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FOXM 1 overexpression is associated with adverse outcome and predicts response to intravesical instillation therapy in stage pT 1 non‐muscle‐invasive bladder cancer
Author(s) -
Breyer Johannes,
Wirtz Ralph M.,
Erben Philipp,
Rinaldetti Sebastien,
Worst Thomas S.,
Stoehr Robert,
Eckstein Markus,
Sikic Danijel,
Denzinger Stefan,
Burger Maximilian,
Hartmann Arndt,
Otto Wolfgang
Publication year - 2019
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/bju.14525
Subject(s) - bladder cancer , medicine , stage (stratigraphy) , proportional hazards model , urology , hazard ratio , concomitant , oncology , cancer , gastroenterology , biology , confidence interval , paleontology
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 .