FOXM 1 overexpression is associated with adverse outcome and predicts response to intravesical instillation therapy in stage pT 1 non‐muscle‐invasive bladder cancer

Objective To investigate the role of forkhead box protein M1 ( FOXM 1) mRNA expression and its prognostic value in stage pT 1 non‐muscle‐invasive bladder cancer ( NMIBC ). Patients and Methods Clinical data and formalin‐fixed paraffin‐embedded tissues from transurethral resection of the bladder from patients with stage pT 1 NMIBC , treated with an organ‐preserving approach, were analysed retrospectively. Total RNA was isolated using commercial RNA extraction kits, and mRNA expression of FOXM 1, MKI 67, KRT 20 and KRT 5 was measured by single‐step quantitative RT ‐ PCR using RNA ‐specific TaqMan Assays. Statistical analysis was performed using Spearman's Rho, Wilcoxon or Kruskal–Wallis tests, Kaplan–Meier estimates of recurrence‐free ( RFS ), progression‐free ( PFS ) and cancer‐specific survival ( CSS ) and Cox regression analysis. Results Data from 296 patients (79.4% men, median age 72 years) were available for the final evaluation. Spearman correlation analysis showed that mRNA expression of FOXM 1 was significantly correlated with MKI 67 (ρ: 0.6530, P < 0.001) and with the luminal subtype, reflected by the positive correlation with KRT 20 (ρ: 0.2113, P < 0.001). Furthermore, there was also a strong correlation of FOXM 1 expression with adverse clinical and pathological variables, such as concomitant carcinoma in situ ( P = 0.05), multifocal tumours ( P = 0.005) and World Health Organization 1973 grade 3 disease ( P < 0.001). Kaplan–Meier analysis showed overexpression of FOMX 1 to be associated with worse PFS ( P = 0.028) and worse CSS ( P = 0.015). FOXM 1 overexpression was also shown to be a predictive risk factor for CSS (hazard ratio 1.61 [1.13–2.34], L‐R chi‐squared: 7.19, P = 0.007). FOXM 1 overexpression identified a subgroup of patients within the luminal subtype with worse RFS ( P = 0.017), PFS ( P < 0.001) and CSS ( P = 0.015). Patients with low FOXM 1 expression had better outcomes, irrespective of instillation therapy, whereas patients with high FOXM 1 expression benefitted from intravesical chemotherapy with mitomycin C. Conclusion High FOXM 1 expression was associated with adverse clinical and pathological features and worse outcomes, and predicted response to intravesical instillation therapy in patients with stage pT 1 NMIBC .