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).