The interplay between cancer type, panel size and tumor mutational burden threshold in patient selection for cancer immunotherapy

The tumor mutational burden (TMB) is increasingly recognized as an emerging biomarker that predicts improved outcomes or response to immune checkpoint inhibitors in cancer. A multitude of technical and biological factors make it difficult to compare TMB values across platforms, histologies, and treatments. Here, we present a mechanistic model that explains the association between panel size, histology, and TMB threshold with panel performance and survival outcome and demonstrate the limitations of existing methods utilized to harmonize TMB across platforms.
Author summary An increasing number of studies have demonstrated the benefit of tumor mutation burden (TMB), the number of non-silent mutations in the genome, as a predictive biomarker in a clinical setting. Most clinical trials utilize a smaller panel, instead of whole exome sequencing (WES), to estimate the exome-wide mutational load. However, the use of panels introduces panel size dependent sampling noise that could affect the performance of the TMB biomarker. In this work we create a mathematical model of the cancer histology, treatment response, and TMB device system to assess the interplay between cancer type, panel size and tumor mutational burden threshold in patient selection for cancer immunotherapy.