ID #491 Genomic adjusted radiation dose enables biologically personalized radiotherapy in pediatric brain tumors

Background

Radiotherapy (RT) is a cornerstone of the pediatric cancer care paradigm. However, not all patients are responsive to radiotherapy, with many displaying normal tissue toxicities and irradiation-associated late effects. Despite major advances in genomics and precision medicine, RT dosing continues to be prescribed in a uniform manner irrespective of patient-specific tumor biology. Numerous recent works across cancers have demonstrated the utility of the genomic-adjusted radiation dose (GARD) as a model for determining the expected biological effect of radiation to determine the optimal RT for patients in a personalized manner.[1][2][3] Here, we characterized if GARD could predict RT response and inform biologically personalized treatment strategies in pediatric brain tumors.

Methods

We analyzed 207 patient samples from the Children’s Brain Tumor Network (CBTN) that received radiotherapy for primary high-grade glioma, ependymoma, or medulloblastoma. GARD was calculated for each patient by integrating tumor-specific radiosensitivity into the classical linear-quadratic model for radiation dosing. Cox proportional hazards models were used to evaluate GARD as a continuous variable, with overall survival (OS) and local recurrence (LC) provided as clinical endpoints.

Results

We determined broad variability in the expected biological effect of radiotherapy (GARD) in patients regardless of physical dose or tumor type (Range: 0 - 74). GARD was significantly associated with overall survival (HR = 0.96, p = 0.01) and local recurrence (HR = 0.95, p < 0.001), in pooled analyses of patients that received radiotherapy. These results suggest a robust 5% benefit per unit increase in GARD , supporting its efficacy as a predictive metric for patient-specific radiation benefit.

Conclusion

GARD-based dosing paradigms predict the biological effect of radiotherapy and demonstrate improvements in time to first recurrence and overall survival in pediatric brain tumor patients. This suggests that incorporating GARD can effectively inform decision-making and dosing of radiotherapy in pediatric brain tumors.

1. Scott JG, Berglund A, Schell MJ, et al. Pan-cancer prediction of radiotherapy benefit using genomic-adjusted radiation dose (GARD): a cohort-based pooled analysis. Lancet Oncol. 2021;22(8):1221–1229. doi:10.1016/S1470-2045(21)00347-8.

2. Ho E, De Cecco L, Eschrich SA, et al. Personalized treatment in HPV+ oropharynx cancer using genomic adjusted radiation dose. J Clin Invest. 2025;135(19):e194073. doi:10.1172/JCI194073.

3. Scott JG, Sharifi H, Osborne EM, et al. Personalizing radiotherapy prescription dose using genomic markers of radiosensitivity and normal tissue toxicity in non-small cell lung cancer. J Thorac Oncol. 2021;16(7):1130-1141. doi:10.1016/j.jtho.2020.10.046.