Tumor Mutational Burden (TMB) quantifies the number of genetic changes, or mutations, found within a tumor’s DNA. This measurement is important in personalized cancer care, particularly for identifying potential responses to certain therapies.
What is Tumor Mutational Burden?
Tumor Mutational Burden (TMB) represents the total number of non-inherited genetic mutations present per megabase (Mb) of DNA in a tumor. These mutations are somatic, meaning they arise in body cells after conception rather than being inherited from parents.
As cancer cells divide and grow uncontrollably, they accumulate mutations at a higher rate than healthy cells, leading to a quantifiable number of changes in the tumor’s DNA. A higher number of these somatic mutations increases the likelihood that the tumor will produce abnormal proteins, known as neoantigens. These neoantigens are unique to the tumor and are not found in normal cells.
When neoantigens are present on the surface of tumor cells, the immune system, specifically T-cells, may recognize them as foreign. This recognition can trigger an immune response aimed at destroying the cancer cells. A higher TMB suggests a greater potential for the immune system to identify and target the tumor due to the increased production of these distinct neoantigens.
How TMB is Measured
Measuring Tumor Mutational Burden involves analyzing a sample of the tumor’s DNA, primarily using Next-Generation Sequencing (NGS). This process can utilize DNA extracted from a tumor tissue sample. In some cases, a blood sample can be used for a “liquid biopsy,” analyzing circulating tumor DNA (ctDNA) released from cancer cells into the bloodstream.
The measurement process begins with DNA extraction from the tumor or blood sample. This DNA then undergoes sequencing to read its genetic code. Specialized bioinformatics analysis identifies and counts the total number of mutations within a defined genomic region. The result is reported as mutations per megabase (mut/Mb) of DNA; targeted gene panels are commonly used for TMB assessment in clinical practice.
TMB’s Role in Cancer Treatment
TMB has emerged as a biomarker for predicting how a patient might respond to certain cancer treatments, particularly immune checkpoint inhibitors (ICIs). These therapies work by unleashing the body’s own immune system to fight cancer. The underlying idea is that tumors with a higher TMB produce more neoantigens, making the cancer cells more “visible” and recognizable to the immune system. This increased visibility can lead to a more robust anti-tumor immune response when checkpoint inhibitors remove the “brakes” on immune cells.
Clinical studies have shown that a higher TMB is associated with an improved likelihood of responding to immunotherapy and, in some cases, better survival rates. This utility has been observed in several cancer types, including non-small cell lung cancer, melanoma, and microsatellite instability-high (MSI-H) colorectal cancer. The U.S. FDA has approved the use of TMB as a biomarker to help guide treatment decisions for certain immunotherapies across various solid tumors. For instance, a TMB value of 10 mutations per megabase (mut/Mb) or greater is often considered a threshold for potential benefit from immunotherapy in many cancers.
Understanding Your TMB Results
TMB results are categorized as “high TMB” or “low TMB,” indicating the number of mutations found in the tumor’s DNA. A high TMB suggests a greater chance that the tumor will respond positively to immune checkpoint inhibitor therapies, as it implies more neoantigens are available for immune recognition. Conversely, a low TMB might indicate a reduced likelihood of benefiting from these specific immunotherapies, as fewer mutations mean fewer potential neoantigens for the immune system to target.
TMB is one piece of information oncologists consider when developing a treatment plan. Results are interpreted alongside other factors, including the specific cancer type and stage, other biomarkers, and the patient’s overall health. While TMB is a useful predictor, ongoing research continues to refine its application and understanding. Ultimately, TMB helps guide personalized treatment decisions, aiming to select the most appropriate therapy for each individual patient.