Challenges and Future Directions in the Management of Tumor Mutational Burden-High (TMB-H) Advanced Solid Malignancies

Abstract

A standardized assessment of Tumor Mutational Burden (TMB) poses challenges across diverse tumor histologies, treatment modalities, and testing platforms, requiring careful consideration to ensure consistency and reproducibility. Despite clinical trials demonstrating favorable responses to immune checkpoint inhibitors (ICIs), not all patients with elevated TMB exhibit benefits, and certain tumors with a normal TMB may respond to ICIs. Therefore, a comprehensive understanding of the intricate interplay between TMB and the tumor microenvironment, as well as genomic features, is crucial to refine its predictive value. Bioinformatics advancements hold potential to improve the precision and cost-effectiveness of TMB assessments, addressing existing challenges. Similarly, integrating TMB with other biomarkers and employing comprehensive, multiomics approaches could further enhance its predictive value. Ongoing collaborative endeavors in research, standardization, and clinical validation are pivotal in harnessing the full potential of TMB as a biomarker in the clinic settings.

Keywords: ICI; TMB; biomarker; immune checkpoint inhibitor; tumor mutational burden.

Figure 1

TMB workflow from tissue specimens to clinical report. The boxes with red outlines are steps that are substantially different in labs and workflows. Abbreviations: NGS, next-generation sequencing; PBMC, peripheral blood mononuclear cells; TMB, Tumor Mutational Burden.