FGFR Alterations in Cancer: Fusions, Mutations and Amplifications

The Receptor Family

FGFR1 to FGFR4 bind fibroblast growth factors, dimerise and activate RAS-MAPK, PI3K-AKT and other pathways. Alternative splicing of the ligand-binding domain (IIIb and IIIc isoforms) tunes which ligands each receptor responds to.

The receptors have roles in development, wound healing and phosphate metabolism, which is relevant to the side effects of blocking them.

The Most Actionable Alterations

FGFR2 fusions and rearrangements are recurrent in intrahepatic cholangiocarcinoma (around 10 to 15 percent) and respond well to FGFR inhibitors. Alterations that truncate the C-terminus of FGFR2, whether by fusion or by nonsense or frameshift mutation, appear to be a unifying actionable feature.

FGFR3 activating mutations and FGFR3-TACC3 fusions are common in urothelial (bladder) cancer, where the FGFR inhibitor erdafitinib is approved for susceptible alterations.

Amplifications Are Less Predictive

FGFR1 amplification occurs in squamous lung cancer and a subset of breast cancer, and FGFR2 amplification in gastric cancer. However, response to FGFR inhibitors in amplified tumours has been inconsistent, likely because amplification does not always mean the receptor is the dominant driver.

The copy number level and whether the receptor protein is actually overexpressed both influence the likelihood of benefit.

Inhibitors and Their Effects

Approved FGFR inhibitors include pemigatinib and futibatinib for FGFR2-fusion cholangiocarcinoma and erdafitinib for FGFR-altered urothelial cancer. Class effects include hyperphosphataemia (from blocking FGF23 signalling), nail and skin changes, and retinal effects.

Acquired resistance commonly arises through secondary FGFR kinase-domain mutations, notably gatekeeper mutations, prompting development of next-generation and covalent inhibitors.

Interpretation Notes

An FGFR report should state the gene, the alteration type (fusion, mutation, amplification) and, for mutations, the exact change, since only specific alterations are considered susceptible.

Fusions are best confirmed by RNA-based sequencing, and a defined list of qualifying alterations applies for the approved drugs.

Key Takeaways

• ·FGFR2 fusions (cholangiocarcinoma) and FGFR3 alterations (bladder) are the most actionable.
• ·C-terminal truncation of FGFR2 appears to be a unifying targetable feature.
• ·FGFR1/2 amplifications are inconsistent predictors of inhibitor benefit.
• ·Hyperphosphataemia is a class effect; gatekeeper mutations drive acquired resistance.