HER2 positivity predicts BCG unresponsiveness and adaptive immune cell exhaustion in EORTC risk-stratified cohort of bladder cancer

Front Immunol. 2023 Dec 8:14:1301510. doi: 10.3389/fimmu.2023.1301510. eCollection 2023.


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.

Keywords: Bacillus Calmette–Gúérin; Bladder neoplasm; EORTC risk; ERBB2 mutation; HER2; PD-L1; T-cell exhaustion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • B7-H1 Antigen
  • BCG Vaccine / therapeutic use
  • Disease Progression
  • Humans
  • Neoplasm Staging
  • Non-Muscle Invasive Bladder Neoplasms*
  • Retrospective Studies
  • Tumor Microenvironment
  • Urinary Bladder Neoplasms* / genetics
  • Urinary Bladder Neoplasms* / pathology
  • Urinary Bladder Neoplasms* / therapy


  • B7-H1 Antigen
  • BCG Vaccine

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The funds included in this study were not associated with the collection of data, data analysis, or the writing of the manuscript. This research received support from the Gangneung Asan Hospital Medical Institute and Asan Foundation (2023II0004), the National Research Foundation of Korea (NRF-2022R1F1A1071736), and “Regional Innovation Strategy (RIS)” through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (MOE) in 2023 (2022RIS-005).