Tumour mutational burden: clinical utility, challenges and emerging improvements

Area of Science:

• Oncology
• Genomics
• Immunology

Background:

• Tumour mutational burden (TMB) is the count of somatic mutations in cancer genomes and varies by cancer type.
• TMB is a validated biomarker for predicting response to immune-checkpoint inhibitors, leading to approvals like pembrolizumab for TMB-high tumors.
• Current research addresses limitations in TMB assessment and explores its broader clinical utility.

Purpose of the Study:

• To review the current landscape and future directions of research in tumour mutational burden (TMB).
• To highlight advancements in TMB assessment methodologies and conceptual frameworks.
• To emphasize the integration of TMB with other biomarkers for enhanced cancer treatment strategies.

Main Methods:

• Review of retrospective and prospective research on TMB as a predictive biomarker.
• Analysis of advancements in laboratory quality control for TMB assessment, addressing panel scope and tumour purity.
• Exploration of refined TMB concepts (clonal, persistent, HLA-corrected TMB, neoantigen load, mutational signatures).
• Examination of TMB integration with biomarkers like PD-L1, microsatellite instability, and immune gene expression.

Main Results:

• TMB has been established as a predictive biomarker for immune-checkpoint inhibitor response.
• Research is progressing in enhancing TMB measurement accuracy and refining its definition.
• Integration of TMB with other biomarkers shows promise for personalized cancer therapy.

Conclusions:

• Understanding TMB's role in cancer pathogenesis and immune recognition is crucial for oncology.
• Continued evolution of TMB assessment and integration with other biomarkers will advance precision oncology.
• Further research is needed to ascertain optimal TMB thresholds and applicability across all cancer types.