Tumor Mutational Burden (TMB) is a characteristic of cancerous tissue that reflects the number of genetic changes within a tumor’s DNA. Understanding TMB helps guide treatment approaches by indicating how likely a tumor is to respond to certain therapies.
Defining Tumor Mutational Burden
TMB quantifies the total number of somatic mutations found in the DNA of cancer cells. Somatic mutations are genetic alterations that occur after conception, meaning they are not inherited. These mutations are typically measured as the number of mutations per megabase (Mb) of DNA, where one megabase equals one million DNA base pairs.
A higher TMB, indicating more genetic changes, can lead to the formation of abnormal proteins called neoantigens. Neoantigens are unique to cancer cells and are not found in healthy cells.
The presence of neoantigens can make the tumor more “visible” to the body’s immune system, allowing T-cells to recognize and attack cancer cells. This recognition and subsequent immune response form the basis of TMB’s role in cancer treatment.
How TMB is Assessed
TMB is primarily assessed using next-generation sequencing (NGS) technologies. This involves analyzing DNA extracted from tumor tissue. NGS allows for the detection of numerous somatic mutations across the tumor’s genome.
Two main approaches within NGS are used for TMB assessment: whole exome sequencing (WES) and targeted gene panels. WES analyzes the entire exome, which represents the protein-coding regions of the genome. While WES is considered a comprehensive method, it can be time-consuming and costly for routine clinical use.
Targeted gene panels, which analyze a specific set of genes, offer a more practical alternative for clinical settings. These panels vary in size, but are designed for accurate TMB assessment. The results from these tests are typically reported as either “low” or “high” TMB.
TMB as a Predictive Biomarker
TMB is particularly relevant in predicting a patient’s likely response to immune checkpoint inhibitors (ICIs). ICIs are a type of immunotherapy that helps the body’s immune system recognize and fight cancer cells.
The rationale behind TMB’s predictive power is linked to neoantigens. Tumors with a higher TMB tend to have more neoantigens, potentially making them more easily recognized by the immune system. This increased visibility can lead to a more robust immune response when ICIs are administered, thereby improving the chances of treatment success.
TMB assessment is relevant in various cancer types, including melanoma, non-small cell lung cancer (NSCLC), and tumors with microsatellite instability-high (MSI-H). Studies have shown that patients with higher TMB often experience longer survival and better response rates when treated with ICIs. Specific TMB thresholds have been identified in some studies for predicting benefit from immunotherapy.
Considerations for TMB Testing
Several factors influence TMB testing and its interpretation. TMB values can vary significantly across different tumor types, and the optimal “TMB-high” cutoff can differ between cancer types and even between studies. For instance, specific cutoffs like 10 mutations/Mb in lung cancer or 20 mutations/Mb in other cancers illustrate this variability.
Ongoing efforts aim to standardize TMB measurement across different testing platforms and bioinformatics pipelines to ensure consistency and reliability. TMB is often considered in conjunction with other biomarkers, such as PD-L1 expression, rather than as a standalone predictor. While TMB and PD-L1 can both predict ICI response, they often act independently, meaning a tumor can have high TMB but low PD-L1 expression, or vice versa.
Factors like the quality of the tumor sample and the specific assay used can also influence the TMB result. Continuous research is underway to refine TMB assessment and better integrate it with other diagnostic tools to optimize treatment decisions for cancer patients.