Discussion
Recent studies indicated that TMB may be a new biomarker to predict the
response to ICIs in different tumor entities.10-13Several clinical trials have provided different cut-off values for TMB
which leads to difficulties in clinical application. The data providing
clinical guidance for TMB cut-off values are scarce. Moreover, the
cut-off values of TMB for pan-cancer may not be ideal for clinical use.
Therefore, we calculated and compared the difference in TMB cut-offs
between primary and metastatic lesions on the basis of cBioPortal
mutational data.
In this study, the co-occurring mutations and TMB scores were
significantly higher in metastatic lesions than in primary lesions.
Several theories might explain why metastatic tissues have more gene
mutations than primary tissues. First, genetic analysis of matched sets
of patients’ primary and metastasis lesions revealed that metastatic
lesions had mutations common to both and mutations that were distinct
from primary lesions, which is the biggest cause of cancer death.
Mutations in metastatic lesions were located at the chromosome ends and
affected chromosome stability, gene expression regulation, and DNA
repair. Previous research indicated that genomic instability was
observed in metastatic subclones and/or metastatic lesions of primary
lesions.14-17 Additionally, studies revealed that new
genetic alterations, not seen in primary lesions, were observed in
metastasis lesions.
Hong, M. K. H. et al. 18 revealed that mutation
or amplification of both DNA double-strand break repair and mismatch
repair gene was indicative of metastasis in prostate cancer progression.
Similarly, Brastianos, P. et al. 19 demonstrated
that 53% of brain metastasis harbored mutations not seen in primary
lesions. These data revealed that metastasis lesions would obtain new
additional mutations compared to primary lesions, which was consistent
with our findings.
Additionally, the variable cut-offs of TMB between primary and
metastatic lesions can be attributed to distinct tumor microenvironments
and other factors that independently predict response to ICIs including
immune infiltration, human leukocyte antigen genotype, clonality, and
expression levels of checkpoint molecules.20-23 Our
result suggested high TMB was associated with the increased OS based on
the optimal cut-offs in pan-cancer types. Therefore, TMB as a new
biomarker in pan-cancer may reflect fundamental mechanisms that
determine the response to ICIs treatment.
Our data addresses a fundamentally important question in ICIs treatment
for clinicians. Although TMB could predict survival and response to ICIs
across pan-cancer types, the cut-off values of TMB differed between
primary and metastatic lesions. Therefore, the TMB score for primary and
metastatic lesions should be determined separately. This finding will
greatly influence clinical guidance.
This study has a few limitations. This was a retrospective study using
data from the cBioPortal database. Therefore, the results should be
verified in a prospective study. Furthermore, clarification of
appropriate cut-offs of TMB and the integration of relevant clinical
variables for each cancer type will be necessary to allow for the
application of TMB as a prognostic biomarker to reflect ICIs treatment
in future clinical studies.