Background: The role of tumor genomics in influencing treatment outcomes remains a critical area of investigation in personalized medicine. This study is the first to evaluate the relationship between tumor mutational burden (TMB) and driver mutations (DM) in pediatric brain tumors, examining their association with treatment modalities and patient outcomes. Methods: We conducted a retrospective study of 160 pediatric patients (78 males, 82 females) with a median age of 9 years (range: 2 months to 26 years) who were diagnosed with primary CNS tumors across four academic institutions between 2008 and 2023. The analysis included TMB (high TMB ≥3 mutations/megabase, low TMB <3), DM, treatment modality, clinical outcomes, and matching status, defined as the alignment of tumor genomic markers with corresponding pharmacologic targets. Results: Low-grade glioma (42.5%) and high-grade glioma (22.5%) were the most common tumors, followed by medulloblastoma (10.6%), ependymoma (5%), ganglioglioma (4.4%), atypical teratoid rhabdoid tumor (2.5%), and other rare tumor types. Among patients receiving targeted or immunotherapy (N=30), most had matched therapy (N=19) and were found to have no significant survival advantage. High TMB tumors had better survival with standard therapy (p=0.026). Targeted and immunotherapy were used as second or later lines of treatment, with a non-significant trend suggesting better survival in recurrent or progressive disease. Conclusions: This study found no statistical significance linking matched therapy with molecular markers to improved overall survival. Most patients received targeted or immunotherapy as second-line or later treatment. High TMB tumors had better outcomes with standard therapy. The increased resistance and aggressiveness of recurrent tumors complicate the ability to evaluate targeted therapies as initial treatment options.

Background: Pediatric CNS tumors are the leading cause of pediatric cancer mortality. Research addressing genomic biomarkers and clinical outcomes is needed to inform therapeutic decision making. Methods: We conducted a retrospective analysis of pediatric patients (age <21) diagnosed with a primary CNS tumor at four upstate New York hospitals from 2008 to 2021. Clinical and histopathologic data were identified from each patient, including genomic analysis of somatic mutations and tumor mutation burden (TMB) where available. These variables were each compared with overall survival using cox-regression analyses. Multivariable analysis was conducted to identify patient characteristics that may independently predict survival. Results: We identified 119 patients. Common tumor types included low-grade glioma (N=51), high-grade glioma (N=29), and medulloblastoma (N=11). Common driver-mutations included TP53 inactivation (N=16), BRAF-KIAA1549 fusion (N=16), FGFR1 amplification (N=12), BRAF V600E mutation (N=12), NF1 loss (N=12), and H3F3A K28M mutation (N=6). Median TMB was 1 mutation/megabase (mut/Mb, range=0-132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p=0.002, HR 4.97), high grade tumors (p=0.009, HR 84.3), and high-grade glioma histology (p=0.021, HR 3.14). Multivariable analyses further identified TMB (p=0.011, HR 4.46) and high-grade histology (p=0.015, HR 5.28) as independently predictive of worse survival. Tumor progression was more common in high TMB (N=15, 44%) than in low TMB tumors (N=19, 35%). Conclusions: High TMB is correlated with higher rates of progression and death as compared to low TMB tumors. These findings may help identify patients who may benefit from alternative treatments, such as immunotherapies.