FGFR3 mRNA overexpression defines a subset of oligometastatic colorectal cancers with worse prognosis

// Julia Elisabeth Fromme 1, * , Katja Schmitz 1, * , Astrid Wachter 2 , Marius Grzelinski 3 , Dirk Zielinski 3 , Christina Koppel 3 , Lena-Christin Conradi 4 , Kia Homayounfar 4 , Tabea Hugo 1 , Sara Hugo 1 , Laura Lukat 1 , Josef Rüschoff 3 , Philipp Ströbel 1 , Michael Ghadimi 4 , Tim Beißbarth 2 , Kirsten Reuter-Jessen 1, ** , Annalen Bleckmann 2, 5, ** and Hans-Ulrich Schildhaus 1, 3, ** 1 Institute of Pathology, University Hospital Göttingen, Göttingen, Germany 2 Department of Medical Statistics, University Medical Center Göttingen, Göttingen, Germany 3 Targos Molecular Pathology Inc., Kassel, Germany 4 Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Georg-August-University, Goettingen, Germany 5 Department for Hematology and Medical Oncology, University Hospital Göttingen, Göttingen, Germany * These authors have contributed equally to this work ** KRJ, AB, HUS share senior authorship Correspondence to: Hans-Ulrich Schildhaus, email: Hans-Ulrich.Schildhaus@med.uni-goettingen.de Keywords: colorectal cancer; metastases; FGFR3; fibroblast growth factor receptors; RNA in situ hybridization Received: March 26, 2018      Accepted: July 12, 2018      Published: August 14, 2018 ABSTRACT Objectives: Metastatic colorectal cancer (CRC) remains a leading cause of cancer related deaths. Patients with oligometastatic liver disease represent a clinical subgroup with heterogeneous course. Until now, biomarkers to characterize outcome and therapeutic options have not been fully established. Methods: We investigated the prevalence of FGFR alterations in a total of 140 primary colorectal tumors and 63 liver metastases of 55 oligometastatic CRC patients. FGF receptors ( FGFR1-4 ) and their ligands ( FGF3, 4 and 19 ) were analyzed for gene amplifications and rearrangements as well as for RNA overexpression in situ . Results were correlated with clinico-pathologic data and molecular subtypes. Results: Primary tumors showed FGFR1 (6.3%) and FGF3,4,19 (2.2%) amplifications as well as FGFR1 (10.1%), FGFR2 (5.5%) and FGFR3 (16.2%) overexpression. In metastases, we observed FGFR1 amplifications (4.8%) as well as FGFR1 (8.5%) and FGFR3 (14.9%) overexpression. Neither FGFR2-4 amplifications nor gene rearrangements were observed. FGFR3 overexpression was significantly associated with shorter overall survival in metastases (mOS 19.9 vs. 47.4 months, HR=3.14, p=0.0152), but not in primary CRC (HR=1.01, p=0.985). Although rare, also FGFR1 amplification was indicative of worse outcome (mOS 12.6 vs. 47.4 months, HR=8.83, p=0.00111). Conclusions: We provide the so far most comprehensive analysis of FGFR alterations in primary and metastatic CRC. We describe FGFR3 overexpression in 15% of CRC patients with oligometastatic liver disease as a prognosticator for poor outcome. Recently FGFR3 overexpression has been shown to be a potential therapeutic target. Therefore, we suggest focusing on this subgroup in upcoming clinical trials with FGFR-targeted therapies.