Abstract
BACKGROUND: Pleomorphic xanthoastrocytoma (PXA) represents a rare glial brain tumor with variable prognosis. The majority of cases in adulthood harbor BRAFV600E mutation and CDKN2A homozygous deletion, while pediatric PXA remained poorly investigated. METHODS: 42 pediatric patients with morphologically verified PXA (28 grade 2 and 14 grade 3) with median age of 9.9 years were investigated. Molecular studied included BRAF codon 600 allele-specific PCR, targeted RNA sequencing, DNA methylation assay. First-line management was conducted as per SIOP-LGG or HIT-HGG protocols depending on tumor grade. Targeted therapy was applied mostly after disease progression and first-line in two cases. Median of follow-up time achieved 4.0 years. RESULTS: Molecular genetic markers included BRAF V600E mutation in 25 cases (59.5%), CDKN2A deletion either homo or heterozygous in 23 (54.8%) and rearrangements of receptor tyrosine-kinase (RTK) genes (CCDC88A::ALK, SFPQ::ALK, NOS1AP::NTRK1, TPM3::NTRK1, NACC2::NTRK2, ETV6::NTRK2, VIM::NTRK3, GOPC::ROS1) in 8 patients (19.0%). Remarkably, four patients with RTK fusions aged >10 years did not matched any known DNA methylation class (DKFZ v.12.8) while others were perfectly consistent with MC PXA (>0.90). CDKN2A deletions were uniformly distributed between BRAF-mutated and RTK-fused cases. Patients with PXA grade 2 were observed after surgery and extent of tumor resection predicted survival (p=0.01). Radiation therapy of PXA grade 3 was not able to control the disease: 2-year progression-free survival (PFS) – 31% (95%CI14-70%). Targeted therapy was used in 15 cases (9 PXA grade 3 and 6 PXA grade 2) with combination of dabrafenib and trametinib in 12 and entrectinib in 3. This resulted in 2-year PFS 100% and 50.0%(95%CI27-93%) for PXA grade 2 and 3, respectively. CONCLUSION: PXA is a molecularly heterogenic tumor with high frequency of actionable genetic alterations. RTK fusions should be investigated in all BRAF-negative cases. Targeted therapy demonstrated promising results.