Genomically Adjusted Radiation Dose Predicts Outcomes in Pediatric Brain Tumors and Supports Biologically Personalized Radiotherapy

Background: Radiotherapy is a cornerstone of treatment for pediatric central nervous system (CNS) tumors, but dose selection remains largely uniform despite substantial interpatient variability in tumor radiosensitivity. This limitation is particularly consequential in children, in whom radiation-associated toxicity has lifelong impact. The genomic-adjusted radiation dose (GARD), which integrates tumor genomics with delivered radiation dose, quantifies the biological effect of radiotherapy and has been validated across multiple adult malignancies. Its relevance in pediatric CNS tumors remains unknown. Methods: We performed a retrospective cohort study using gene expression and clinical data from 246 pediatric patients with high-grade glioma, medulloblastoma, or ependymoma from the Childrens Brain Tumor Network. GARD was calculated using a sequencing-adapted radiosensitivity index integrated with radiation dose via the linear-quadratic model. Associations between GARD, physical radiation dose, and clinical outcomes (event-free survival and overall survival) were evaluated using Cox proportional hazards models stratified by tumor type and anatomic location. Patients who did not receive radiotherapy were analyzed as a negative control cohort (sham-GARD). Results: Among patients receiving radiotherapy, physical radiation dose was relatively uniform, yet GARD demonstrated substantial interpatient variability in predicted biological effect. Higher GARD was significantly associated with improved event-free survival (hazard ratio [HR] 0.90, 95% CI 0.83-0.97; p=0.004) and overall survival (HR 0.90, 0.83-0.99; p=0.018). By contrast, physical radiation dose was not associated with either endpoint. In patients who did not receive radiotherapy, sham-GARD was not associated with outcomes, supporting its role as a treatment-specific predictor rather than a general prognostic biomarker. Conclusions: In pediatric CNS tumors, the biological effect of radiotherapy as quantified by GARD is associated with clinical outcomes, whereas physical dose alone is not. These findings challenge the current paradigm of uniform radiotherapy dosing and support a genomically informed approach to dose individualization. Prospective evaluation of GARD-guided radiotherapy is warranted to optimize tumor control while minimizing long-term toxicity in children.