ID #284 The impact of driver alterations on the long-term outcomes of paediatric low-grade gliomas treated with upfront chemotherapy

Abstract Background In the era of molecular characterization and targeted therapies for paediatric low-grade gliomas (pLGG), it is essential to understand the role of driver alterations in determining responses and long-term outcomes for upfront chemotherapy. Methods We performed a population-based study of pLGG treated with upfront chemotherapy. Chemotherapy responses (RAPNO) were assessed by expert neuroradiologists. Results We analyzed 247 BRAF fused, 139 BRAF V600E, and 188 NF1 pLGG (median follow-up 8.2 years). Incompletely resected BRAF-altered pLGG could be stratified into 3 groups based on location and need for chemotherapy/radiation: hemispheric/cerebellar (25% BRAF fused and 10% BRAF V600E treated by 5 years), midline (59% 0.002). All disseminated pLGG required treatment. The objective response rates (25% reduction) to chemotherapy were 39% (22/56) for BRAF fused, 20% (3/15) for V600E, and 32% (12/38) for NF1. Interestingly, BRAF fused responders had superior clinician-determined progression-free survival (PFS) relative to initially stable tumours (p = 0.0041). Dismal long-term control was observed for BRAF fused (n = 73) and V600E (n = 22) pLGG with 15-year PFS of 16% and 22% (p = 0.5953), contrasting 49% for NF1 (n = 51) (p 0.0001). Strikingly, all V600E pLGG in patients 7 y.o. progressed within 3 years (p = 0.0063). V600E optic pathway gliomas also fared poorly with 4-year PFS of 8%, versus 34% for BRAF fused (p = 0.0721) versus 73% for NF1 (p 0.0001). Despite superior PFS for NF1 optic pathway glioma patients, 49% had profound or worse visual impairment at last follow-up, versus 23% for BRAF fused (p = 0.0441). Imaging review revealed further 25% shrinkage beyond the chemotherapy period in 16% of BRAF fused and 27% of NF1 tumours, with 91% showing best response at 5 years. Conclusion This study provides important driver alteration-specific information on long-term pLGG tumour control and patient outcomes. Insights from these observations can inform trial design and comparison with targeted therapies.