Abstract
BackgroundTumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness. Genomic landscape heterogeneity is a well-established cancer feature. Molecular characteristics may differ even within the same tumor specimen and undoubtedly evolve with time. However, the degree to which TMB differs between tumor biopsies within the same patient has not been established.MethodsWe curated data on 202 patients enrolled in the PREDICT study (NCT02478931), seen at the University of California San Diego (UCSD), who had 404 tissue biopsies for TMB (two per patient, mean of 722 days between biopsies) to assess difference in TMB before and after treatment in a pan-cancer cohort. We also performed an orthogonal analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database to examine difference in TMB between first and last biopsies.ResultsThe mean (95% CI) TMB difference between samples was 0.583 [− 0.900–2.064] (p = 0.15). Pearson correlation showed a flat line for time elapsed between biopsies versus TMB change indicating no correlation (R2 = 0.0001; p = 0.8778). However, in 55 patients who received ICIs, there was an increase in TMB (before versus after mean mutations/megabase [range] 12.50 [range, 0.00–98.31] versus 14.14 [range, 0.00–100.0], p = 0.025). Analysis of 2872 paired pan-solid tumor biopsies in the Foundation Medicine database also indicated largely stable TMB patterns; TMB increases were only observed in specific tumors (e.g., breast, colorectal, glioma) within certain time intervals.ConclusionsOverall, our results suggest that tissue TMB remains stable with time, though specific therapies such as immunotherapy may correlate with an increase in TMB.Trial registrationNCT02478931, registered June 23, 2015.
Highlights
Tumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness
Tumor mutational burden (TMB) is currently emerging as a predictive biomarker of response to checkpoint blockade immunotherapy as noted by the recent Food and Drug Administration approval of the anti-programmed cell death protein (PD-1) antibody pembrolizumab for solid cancers with TMB ≥ 10 mutations/Mb [1,2,3,4], though there is still controversy regarding its value due to its variable distribution depending on cancer type [5,6,7,8], sequencing methodology, and lack of standards for the definition of “high,” “medium,” or “low” TMB, and the consequent lack of harmonized clinical validation [9]
Patient and sample demographics We examined clinical data, diagnosis and oncology drug treatments with associated dates and outcomes, sex, and dates of birth and last follow-up or death, from 225 University of California San Diego (UCSD) patients enrolled in the UCSD PREDICT study (Trial Registration NCT02478931, https://clinicaltrials. gov/ct2/show/NCT02478931) who had ≥ 2 biopsies that underwent next-generation sequencing (NGS)
Summary
Tumor mutational burden (TMB) may be a predictive biomarker of immune checkpoint inhibitor (ICI) responsiveness. Tumor mutational burden (TMB) is currently emerging as a predictive biomarker of response to checkpoint blockade immunotherapy as noted by the recent Food and Drug Administration approval of the anti-programmed cell death protein (PD-1) antibody pembrolizumab for solid cancers with TMB ≥ 10 mutations/Mb [1,2,3,4], though there is still controversy regarding its value due to its variable distribution depending on cancer type [5,6,7,8], sequencing methodology, and lack of standards for the definition of “high,” “medium,” or “low” TMB, and the consequent lack of harmonized clinical validation [9]. Riaz et al [17] reported that TMB decreases in melanoma when immunotherapy treatment is successful and that certain subclonal populations within the tumor are eliminated due to the action of tumor infiltrating lymphocytes (TIL) activated by the checkpoint inhibitor nivolumab, changing the tumor’s composition and post-treatment immune microenvironment [17]
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