FOXM1 overexpression is associated with adverse outcome and predicts response to intravesical instillation therapy in stage pT1 non-muscle-invasive bladder cancer.

Abstract

OBJECTIVE:

To investigate the role of forkhead box protein M1 (FOXM1) mRNA expression and its prognostic value in stage pT1 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 pT1 NMIBC, treated with an organ-preserving approach, were analysed retrospectively. Total RNA was isolated using commercial RNA extraction kits, and mRNA expression of FOXM1, MKI67, KRT20 and KRT5 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 FOXM1 was significantly correlated with MKI67 (ρ: 0.6530, P < 0.001) and with the luminal subtype, reflected by the positive correlation with KRT20 (ρ: 0.2113, P < 0.001). Furthermore, there was also a strong correlation of FOXM1 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 FOMX1 to be associated with worse PFS (P = 0.028) and worse CSS (P = 0.015). FOXM1 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). FOXM1 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 FOXM1 expression had better outcomes, irrespective of instillation therapy, whereas patients with high FOXM1 expression benefitted from intravesical chemotherapy with mitomycin C.

CONCLUSION:

High FOXM1 expression was associated with adverse clinical and pathological features and worse outcomes, and predicted response to intravesical instillation therapy in patients with stage pT1 NMIBC.

• Authors: Johannes Breyer, Ralph M Wirtz, Philipp Erben, Sebastien Rinaldetti, Thomas S Worst, Robert Stoehr, Markus Eckstein, Danijel Sikic, Stefan Denzinger, Maximilian Burger, Arndt Hartmann, Wolfgang Otto
• Journal: BJU international (BJU Int) Vol. 123 Issue 1 Pg. 187-196 (01 2019) ISSN: 1464-410X [Electronic] England
• PMID: 30120861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors BJU International © 2018 BJU International Published by John Wiley & Sons Ltd.

Chemical References

• Antibiotics, Antineoplastic
• FOXM1 protein, human
• Forkhead Box Protein M1
• KRT20 protein, human
• Keratin-20
• Ki-67 Antigen
• MKI67 protein, human
• RNA, Messenger
• Mitomycin

Topics

• Administration, Intravesical
• Aged
• Antibiotics, Antineoplastic (therapeutic use)
• Disease-Free Survival
• Female
• Forkhead Box Protein M1 (genetics)
• Humans
• Kaplan-Meier Estimate
• Keratin-20 (genetics)
• Ki-67 Antigen (genetics)
• Male
• Middle Aged
• Mitomycin (therapeutic use)
• Neoplasm Staging
• Neoplasms, Multiple Primary (genetics)
• Prognosis
• Progression-Free Survival
• Proportional Hazards Models
• RNA, Messenger (metabolism)
• Retrospective Studies
• Survival Rate
• Urinary Bladder Neoplasms (drug therapy, genetics, pathology)