FGFR2c Mesenchymal Isoform Expression Is Associated with Poor Prognosis and Further Refines Risk Stratification within Endometrial Cancer Molecular Subtypes

Abstract

Purpose: The two most common molecular subtypes of endometrial cancers (EC), mismatch repair deficient (MMRd) and p53 wildtype (p53wt) comprise the majority of ECs and have intermediate prognoses where additional risk stratification biomarkers are needed. Isoform switching of fibroblast growth factor receptor 2 (FGFR2) from FGFR2b to FGFR2c (normally expressed in mesenchymal cells), has been reported in other solid carcinomas. The objective of this study was to investigate the role of FGFR2c in risk stratification of EC. Experimental Design: We have developed and optimized a BaseScope^TM RNA ISH assay to detect FGFR2c. FGFR2c expression was determined in a preliminary screening cohort of 78 ECs and a clinically and molecularly annotated Vancouver cohort (n=465). Cox regression model analyses were performed to assess the prognostic value of FGFR2c. Results: Univariable and multivariable analyses revealed FGFR2c expression was significantly associated with shorter disease-specific survival (DSS) and progression-free survival (PFS) in endometrioid EC (n=302). Notably, FGFR2c expression was significantly associated with shorter PFS and DSS in patients with grade 3 endometrioid ECs (p <0.003 and p <0.002) and the ESMO high-risk group (p <0.0001 and p <002) respectively. Moreover, within the MMRd subtype, FGFR2c expression was significantly associated with shorter PFS (P <0.048) and DSS (P <0.001). Conclusions: FGFR2c expression appears an independent prognostic biomarker in endometroid EC patients and further discerns the outcomes within grade 3 tumours, ESMO high-risk groups, as well as within the MMRd and p53wt subtypes. FGFR2c inclusion into future molecular subtyping can further refine risk stratification of endometrioid EC.