Journal Article

Complexity of FGFR signalling in metastatic urothelial cancer

Rudman, Sarah, Kilgour, Elaine, Dougherty, Brian, Lawrence, Peter, Saggese, Matilde, Rodriguez-Vida, Alejo, Smith, Neil R., Hughes, Simon, Landers, Donal, Arkenau, Hendrik-Tobias, Chowdhury, Simon, Rooney, Claire

2015

Overview

Background Urothelial cancers (UC) are the fourth most common tumours worldwide after prostate (or breast), lung and colorectal cancer. Despite recent improvements in their management, UC remain an aggressive disease associated with a poor outcome. Following disease progression on first-line platinum-based chemotherapy, very few effective treatment options are available and none of them have shown significant improvement in overall survival. Alterations of the fibroblast growth factor receptor (FGFR) pathway including amplification, mutations and overexpression are common in UC. Pre-clinical data suggest that the presence of such dysregulations may confer sensitivity to FGFR inhibitors. Materials and methods We present here the case of a patient with a metastatic UC of the renal pelvis with lymph node metastases treated with the selective FGFR inhibitor AZD4547. Results To date, the patient has been on a study drug for 32 months with acceptable tolerance and maintained radiological partial response as per RECIST 1.1 criteria. Exploratory biomarker analysis showed FGFR3, FGFR1, FGF-ligand and fibroblast growth factor receptor substrate 2 (FRS2) expression in the patient’s tumour, together with the presence of a germ-line mutation in the FGFR3 extracellular binding domain. This is not a known hotspot mutation, and the functional significance remains unclear. Conclusions The FGFR inhibitor AZD4547 exhibits antitumour activity in a metastatic urothelial cancer displaying FGFR1, FGFR3, FGF-ligand and FRS2 expression. This lends support to the further exploration of FGFR inhibitors in urothelial cancer. Further studies are required to determinate the most effective way to select those patients most likely to respond.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Analysis / Antineoplastic Agents - therapeutic use / Benzamides - therapeutic use / Bladder / Cancer / Cancer Research / Care and treatment / Case Report / Chemotherapy / Colorectal cancer / Complications and side effects / Development and progression / Diagnosis / Drug dosages / ErbB Receptors - genetics / ErbB Receptors - metabolism / Fibroblast growth factors / Fibroblasts / Gene amplification / Gene Expression Regulation, Neoplastic - drug effects / Genetic aspects / Growth factors / Health aspects / Hematology / Humans / Immunohistochemistry / Immunotherapy / In Situ Hybridization, Fluorescence / Kidney Pelvis - metabolism / Kidney Pelvis - pathology / Kinases / Ligands / Lymphatic system / Male / Medical imaging / Medical research / Medicine / Medicine & Public Health / Medicine, Experimental / Metastasis / Middle Aged / Mutation / Neoplasm Metastasis / Oncology / Patients / Piperazines - therapeutic use / Pyrazoles - therapeutic use / Receptor, Fibroblast Growth Factor, Type 1 - genetics / Receptor, Fibroblast Growth Factor, Type 1 - metabolism / Receptor, Fibroblast Growth Factor, Type 3 - genetics / Receptor, Fibroblast Growth Factor, Type 3 - metabolism / Signal Transduction - drug effects / Signal Transduction - genetics / Tumors / Ureteral Neoplasms - drug therapy / Ureteral Neoplasms - genetics / Ureteral Neoplasms - metabolism / Urinary Bladder Neoplasms - drug therapy / Urinary Bladder Neoplasms - genetics / Urinary Bladder Neoplasms - metabolism