Tumor Mutation Burden (TMB) measures the number of genetic changes found within the DNA of cancer cells. This characteristic provides insights that inform cancer research and treatment strategies. TMB serves as a biomarker to help guide personalized treatment approaches.
Understanding Tumor Mutation Burden
Cancer cells accumulate genetic mutations, which are changes in their DNA not present in healthy cells. These mutations can vary in number, creating a spectrum from low to high TMB.
These mutations can potentially create new proteins, called neoantigens, on the surface of cancer cells. Neoantigens can be recognized by the body’s immune system as foreign, potentially triggering an immune response against the tumor. A higher number of mutations generally correlates with a greater likelihood of producing more neoantigens, which may make the tumor more visible to the immune system.
Measuring Tumor Mutation Burden
Assessing TMB in a clinical setting typically involves genetic sequencing of tumor tissue. This process begins with obtaining a tissue sample, often through a biopsy, from which DNA is extracted from the cancer cells.
The extracted DNA then undergoes sequencing, commonly using Next-Generation Sequencing (NGS) technologies. While whole exome sequencing (WES) was initially the standard for TMB measurement, targeted gene panels are now widely used due to their efficiency and smaller DNA input requirements. After sequencing, computational analysis counts the number of mutations per megabase (mut/Mb) of DNA, providing the tumor’s TMB value.
Implications of Low Tumor Mutation Burden
A low TMB indicates a tumor has a relatively small number of genetic mutations. This impacts certain cancer treatments, particularly immunotherapies like checkpoint inhibitors. Tumors with low TMB generally produce fewer neoantigens.
With fewer neoantigens, the immune system may have a reduced ability to identify and attack cancer cells. Low TMB is often associated with a lower likelihood of response to immune checkpoint inhibitor therapies. While a universal cutoff for low TMB is still being refined, some studies suggest that tumors with levels of 10 mut/Mb or lower may be less successful in activating the immune system.
Alternative Approaches for Low TMB Cancers
When a tumor exhibits low TMB, treatment strategies often shift to explore other emerging options beyond standard immunotherapy. Chemotherapy and radiation therapy remain conventional and effective approaches for many cancers, regardless of TMB status. Targeted therapies are also considered if specific actionable mutations are identified within the tumor.
Participation in clinical trials offers another avenue, as researchers investigate new approaches for low TMB cancers. For instance, some research suggests that radiation therapy combined with immunotherapy might induce an anti-tumor immune response in lung cancers that typically do not respond to immunotherapy alone, including those with low mutation burden. Treatment decisions are individualized, taking into account the specific cancer type, patient health, and other molecular characteristics of the tumor.