Molecular Diagnostic Factors and Prognostic Implications of Over 300 Patients with Pediatric Pilocytic Astrocytoma

Introduction: Previous studies suggest genomic analysis may inform treatment decisions and predict long-term outcomes in pediatric pilocytic astrocytomas. We explore the impact of BRAF alterations on clinical course of pediatric PA in the largest cohort reported to date.

Methods: Retrospective review of patients with PA from 2000-2022 who were < 18 at diagnosis was conducted. BRAF-KIAA1549 (B-K) fusion and BRAF-V600E mutations were detected through immunohistochemistry, chromosomal microarray, and next-generation sequencing. Cox proportional hazards was used to calculate the hazard ratio (HR) of disease progression.

Results: We analyzed clinical characteristics of 306 patients (52.0% female, mean age at diagnosis 11.2 years). Tumor locations included posterior fossa (59.5%), suprasellar region (20.3%), and brainstem (7.5%). GTR was achieved in 60.1% of patients. Among 94 patients screened for BRAF alterations, B-K fusion was detected in 44/77(57.1%) while BRAF V600E was present in 9/67 (13.4%). B-K fusion was associated with posterior fossa location (P < 0.05). Recurrence or progression occurred in 67 (22%) patients. Recurrence or progression rates were lower in patients in whom GTR was achieved (P < 0.001). On Kaplan-Meier analysis, mean progression-free survival time was significantly worse for V600E (27.2 months) and B-K Fusion patients (18.4 months) as compared to wildtype (64.4 months) (P=0.0057). The HR for patients with V600E mutation versus wild-type was 4.80 (95% confidence interval (CI):1.03-22.33). HR for fusion versus wild-type was 3.48 (95% CI:1.56-7.76).

Conclusion : Our series represents the largest cohort of pediatric PA, demonstrating that progression-free survival is significantly shorter in patients with B-K fusion and V600E. Posterior fossa tumors were more likely to harbor B-K fusions. Extent of resection plays a well-established role in moderating risk of recurrence, and achieving GTR predicts better disease course regardless of tumor genomics. A deeper understanding of long-term outcomes of patients with BRAF alterations is critical for exploring effective initial, adjuvant, and targeted therapies.