LGG-12. INTEGRATED CLINICAL AND MOLECULAR CHARACTERIZATION OF 200 DISSEMINATED PEDIATRIC LOW-GRADE GLIOMAS

Pediatric low-grade gliomas (PLGG) have excellent outcomes overall but are a major clinical challenge when disseminated. Diffuse leptomeningeal glioneuronal tumor (DLGNT) is a recognised entity both clinically and pathologically, however many disseminated LGG (DLGG) fall outside this diagnosis. To better understand the clinical and molecular features of DLGG as well as risk factors for dissemination, we assembled an international consortium of 30 sites, contributing over 200 patients with clinical annotation, along with genomic and methylation profiling. DLGG have worse progression-free (PFS) and overall survival (OS) than PLGG overall (p<0.0001). Seventy (35%) presented with a localized mass and secondary dissemination, including some with initial gross-total resection. The most common growth pattern observed (n=77, 40%) is a dominant suprasellar/optic pathway tumor with leptomeningeal drop-metastases involving the brainstem and spinal cord. Only 27 (14%) patients had diffuse tumors (without an identifiable dominant mass), and these had significantly worse OS (p=0.03). The most common pathologic diagnosis was pilocytic/pilomyxoid astrocytoma (n=92; 53%). DLGNT comprised a minority of cases (n=23, 14%), with a trend (p=0.056) towards worse survival compared to other diagnoses. The most frequent molecular alteration was BRAF fusion (78/151 with molecular testing; 52%), followed by FGFR mutations or fusions (18/151; 12%). BRAF V600E was underrepresented (14/151; 9%). 1p deletion was rare (17 patients) but highly associated with DLGNT. Methylation classification (n=70) was highly concordant with histologic diagnoses rather than clinical behavior. Importantly, patients who received upfront targeted therapies (TT; BRAF and/or MEK inhibition, n=9) had better PFS compared to those receiving chemotherapy (n=146, p=0.05). Furthermore, patients who were treated sequentially with chemo then TT had longer PFS on TT (p=0.011). This study presents the largest cohort of DLGG to date, expanding our understanding of the clinical, pathologic, and molecular features of this disease and supports the use of upfront targeted therapy.