Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Abstract

PURPOSE Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations ( FGFR1-4) in pediatric cancers to inform future clinical trial design. METHODS 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. RESULTS We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions ( FGFR3:: TACC3 [n = 3], FGFR1:: TACC1 [n = 1], FGFR1:: EBF2 [n = 1], FGFR1:: CLIP2 [n = 1], and FGFR2:: CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. CONCLUSION In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.

FGFR1 fusions as a novel molecular driver in rhabdomyosarcoma

“…28 In contrast, FGFR1-related fusions are rare in sarcomas and have mostly been described in central nervous system malignancies. [33][34][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. Moreover, clinical activity of an FGFR inhibitor has been reported in a pLGG patient with this fusion.…”

“…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 In RMS, FGFR alterations have been reported in 7-13% of cases, 3,4,47,48 mostly activating point mutations or/and amplifications and involving FGFR4. 3 FGFR1 overexpression in RMS was also described possibly related to hypomethylation of a CpG island upstream to FGFR1 exon 1 49 or to increased copy number.…”

“…15,52 In the sarcoma field, a single case of a FGFR1 fusionpositive unclassified infantile spindle cell tumor also showed an objective response to erdafitinib. 35 In RMS, the most common FGFR alteration occurs in FGFR4 gene, which is altered in 10% of cases, either by amplifications or mutations,…”

FGFR1 tyrosine kinase domain duplication in infantile soft tissue spindle cell tumor

“…[1][2][3] A recent intensive study of pediatric solid tumors revealed FGFR1 alterations in a small proportion of non-CNS tumors. 12 Among eight sarcoma cases with the FGFR1 alteration, seven cases revealed FGFR1 amplification, while one case revealed FGFR1 structural variant. 12 Thus, to the best of our knowledge, our patient is the first reported case of FGFR1 TKDD-positive soft tissue tumor.…”

“…12 Among eight sarcoma cases with the FGFR1 alteration, seven cases revealed FGFR1 amplification, while one case revealed FGFR1 structural variant. 12 Thus, to the best of our knowledge, our patient is the first reported case of FGFR1 TKDD-positive soft tissue tumor. There was no clinicopathological similarity between the present soft tissue tumor and FGFR1 TKDD-positive LGGs or DNTs, except that these tumors are not high-grade malignancies.…”