BIOM-59. PEDIATRIC PLEOMORPHIC XANTHOASTROCYTOMA: INSIGHTS IN BIOLOGY AND TARGETED THERAPY

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.