Systemic humoral responses of non-muscle-invasive bladder cancer during BCG treatment: less is more

Abstract

Aim: Intravesical Bacille Calmette-Guérin (BCG) is the mainstay adjuvant treatment of non-muscle-invasive bladder cancer. However, one third of the patients on BCG regimen relapse within the first year of treatment. This study aimed at identifying biomarkers to predict response to BCG treatment.

Methods: Gene expression was analyzed in blood cells of 58 patients treated with BCG through six consecutive weekly instillations and then at month 3, 6, 9, and 12. Cytokines tumor necrosis factor (TNF)-α, interleukin (IL)-10, interferon (IFN)-γ, IL-1β, IL-2, IL-4, and IL-6; chemokines CCL2, CCL3, CCL8, CXCL9, and IP-10; and mediators of cytotoxicity CTLA4, Fas-L, Perf, GNLY, NOS2A, and HMOX-1 were analyzed before the 1st and the 6th week instillation and 24 h after to assess fast (within 24 h) and prolonged changes resulting from treatment.

Results: BCG instillation led to fast-increased expression of IL-1β, TNF-α, and IL-10 genes. When compared to relapsing patients, patients with no relapses within one year showed significantly lower expression of IL-1β at 1st week and less IFN-γ, HMOX-1, and GNLY at week 6. HMOX-1 and GNLY were independent predictive biomarkers, and values above the cut-off ≥ 110 and ≥ 13.0 ‰ mRNA, respectively, were considered prejudicial factors. Patients with two HMOX-1 and GNLY factors had highest (66.7%) relapsing risk.

Conclusion: Assessing immunomodulators’ expression in blood allows the establishment of predictive cut-off values and identification of probabilities for patients’ relapses after BCG treatment.

Keywords

Bladder cancer / Bacille Calmette-Guérin / immunomodulatory molecules / multivariate analysis

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