Abstract 3893: Rare FGFR oncogenic alterations in sequenced pediatric solid and brain tumors suggest FGFR is a relevant molecular target in childhood cancer

Abstract

Oncogenic FGFR alterations in the form of activating mutations, amplifications, and fusions are detected in a variety of solid tumors, including those in children. Major advances in FGFR-targeted drug development have led to investigation of multiple generations of FGFR inhibitors in adult clinical trials. In contrast, there are few clinical trials of FGFR inhibitors enrolling children. There is a need to identify and characterize molecular targets including oncogenic FGFR alterations in pediatric cancers so that drug development can occur in accordance with the RACE (Research to Accelerate Cures and Equity) for Children Act. The goal of this study was to determine the frequency and types of FGFR alterations in pediatric cancers to inform future clinical trial design. Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children’s Profile Study (n=888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n=571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed. We identified 42 patients with tumors harboring an oncogenic or possibly oncogenic FGFR alteration (FGFR1 in 22; FGFR2 in 4; FGFR3 in 5; FGR4 in 11). Median age at diagnosis was 8 years (range 6 months-26 years old). Diagnoses included 11 rhabdomyosarcomas, 8 low-grade gliomas, 3 high-grade gliomas, and 16 other tumor types. We identified 20 patients with a gain-of-function (GoF) mutation, 10 patients with amplifications (copy number ≥7), 7 patients with fusions, 4 patients with a variant of uncertain significance (VUS) assessed and determined to be possibly oncogenic, and 1 patient with an amplification and VUS. Four of the fusion cases had oncogenic FGFR3-TACC3 (n=3) and FGFR1-TACC1 (n=1) fusions previously reported in the literature. Three cases had novel fusions (FGFR1-EBF2, FGFR1-CLIP2, FGFR2-CTNNA3) found in a spindle cell sarcoma and two low-grade gliomas. Tumors with an FGFR missense mutation were primarily those with oncogenic hotspot mutations in FGFR1 [N546K (n= 5); K656E (n=4)] and FGFR4 [N535K/D (n=2); V550L/E (n=5)]. In summary, this study identified oncogenic FGFR alterations in 42 of 1395 patients (3%) with solid and brain tumors sequenced through the Profile and GAIN/iCAT2 studies who would potentially be eligible for clinical trials evaluating FGFR-targeted therapy. Citation Format: Lorena Lazo De La Vega, Alanna J. Church, Hannah Comeau, Wenjun Kang, AeRang Kim, Navin R. Pinto, Margaret E. Macy, Luke D. Maese, Steven G. DuBois, Bruce E. Johnson, Katherine A. Janeway, Suzanne J. Forrest. Rare FGFR oncogenic alterations in sequenced pediatric solid and brain tumors suggest FGFR is a relevant molecular target in childhood cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3893.

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma

“…The FGFR alterations found in these tumor types are exclusively copy number amplifications or activating single nucleotide variations 28 . In contrast, FGFR1 ‐related fusions are rare in sarcomas and have mostly been described in central nervous system malignancies 33–35 . Thus, FGFR1::TACC1 fusion identified in case #2 has been a recurrent event in pediatric low‐grade gliomas (pLGG), occurring in 2%–3% of cases, 36 further supporting its oncogenic nature.…”

“…In contrast, a handful of FGFR fusions have been described in gastrointestinal stromal tumors (GIST) lacking activating KIT / PDGFRA mutations 44–46 and in one KIT exon 11 mutant GIST which acquired an FGFR2::TACC2 fusion in the setting of multi‐drug resistance 27 . In addition, an FGFR1::EBF2 fusion was reported in an CD34‐positive infantile spindle cell sarcoma, NOS, which responded to erdafitinib (a pan‐FGFR inhibitor) 35 …”

“…Recent phase II clinical trials for patients with urothelial carcinoma and cholangiocarcinoma harboring FGFR1 / 2 amplification have shown a clinical benefit using FGFR inhibitors, in particular, with erdafitinib 15,52 . In the sarcoma field, a single case of a FGFR1 fusion‐positive unclassified infantile spindle cell tumor also showed an objective response to erdafitinib 35 …”