Activating FGFR3 mutations occur in about 15% MIBC and 70% non-MIBC (NMIBC), raising the potential for FGFR inhibitors as a therapy option. Clinical trials of anti-programmed cell death protein 1 (PD1) and anti-PD1 ligand (PD-L1) agents have shown benefit in advanced bladder cancer patients and provided evidence for PD-L1 as a predictive marker. We have assessed the association of FGFR3 mutations with FGFR3 expression, PD-L1 and T-cell infiltrates in MIBC samples.
FGFR3, PD-L1 and CD8 (cytotoxic T-cell marker) expression were assessed by immunohistochemistry (IHC) and FGFR3 mutations by SNaPshot analysis in a cohort of 60 MIBC. FGFR3/FGFR1 expression were also assessed in a cohort of 40 MIBC, 30 NMIBC and 18 normal urothelium (NU) tissues.
FGFR3 expression (H-score >20) was observed in 20% (8/40) of MIBC compared to 60% (23/39) of NMIBC while 94% (17/18) NU were negative. In contrast, FGFR1 expression was low and did not differ between MIBC, NMIBC and NU. FGFR3 mutations were detected in 16% MIBC (10/60) and an association was observed with FGFR3 expression (p 25% cells positive) was 12% (7/59) and immune cell (IC) positivity was 32% (19/59) and FGFR3 mutant samples all displayed low TC PD-L1 (≤5% cells expressing PD-L1) and low CD8 ( 5% cells PDL1 positive) and CD8 from 5-1453 cells/mm2 (23% with > 250 cells/mm2 positive). Consistent with these observations, analysis of the Cancer Genome Atlas MIBC data-set showed FGFR3 mutant/fusion bladder cancers cluster into a low immune subtype.
FGFR3 mutation is associated with increased FGFR3 expression and low PD-L1 and cytotoxic T-cell infiltrates, suggesting these tumours may respond differently to anti-PD1/PD-L1 therapy and supporting investigation of FGFR3 inhibitors as a therapeutic option. Clinical studies with FGFR inhibitors in bladder cancer are ongoing, including assessment of AZD4547 in monotherapy and combination with the anti-PD-L1 agent durvalumab (NCT02546661).
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Legal entity responsible for the study
E. Kilgour, H. Angell, N.R. Smith, M. Ahdesmaki, J.C. Barrett, E.A. Harrington: Employee of AstraZeneca and holds stock in AstraZeneca. All other authors have declared no conflicts of interest.