Fibroblast Growth Factor Receptor 3 (FGFR3) is a potentially actionable target in bladder cancer (BC). FGFR3 mutations are associated with favorable prognosis in non-muscle invasive (NMI) BC and MIBC. Over-expression of FGFR3 was reported in up to 40% of FGFR3 wild-type MIBC. p53 alterations rarely coincide with FGFR3 mutations. We analyzed FGFR3 mutations, protein-expression of FGFR3 and p53 and assessed their prognostic value in a multi-center, multi-laboratory setting.
We included 1000 cN0M0, chemotherapy-naive patients who underwent radical cystectomy (RC) with pelvic node dissection. Specimens were reviewed by eight uro-pathologists. At seven laboratories, FGFR3 mutation status was examined using PCR-SNaPshot. p53 and FGFR3 expression were determined by immunohistochemistry (IHC). FGFR3 mutation status, p53 and FGFR3 protein expressions were correlated to each-other, clinico-pathological parameters and disease-specific survival (DSS).
FGFR3 mutations were found in 107/1000 RCs (11%), of which 67 were S249C. Over-expression of FGFR3 was found in 279/1000 (28%) of tumors. p53 overexpression (cut-off>10%) was found in 638/926 (69%) of available cases. Among FGFR3 mutant tumors, 73% had FGFR3 over-expression. Among FGFR3 wild-type tumors, 22% had FGFR3 over-expression. FGFR3 mutations were associated with lower pT-stage (P<0.001), lower grade (G2-WHO 1973) (P<0.001), absence of CIS (P=0.009), pN0 (P<0.001), normal p53 (P<0.001) and prolonged DSS (Plog-rank=0.001). FGFR3 over-expression was associated with lower pT-stage (P<0.001) and G2 (P<0.001) but not with absence of CIS (P=0.860), pN0 (P=0.230), normal p53 (P=0.330) nor prolonged DSS (Plog-rank=0.204). We found no significant difference in DSS for patients with FGFR3 mutant tumors comparing normal vs over-expression of FGFR3 (Plog-rank=0.444). Furthermore, we also found no significant difference in DSS for patients with FGFR3 wild-type tumors comparing normal vs over-expression of FGFR3 (Plog-rank=0.754).
FGFR3 mutations identified patients with favorable BC with fewer p53 alterations at RC. FGFR3 over-expression was not associated with DSS in patients with FGFR3 wild-type tumors. Our results suggest that FGFR3 mutations (driver effect) have a distinct functional role than FGFR3 over-expression (passenger effect). Hence, patients with FGFR3 mutations may be more likely to benefit from anti-FGFR3 therapy than patients with only over-expression of FGFR3.