Background Pediatric central nervous system (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 mutational 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 one mutation/megabase (mut/Mb, range = 0–132). Overall survival was 79.9%. Variables associated with poorer survival on univariable analysis were higher TMB (p = .002, HR 4.97), high‐grade tumors (p = .009, HR 84.3), and high‐grade glioma histology (p = .021, HR 3.14). Multivariable analyses further identified TMB (p = .011, HR 4.46) and high‐grade histology (p = .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.

Background Although tumor genomic profiling has aided the advancement of targeted genetic therapy, its clinical integration remains a challenge in pediatric cancers due to lower mutation frequency and less available targeted drugs. There have been multiple novel studies examining molecular sequencing in pediatrics; however, many of these studies primarily utilized large‐scale, genome‐wide screening applications that limit applicable use due to the availability of testing. This study examined the institutional use of a targeted, clinically available approach to tumor genomic sequencing. Methods A retrospective chart review was performed on pediatric patients with solid tumors who were managed at Roswell Park Comprehensive Cancer Center and underwent molecular testing of their tumor biopsy via OmniSeq from August 2016 to July 2021. Results were reviewed for mutations considered to be “actionable” by targeted therapy. Patients with actionable mutations were further examined to evaluate treatment course, receival of targeted therapy, and clinical outcomes. Results We identified 64 pediatric patients consisting of 20 (31%) with CNS tumors and 44 (69%) with non‐CNS tumors, ranging in age from 9 months to 21 years. Thirty‐five total actionable mutations were identified amongst 27 patients (42%). Of these 27, 12 patients (44%) received at least 1 targeted drug against a respective actionable mutation, of which 6 patients (50%) achieved clinical benefit to therapy, including 1 complete response. Conclusions The use of a clinically focused and readily available targeted molecular sequencing panel identified actionable mutations at a comparable rate to the large‐scale, less readily available sequencing panels utilized in other studies. Half of our patients who received targeted therapy achieved a complete response or clinical benefit from therapy. Although targeted therapy has a role in pediatric cancer treatment, many newer drugs require further research on their safety and efficacy.

In pediatric central nervous system (CNS) tumors, high tumor mutational burden (TMB) (≥3 mutations/megabase (mut/Mb)) has been correlated with lower overall survival and higher rates of progression as compared to low TMB tumors (&lt;3 mut/Mb). This study is the first to examine a subset of pediatric CNS hypermutated tumors (≥10 mut/Mb) in comparison to high TMB tumors. We conducted a retrospective analysis of 121 pediatric patients (61 female (50%)) with a median age of 9 years diagnosed with a primary CNS tumor (high TMB, N=34; low TMB, N=55) at four academic medical centers from 2008 to 2021. Hypermutated tumors (N=3) were exclusively high grade tumors; subtypes were ependymoma, medulloblastoma, and oligodendroglioma. Hypermutated tumors had an average TMB of 65 mut/Mb (range=11-132 mut/Mb). Most of the hypermutated tumors had TP53 mutations (N=2; 67%) as compared to 29% of high TMB patients (N=12). Sixty-seven percent of patients with hypermutated tumors experienced tumor progression (N=2) as compared to 44% (N=15) of patients with high TMB tumors. Average time to progression was 2.4 years in hypermutated tumors and 1.4 years in high TMB tumors. No patients with a hypermutated tumor experienced a death event, as compared to 41% (N=14) of patients with high TMB. Although we report a small subset of hypermutated pediatric CNS tumors, this multi-institution case series suggests that hypermutated tumors may be associated with higher rates of progression, slower time to progression, and lower mortality as compared to high TMB tumors. Future research with a larger population of hypermutated tumors is needed to better characterize outcomes to optimize treatment for this subset of patients.

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. Tumor mutational burden (TMB) has been correlated with decreased survival across cancer types. This study is the first to examine TMB and outcomes in pediatric CNS tumor patients across multiple academic medical centers. We conducted a retrospective analysis of 121 pediatric patients (61 female (50%)) with a median age of 9 diagnosed with a primary CNS tumor at Albany Medical Center, Roswell Park Comprehensive Cancer Center, Upstate University Hospital, or University of Rochester Medical Center from 2008 to 2021. Common tumor types included low-grade glioma (N=51), high-grade glioma (N=30), medulloblastoma (N=11), ependymoma (N=7), ganglioglioma (N=4), and 18 other CNS tumors. Seventy-one patients had driver-mutations, including TP53 inactivation (n=17), BRAF-KIAA1549 fusion (n=16), FGFR1 amplification (n=12), BRAF V600E mutation (n=12), NF1 loss (n=12), and H3F3A K28M mutation (n=6). TMB data was available for most patients (N=91), median TMB was 1 mutations/megabase (mut/Mb, range=0-132). There were 26 deaths observed; patients with high TMB (≥3 mut/Mb; N=35) as compared to patients with low TMB (&lt;3 mut/Mb; N=56) were more likely to have a death event, 43% (N=15) vs 9% (N=5), respectively. High TMB tumors were more frequently high-grade (77%) than low-grade (41%). High TMB tumors were more frequently treated with systemic therapy (86%) compared to low TMB tumors (70%). Tumor progression was more common in high TMB (71%) than in low TMB tumors (54%). This multi-institutional analysis suggests that high TMB is correlated with higher rates of progression and death as compared to low TMB tumors. Knowledge of these findings is critical for identifying patients who may benefit from alternative treatments, such as immunotherapies.

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.