Fibroblast growth factor receptor 3 (FGFR3) mutant muscle invasive bladder cancers (MIBC) are associated with low immune infiltrates


Year:

Session type:

Elaine Kilgour1,Elaine Kilgour1,Helen K. Angell2,Neil R. Smith3,Miika J. Ahdesmaki2,J. Carl Barrett4,Elizabeth A. Harrington2,Carolyn Hurst5,Margaret Knowles5
1AstraZeneca,2AstraZeneca, Cambridge UK,3AstraZeneca, Macclesfield UK,4AstraZeneca, Boston USA,5Institute of Cancer Studies, Leeds UK

Abstract

Background

FGFR3 mutations occur in  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)/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.

Method

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. 

Results

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 associatedwith FGFR3 expression (p<0.05). In MIBC the prevalence of tumour cell (TC) PD-L1 positivity (>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 (<250 cells/mm2) expression.  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.

Conclusion

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).