FGFR3 gene mutation: Favourable prognostic impact in bladder cancer

The fibroblast growth factor receptor (FGFR) pathway is very important in bladder cancer. Dr Laura Mertens (VU Amsterdam Medical Center, the Netherlands) shared her data analysing activating FGFR3 mutations vs FGFR3 protein overexpression in bladder tumours and their relation to clinic-pathological parameters and prognosis in a multicentre, multi-laboratory setting. She concluded that FGFR3 mutation has favourable prognostic impact regardless of FGFR3 protein expression level.

FGFR3 activating mutations are known to be associated with favourable prognosis in bladder cancer [1], yet little is known about whether immunohistochemical detection of overexpression of FGFR3 is a relevant prognostic tool. Because the FGFR3 receptor is an actionable target and there are drugs in the pipeline, Dr Mertens took 1,000 cN0M0 (chemo-naïve) bladder cancer patients who underwent radical cystectomy (in 9 hospitals) and concomitantly screened them for FGFR3 mutation as well as overexpression. Specimen review by uro-pathologists confirmed that 89% of patients had a tumour ≥pT2.

An FGFR3 activating mutation (the most common mutation is p.S249C) was found in 11% of the samples; and of those tumours, 73% demonstrated FGFR3 overexpression as stained by immunohistochemistry. In the FGFR3 wildtype subset of tumours, 22% had overexpression of FGFR3. Notably, p53 overexpression was 69% throughout the cohort (cut-off is 10%), but the relevance of this finding is not yet clear.

Conclusions of this study were: (1) FGFR3 mutation has favourable prognostic impact regardless of FGFR3 protein expression level; (2) FGFR3 overexpression has no prognostic impact in tumours with wildtype FGFR3 sequence; and (3) gene sequence of FGFR3 should be used in the selection for targeted therapy with anti-FGFR3 agents in the future. Developments in this field should be watched carefully because FGFR3 mutation itself seems to be the key driver, not just amplification of the protein levels.

1. van Rhijn et al. J Clin Oncol. 2003 May 15;21(10):1912-21.

Posted on 21 May, 201927 March, 2024