The FGFR Landscape in Cancer: Analysis of 4,853 Tumors by Next-Generation Sequencing

TLDR

Molecular profiling has prognostic and predictive value and is increasingly used clinically, while many FGFR inhibitors are in development. The study aimed to determine the frequency and types of FGFR aberrations across 4,853 solid tumors to inform therapeutic use of FGFR inhibitors. Next‑generation sequencing of 182 or 236 genes was performed on physician‑requested samples in a CLIA laboratory and analyzed on an N‑of‑One basis. FGFR aberrations were found in 7.1% of cancers, mainly amplifications (66%), with FGFR1, FGFR2, FGFR3, and FGFR4 affected in 3.5%, 1.5%, 2.0%, and 0.5% of patients, respectively, and were observed across most tumor types, suggesting FGFR inhibition could be a therapeutic option.

Abstract

Molecular profiling may have prognostic and predictive value, and is increasingly used in the clinical setting. There are more than a dozen fibroblast growth factor receptor (FGFR) inhibitors in development. Optimal therapeutic application of FGFR inhibitors requires knowledge of the rates and types of FGFR aberrations in a variety of cancer types.We analyzed frequencies of FGFR aberrations in 4,853 solid tumors that were, on physician request, tested in a Clinical Laboratory Improvement Amendments (CLIA) laboratory (Foundation Medicine) using next-generation sequencing (182 or 236 genes), and analyzed by N-of-One.FGFR aberrations were found in 7.1% of cancers, with the majority being gene amplification (66% of the aberrations), followed by mutations (26%) and rearrangements (8%). FGFR1 (mostly amplification) was affected in 3.5% of 4,853 patients; FGFR2 in 1.5%; FGFR3 in 2.0%; and FGFR4 in 0.5%. Almost every type of malignancy examined showed some patients with FGFR aberrations, but the cancers most commonly affected were urothelial (32% FGFR-aberrant); breast (18%); endometrial (∼13%), squamous lung cancers (∼13%), and ovarian cancer (∼9%). Among 35 unique FGFR mutations seen in this dataset, all but two are found in COSMIC. Seventeen of the 35 are known to be activating, and 11 are transforming.FGFR aberrations are common in a wide variety of cancers, with the majority being gene amplifications or activating mutations. These data suggest that FGFR inhibition could be an important therapeutic option across multiple tumor types.