Fibroblast Growth Factor Receptors and Ligands in Context of Bevacizumab Response in Ovarian Carcinoma: An Exploratory Analysis of AGO-OVAR 11/ICON-7

With more novel drugs being approved for the treatment of ovarian carcinoma (OC), the question remains to what extent patients benefit from anti-angiogenic treatment with bevacizumab, either in combination with poly (ADP-ribose) polymerase (PAPR) inhibitors or as single-agent maintenance. As fibroblast growth factor receptors and their ligands (FGFRs/FGFs) are key players in angiogenic signaling and have been linked to resistance to several drugs, we investigated the prognostic or predictive potential of FGFs/FGFRs signaling in the context of bevacizumab treatment within the prospective phase III AGO-OVAR 11/ICON-7 study. FGFR1, FGFR2, FGFR3, FGFR4, FGF1, and FGF19 gene expression was determined in 380 OC tumor samples collected from German centers in the multicenter phase III AGO-OVAR11 trial/ICON-7 trial. All patients received carboplatin and paclitaxel given every three weeks for six cycles and were randomized to bevacizumab. Expression of FGFR1, FGFR2, FGF1, and FGF19 was associated with progression-free survival (PFS) in both uni- and multivariate (FGFR1: HR=1.6, p<0.001; FGFR2: HR=1.6, p=0.002; FGF1: HR=2.3, p<0.001; FGF19: HR=0.7; p=0.007) analysis. A signature built by FGFR1, FGFR4, and FGF19 defined a subgroup (n=62) of patients that derived the greatest bevacizumab-associated improvement of PFS (HR=0.3, p=0.004). In this exploratory analysis of a prospective randomized phase III trial, we provide evidence that expression of FGFRs/FGFs might have independent prognostic value. An FGFR/FGF-based gene signature identified in our study appears to predict long-term benefit from bevacizumab. This observation is hypothesis-generating and requires validation on independent cohorts.