Fibroblast Growth Factor Receptor 1 Overexpression Is Associated with Poor Survival in Patients with Resected Muscle Invasive Urothelial Carcinoma

Abstract

PurposeTo examine the usefulness of various receptor tyrosine kinase expressions as prognostic markers and therapeutic targets in muscle invasive urothelial cancer (UC) patients.Materials and MethodsWe retrospectively analyzed the data of 98 patients with muscle invasive UC who underwent radical cystectomy between 2005 and 2010 in Yonsei Cancer Center. Using formalin fixed paraffin embedded tissues of primary tumors, immunohistochemical staining was done for human epidermal growth factor receptor 2 (HER2), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 3 (FGFR3).ResultsThere were 41 (41.8%), 44 (44.9%), and 14 (14.2%) patients who have over-expressed HER2, FGFR1, and FGFR3, respectively. In univariate analysis, significantly shorter median time to recurrence (TTR) (12.9 months vs. 49.0 months; p=0.008) and overall survival (OS) (22.3 months vs. 52.7 months; p=0.006) was found in patients with FGFR1 overexpression. By contrast, there was no difference in TTR or OS according to the HER2 and FGFR3 expression status. FGFR1 remained as a significant prognostic factor for OS with hazard ratio of 2.23 (95% confidence interval: 1.27–3.90, p=0.006) in multivariate analysis.ConclusionOur result showed that FGFR1 expression, but not FGFR3, is an adverse prognostic factor in muscle invasive UC patients after radical cystectomy. FGFR1 might be feasible for prognosis prediction and a potential therapeutic target after thorough validation in muscle invasive UC.

BGJ398, A Pan-FGFR Inhibitor, Overcomes Paclitaxel Resistance in Urothelial Carcinoma with FGFR1 Overexpression

“…UC with FGFR1 activation and EMT features would have resistance to anti-cancer treatment, which can result in poor survival outcome compared to UC patients without FGFR1 overexpression. In accordance with our TCGA data analysis, Lim et al suggested that about 45% of UC patients with FGFR1 overexpression by immunohistochemistry had shorter OS with hazard ratio of 2.23 (95% confidence interval: 1.27–3.90, p = 0.006) [ 49 ].…”

Comprehensive Molecular Characterization of Muscle-Invasive Bladder Cancer

“…We inferred the relative activity of 23 candidate ‘regulator’ genes that had previously been reported as associated with bladder cancer: the steroid hormone receptors ESR1/2, AR and PGR ; the nuclear receptors PPARG , three RARs (A/B/G) , and three RXRs (A/B/G); the receptor tyrosine kinases ERBB2/3 and FGFR1/3 ; and the transcription factors FOXA1, FOXM1 , GATA3/6, HIF1A, KLF4 and STAT3 and TP63 (Breyer et al, 2016; Choi et al, 2014a; Dadhania et al, 2016; DeGraff et al, 2013; Eriksson et al, 2015; Godoy et al, 2016; Jones et al, 2016; Kardos et al, 2016; Lim et al, 2016). By ‘regulator’ we mean a gene whose product induces and/or represses a target gene set, which we call a ‘regulon’ (Castro et al, 2016a).…”

FGFR inhibitor BGJ398 and HDAC inhibitor OBP-801 synergistically inhibit cell growth and induce apoptosis in bladder cancer cells

“…FGFR1 is not mutated in bladder cancer, but overexpression is frequent in bladder cancer cell lines regardless of tumor grade and stage (5). In addition, it has been reported that FGFR1 expression is an adverse prognostic risk factor in muscle invasive bladder cancer after radical cystectomy (9). Recently, a number of clinical trials of BGJ398, a selective pan FGFR inhibitor, have progressed in patients with various types of cancers.…”