Cancer-specific thresholds adjust for whole exome sequencing–based tumor mutational burden distribution

PURPOSE To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold. MATERIALS AND METHODS Using whole exome sequencing data from primary tumors in The Cancer Genome Atlas (n = 3,534) and advanced and/or metastatic tumors from Weill Cornell Medicine Advanced (n = 696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds. RESULTS The distribution of TMB varied dramatically among cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, whereas the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared with the static pan-cancer threshold. In addition, no significant difference in survival outcomes was found with the cancer-specific threshold compared with the pan-cancer threshold. Furthermore, the cancer-specific threshold maintained higher predicted neoantigen load for the TMB-high samples compared with the TMB-low samples, even when the threshold was lower than the pan-cancer threshold. CONCLUSION TMB is determined within the context of cancer type, metastatic state, and disease stage. Compared with a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that are not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Because of the potential impact in the care of patients with cancer, TMB status should be determined in a cancer-specific manner.