Implementing tumor mutational burden (TMB) analysis in routine diagnostics—a primer for molecular pathologists and clinicians

Tumor mutational burden (TMB) is emerging as new predictive biomarker to select patients that benefit from immune checkpoint inhibitor therapy (1-7). It is commonly defined as the total number of somatic coding mutations and associated with the emergence of neoantigens that trigger anti-tumor immunity (8-10). As a defense mechanism, tumors acquire expression of checkpoint regulators, like programmed death-ligand 1 (PD-L1), the action of which can be overcome in clinical practice with therapeutic antibodies against PD-1 (programmed cell death protein 1) or PD-L1 alone or in combination with CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) inhibitors or chemotherapy or more recently small-molecule kinase inhibitors (11-13). In numerous clinical trials over the past few years (14-21), these therapies have demonstrated impressive anti-tumor activity and are already approved for a large number of tumor entities in various indications (22) including non-small cell lung cancer (NSCLC) (23,24). Up to now, patient selection for immuno-oncologic (IO) treatment has been mainly based on expression of PD-L1 as assessed by immunohistochemistry (25,26). However, accumulating data suggest a much greater utility of TMB for this purpose