Abstract
FGFR alterations including single nucleotide variants (SNV) and rearrangements represent common oncogenic alterations found in pediatric low-grade gliomas. From a population-based cohort of over 1800 pediatric and AYA (adolescent and young adult) gliomas, FGFR mutations were found in 6% of pediatric low-grade gliomas (LGG) and 16 % of IDH-WT AYA gliomas. Given the frequency of FGFR driver alterations, we assembled a large cohort of 370 FGFR mutated glioma across all ages (6 months to 87 years) 53% of which were LGG. In the pediatric patients, most (87%) of FGFR altered gliomas were low-grade; while in AYA patients only 67%. Fusions were more frequent in pediatric LGG (60%), while SNVs were more common in AYA LGG (57%). The rearranged genes also differed; pediatric LGG: 26% FGFR1 ITD, 20% FGFR1 fusions, 15% FGFR2 fusions. AYA LGG had equal frequency of FGFR1 and FGFR2 fusions (30%). In adults, high grade gliomas were more common (73%), and frequently had additional oncogenic drivers. In general, additional oncogenic drivers were more common with increasing age and grade. In contrast to pediatric and AYA LGG, FGFR3-TACC3 fusions represented 40% of adult cases. Interestingly, this fusion was also found in 10% of FGFR LGGs overall. Although analysis of clinical outcomes are still ongoing, in our preliminary data 18 patients with FGFR altered low grade gliomas were treated with targeted agents; 3 stopped due to toxicity and were not evaluated for response. From patients on MAPKi 1/6 had a minor response and 3/6 stable disease; while 6/9 on FGFRi had partial or minor responses with additional 3 patients recently initiated on the drug. FGFR alterations are frequently encountered in AYA and pediatric population, molecular characterization is important in guiding prognosis and therapy. Although encouraging, further studies are needed to assess the benefit of FGFR inhibition in these patients.