Discussion:
Previous studies have demonstrated a clear correlation between TMB and
DM in pediatric brain tumors.9 This
multi-institutional analysis assessed whether higher TMB tumors
correlate with outcomes in children with a broad range of brain tumors.
We summarized genomic characteristics of pediatric CNS tumors and
outcome data in 119 pediatric patients across 4 academic medical
institutions between 2008-2021. We report a clear link between higher
TMB and worse outcome. Higher TMB was a significant and independent
predictor of reduced OS. Death events and tumor progression were more
common in high TMB tumors as compared to low TMB tumors; high TMB tumors
also had shorter TTD and TTP. These represent novel findings in
understanding the genomics as they relate to outcomes in pediatric CNS
tumors.
TMB and outcomes have previously been studied in many adult, and some
pediatric, tumors. TMB has not always correlated to OS; there are wide
ranges of solid tumor types and data has been
inconsistent.5 TMB has been associated with shorter OS
in adult patients with gliomas, BRCA1 or BRCA2 mutated high-grade serous
ovarian cancer, and lung cancer. Worse outcomes in high TMB tumors are
likely attributed to mutations that inhibit cell cycle checkpoints and
DNA repair mechanisms, leading to high proliferative activity.6,9,12,13 These mutations contribute to more severe
and rapid metastatic disease in high TMB tumors.6 Our
data further demonstrates poor prognostication of
TMB.6,14,15 Poorer outcomes may also be indicative of
inadequate treatment options for this high-risk pediatric CNS tumor
patient subset.
Similar to data presented by Patel et al., high TMB tumors in this
analysis were more likely to have a TP53 inactivation and low TMB
tumors were more likely to have a BRAFmutation.9 Patel et al., postulated this was becauseTP53 inactivation causes an inability to repair DNA mutations andBRAF has a minimal effect on DNA repair.9TP53 inactivation is likely associated with high TMB tumors given
its facilitation of a multi-step malignant
progression.16 The current data further demonstrates
that high TMB tumors often do not have driver mutations that can be
therapeutically targeted; identifying a need for alternative therapies.
Although most high TMB tumors in our dataset were treated with systemic
therapy, only a small fraction of patients were treated with targeted or
immunotherapy. Targeted and immunotherapy may not have had a significant
association with survival because such therapies were most commonly used
second-line, post-tumor recurrence or progression; this is true for all
three patients who received immunotherapy in our study. Literature
supports that first-line immunotherapy may have better outcomes than
when immunotherapy is used as second-line; the hypothesis being that
upfront chemotherapy may destroy the host immune system, decreasing the
efficacy of subsequent immunotherapy.17 A lack of
statistical significance may also be due to low sample size. The use of
ICIs may be indicated for such patients, given our findings that high
TMB tumors are more likely to be associated with loss of tumor
suppressor genes and less likely to be associated with oncogene
mutations.
Furthermore, TMB is a biomarker for ICI enrollment; TMB has been found
to predict ICI response in 20-60% of
patients.3,7,18-21 High TMB (>3 mut/Mb)
has also been demonstrated to predict improved progression-free survival
in patients on ICI.11 Although TMB has been associated
with worse survival, tumors with high TMB tumors are often extremely
responsive to ICI therapy. Additionally, high TMB tumors associated with
poor OS were found to have improved OS with ICI when compared to low TMB
tumors. These responses have been demonstrated in non-small cell lung
cancer, malignant melanoma, cervical cancer, breast cancer, gastric,
esophageal and head and neck cancers.18,19,22-24 In
pediatrics, however, responses have been inconsistent, possibly because
of the relatively low TMB of pediatric cancers.25,26
There are over 2,000 clinical trials investigating ICI in patients of
all ages and with all tumor types (accessed June 2022). Of the 141
trials investigating ICI in pediatric patients, five of which have or
are currently investigating ICI in pediatric CNS tumor
patients.27-31 Only one trial, specifically recruits
pediatric patients with high TMB CNS and solid tumors to analyze the
effect of ICI.28 Pembrolizumab has been approved for
high TMB solid tumors, including pediatric CNS tumors with PD-L1
expression.32 In a post-hoc analysis of the HERBY
trial, hypermutated pediatric HGGs treated with bevacizumab (anti-VEGF)
had significantly more CD8+ tumor-infiltrating lymphocytes and improved
OS as compared to non-hypermutated types.33 This
analysis supports that bevacizumab may be a treatment option for
pediatric CNS tumor patients with high TMB and poor outcomes in need of
more effective treatment regimens. It also emphasizes the importance of
understanding tumor microenvironment as a means of further stratifying
patients, which may be a future direction for
studies.34
Our multi-institutional analysis shows a clear correlation between
higher TMB and poor outcomes for children with brain tumors.Although variables were standardized, discrepancies may exist in data
collection amongst institutions. Additionally, DNA methylation profiling
has increasingly been used for pediatric CNS tumor
classification.2,35,36 Only two patients in our
dataset had DNA methylation profiling and only 75% of patients had TMB
data. In addition, the brain tumor tissue obtained at these institutions
was not routinely sent to FoundationOne for TMB testing for all children
so it is possible our sample is not representative of all children with
brain tumors. We recommend an increase in TMB and DNA methylation
testing, as both may be applicable toward stratifying treatments and
also used to improve research and treatment developments in the
future.2 Lastly, although our analyses were
pre-determined prior to data collection, results should be interpreted
in the context of the retrospective nature of this study.
We identify pediatric CNS high TMB tumor patients as a unique high-risk
patient subset that has poor outcomes: higher progression rates and
poorer overall survival. Our data may help in identifying such patients
who may require alternative treatments, such as ICI.
Conflict of Interest Statement: All authors have no conflicts
of interest to disclose.
Acknowledgements : This study was supported in part by Albany
Medical Center Children’s Hospital Grant, Albany, NY, 2021.