Abstract
BackgroundTumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized.MethodsUsing a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential.ResultsWe find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes.ConclusionsWe find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.
Highlights
Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result
While TMB is generally correlated with downstream metrics such as neoepitope burden, we explore the predictive capacity of neoepitope burden and its derivatives including adjustment for Major histocompatiblity complex (MHC) binding robustness and peptide sequence novelty, as well as RNA-derived sources of neoepitopes
We identified expressed transcripts in matched The Cancer Genome Atlas (TCGA) cancer types for each disease type in our cohort (SKCM for melanoma, Lung adenocarcinoma (LUAD)/Lung squamous cell carcinoma (LUSC) for non-small cell lung cancer (NSCLC), Colon adenocarcinoma (COAD) for colon cancer, Uterine corpus endometrial carcinoma (UCEC) for endometrial cancer, Thyroid carcinoma (THCA) for thyroid cancer, Prostate adenocarcinoma (PRAD) for prostate cancer, and Kidney renal clear cell carcinoma (KIRC) for renal cell carcinoma (RCC)) from transcript per million (TPM) values generated by the National Cancer Institute [47]
Summary
Tumor mutational burden (TMB; the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. Tumor mutational burden (TMB; the overall quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy [1] and overall survival [2]. Other sources of sequence variation such as frameshifting insertions/deletions [7] and tumor-specific alternative splicing (e.g., intron retention [8]) have been found to correlate with immunotherapy response These phenomena are widely accepted and appear to be pronounced in patients harboring DNA repair deficiencies [9]. There is wide variability among techniques for measuring and interpreting TMB, raising questions of utility and reproducibility [11]
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