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Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)—the number of somatic mutations per DNA megabase (Mb)—has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next‐generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole‐exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience …