Results:
One hundred and nineteen patients (60 male, 59 female) with a median age of 9 years (range 2 months-20 years) were diagnosed with a primary CNS tumor at 4 upstate New York hospitals between 2008 and 2021 and had FoundationOne testing (Table 1). There were 25 deaths observed (21%), median age at death was 13 years old (range 1.4 - 22 years). All death events were in high-grade tumor patients. Overall survival was 79.9%.
Tumor types included LGG (N=51, 43%), HGG (N=29, 24%), medulloblastoma (N=11, 9%), ependymoma (N=7, 6%), ganglioglioma (N=4, 3%), ATRT (N=4, 3%), embryonal tumor (N=3, 3%), choroid plexus (N=2, 3%), DIPG (N=1, 1%), and other CNS tumor types (N=7, 6%). Seventy patients had DMs, including TP53 inactivation (n=16, 13%), BRAF-KIAA1549fusion (N=16, 13%), FGFR1 amplification (N=12, 10%), BRAF V600E mutation (N=12, 10%), NF1 loss (N=12, 10%), andH3F3A K28M mutation (N=6, 5%).
TMB data was available for most patients (N=89, 75%); median TMB was 1 mut/Mb (range=0-132). Low TMB was defined as <3 mut/Mb (N=55, 62% of tumors with TMB available); high TMB was defined as ≥3 mut/Mb (N=34, 38% of tumors with TMB available) (Table 1). Two tumors (2%), HGG and medulloblastoma, had DNA methylation data. Patient outcomes were categorized as progression (N=47, 40%), stable disease or cure (N=45, 38%), recurrence (N=29, 24%), or death (N=25, 21%) (Table 1).
High TMB tumors were most commonly HGG (N=11, 32% of patients with high TMB) and medulloblastomas (N=7, 21%). Low TMB tumors were most commonly LGG (N=30, 55% of patients with low TMB), however also prevalent in HGGs (N=11, 20%) (Table 1). High TMB tumors were more commonly identified in high-grade (N=26, 77%) than low-grade (N=8, 24%) histologies. High TMB tumors were more likely to have a TP53inactivation (N=10, 29%) as compared to low TMB tumors (N=3, 6%).NF1 loss was similar amongst high TMB tumors (N=4, 12%) and low TMB tumors (N=5, 9%). All other DMs were more likely to be in low TMB tumors (Figure 1).
Patients with high TMB tumors were more likely to have a death event (N=14, 41%) as compared to patients with low TMB (N=5, 9%) (Figure 2). For patients with a death event and TMB data, the mean TTD was 25.8 months (range 3.27 months-15.5 years); patients with high TMB tumors had a shorter TTD (mean=20.7 months) as compared to those with low TMB (mean=3.3 years). Tumor progression was more common in high TMB (N=15, 44%) than in low TMB tumors (N=19, 35%) (Table 1). Mean TTP was 28.3 months (range 22 days-15.0 years). TTP was shorter in high TMB tumors (mean=17.6 months) as compared to low TMB tumors (mean=30.3 months).
The majority of patients were treated with surgery (N=99, 83.2%). Patients were also treated with chemotherapy (N=77, 64.7%), radiation (N=56, 47.1%), and/or targeted therapy (N=32, 26.9%). Few patients were treated with immunotherapy (N=3, 2.5%), types included were pembrolizumab, dendritic cell-based immunotherapy, and nivolumab; all were used as second-line therapy following progression. High TMB tumors were more frequently treated with systemic therapy (N=29, 85%) compared to low TMB tumors (N=38, 69%) (Table 1). Most patients who were treated with systemic therapy were treated initially at the time of diagnosis (N=75, 87%) rather than after tumor progression (N=11, 13%).
Variables significantly associated with reduced OS on univariable analysis were high TMB (p=0.002, HR=4.97, 95% CI: 1.79-13.83), high grade tumor (p=0.009, HR=84.3, 95% CI: 3.05-2333), and HGG (p=0.021, HR=3.14, 95% CI: 1.19-8.26). Including these factors in a multivariable model, high TMB (p=0.011, HR=4.46, 95% CI: 1.40-14.15) and HGG (p=0.015, HR=5.28, 95% CI: 1.38-20.27) remained significantly associated with reduced OS (Table 2).
There were no statistically significant differences in OS with respect to age, gender, treatment modality (chemotherapy, surgery, radiation, targeted therapy, or immunotherapy), the presence of an oncogenic DM, or non-high-grade glioma histology (Table 2).