Tumor Mutational Burden (TMB)
Tumor Mutational Burden (TMB): Overview and Clinical Implications
Tumor Mutational Burden (TMB) quantifies the number of non-inherited somatic mutations per megabase (Mb) of tumor DNA. It serves as a predictive and prognostic biomarker in oncology, particularly for immunotherapy response. Below is a synthesis of its key aspects, supported by current evidence.
Key Features of TMB
Definition:
- TMB measures somatic mutations (coding region changes) in tumor DNA, excluding germline mutations.
- Expressed as mutations per megabase (mut/Mb).
Mechanism:
- High TMB correlates with increased neoantigen production, enhancing immune recognition via cytotoxic T-cells.
- Immune checkpoint inhibitors (ICIs) amplify this response by blocking regulatory pathways (e.g., PD-1/PD-L1).
Clinical Applications
Immunotherapy Prediction:
- FDA Approval: Pembrolizumab is approved for advanced solid tumors with TMB-High (≥10 mut/Mb) after progression on prior therapies[1][2][5].
- Response Correlation: TMB-High tumors (e.g., melanoma, NSCLC) show improved survival with ICIs[3][6].
Prognostic Value:
- Mixed Outcomes:
- Cervical Cancer: High TMB predicts worse survival post-radiotherapy, suggesting context-dependent utility[4].
- Colorectal Cancer: TMB-High (>20 mut/Mb) linked to microsatellite instability (MSI-High), indicating immunotherapy candidacy[3].
Measurement and Challenges
Testing Methods:
- Next-Generation Sequencing (NGS):
- Whole Exome Sequencing (WES): Gold standard but costly.
- Targeted Panels: Require ≥1.1 Mb coverage for accuracy (e.g., Illumina, Caris Life Sciences)[6][7][8].
- Emerging Techniques: Blood-based TMB (bTMB) via circulating tumor DNA (ctDNA)[3][8].
Standardization Issues:
- Variability: Panel size, gene coverage, and bioinformatics pipelines affect TMB estimates[2][7].
- Thresholds:
- TMB-Low: 10–20 mut/Mb (varies by cancer type)[3][8].
Limitations and Research Directions
Context-Dependent Utility:
- Predictive power varies by cancer type (e.g., limited in prostate/pancreatic cancers)[2][5].
- Combination Biomarkers: Integration with MSI, PD-L1, or neoantigen clonality improves accuracy[2][5][8].
Conflicting Evidence:
- Radiotherapy: High TMB may indicate poor prognosis in cervical cancer, contrasting with ICI benefits[4].
Future Directions
- Standardization: Harmonizing TMB calculation across platforms[7].
- Liquid Biopsies: Validating bTMB for non-invasive monitoring[3][8].
- Comprehensive Genomic Profiling (CGP): Capturing TMB, MSI, and actionable mutations in one assay[8].
Conclusion
TMB is a dynamic biomarker guiding immunotherapy decisions but requires context-specific interpretation. While TMB-High tumors often respond better to ICIs, its prognostic value varies by treatment modality and cancer type. Standardization and multimodal biomarker integration are critical for optimizing clinical utility.
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