Tumour mutational burden (abbreviated as TMB) is a genetic characteristic of tumorous tissue that can be informative to cancer research and treatment. It is defined as the number of non-inherited mutations per million bases (Mb) of investigated genomic sequence,[1] and its measurement has been enabled by next generation sequencing. High TMB and DNA damage repair mutations were discovered to be associated with superior clinical benefit from immune checkpoint blockade therapy by Timothy Chan and colleagues at the Memorial Sloan Kettering Cancer Center.[2]
TMB has been validated as a predictive biomarker with several applications, including associations reported between different TMB levels and patient response to immune checkpoint inhibitor (ICI) therapy in a variety of cancers.[3][4] TMB is also strongly predictive of overall as well as disease-specific survival, independently of cancer type, stage or grade. Patients with both low and high TMB fare notably better than those with intermediate burden.[5]
While both TMB and mutational signatures give us critical information about cancer behaviour, they have different definitions. TMB is defined as the number of somatic mutations/megabase whereas mutational signatures are distinct mutational patterns of single base substitutions, double base substitutions, or small insertions and deletions in tumors.[6] For instance, COSMIC single base substitution signature 1 is characterized by the enzymatic deamination of cytosine to thymine and has been associated with age of an individual.[6]
Scientists postulate that high TMB is associated with an increased amount of neoantigens, which are tumour specific markers displayed by cells.[2][7] An increase in these antigens may then lead to increased detection of cancer cells by the immune system and more robust activation of cytotoxic T-lymphocytes. Activation of T-cells is further regulated by immune checkpoints that can be displayed by cancer cells, thus treatment with ICIs can lead to improved patient survival.[8]
On June 16, 2020 the U.S. Food and Drug Administration expanded the approval of the immunotherapy drug pembrolizumab to treat any advanced solid-tumor cancers with a TMB greater than 10 mutations per Mb and continued growth following prior treatments.[9] This marks the first time that the FDA has approved a drug with its use based on TMB measurements.[10]