD-L1+ cells, as well as other markers of PD-1, CD8, and Ki67.Conclusion: The HER2+ status may be related to genetic characteristics that appear more frequently in older age, which suggests a potential for predicting the recurrence and response to BCG treatment. Additionally, analyzing TME trends of aggressive adaptive immune response characterized by HER2 expression provides insight into recurrence and BCG response mechanisms.

Bacillus Calmette–Guérin (BCG) is the gold standard adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). However, given the current global shortage of BCG, new treatments are needed. We evaluated tumor microenvironment markers as potential BCG alternatives for NMIBC treatment. Programmed death-ligand 1, human epidermal growth factor receptor-2 (HER2), programmed cell death-1 (PD1), CD8, and Ki67 levels were measured in treatment-naïve NMIBC and MIBC patients (pTa, pT1, and pT2 stages). Univariate and multivariate Cox proportional hazard models were used to determine the impact of these markers and other clinicopathological factors on survival, recurrence, and progression. EP263, IM142, PD1, and Ki67 levels were the highest in the T2 stage, followed by the T1 and Ta stages. HER2 and IM263 expressions were higher in the T1 and T2 stages than in the Ta stage. In NMIBC, the significant prognostic factors for recurrence-free survival were adjuvant therapy, tumor grade, and HER2 positivity, whereas those for progression-free survival included age, T-stage, and IM263. Age, T-stage, EP263, PD1, CD8, and Ki67 levels were significant factors associated with overall survival. IM263 and HER2 are potential biomarkers for progression and recurrence, respectively. Therefore, we propose HER2 as a potential target antigen for intravesical therapeutics as a BCG alternative.

Nam KH, et al. Investig Clin Urol. 2024 Jul;65(4):342-350. https://doi.org/10.4111/icu.20240005

Han Kyu Chae, Nayoung Suh, Myong Jin Jang, Yu Seon Kim, Bo Hyun Kim, Joomin Aum, Ha Chul Shin, Dalsan You, Bumsik Hong, Hyung Keun Park, Choung-Soo Kim. IJSC 2023;16:66-77. https://doi.org/10.15283/ijsc21146