Tumor Mutation Burden (TMB) is a genomic indicator in oncology, defined as the total count of genetic changes, or somatic mutations, found within the DNA of a tumor cell. This measurement helps clinicians anticipate how a patient’s cancer may behave and respond to certain treatments. Tumors are typically classified as TMB-High or TMB-Low (TMB-L), with TMB-L signifying a relatively low number of these genetic alterations.
Defining Tumor Mutation Burden and Measurement
TMB quantifies the frequency of somatic mutations accumulated in the tumor’s genetic code. The overall mutational burden provides insight into the genome’s stability and the cell’s ability to repair DNA damage. This measurement is standardized and reported using the unit mutations per megabase (mut/Mb).
The measurement process involves obtaining a tumor tissue sample, usually through a biopsy, which is then analyzed using advanced sequencing technology. Clinically, this is most often done using large panel-based sequencing, which examines hundreds of genes, rather than whole-exome sequencing (WES). Because different assays analyze different portions of the genome, the resulting TMB value can vary depending on the specific test used.
TMB results are generally grouped into low, intermediate, or high categories to guide clinical decision-making. A tumor is classified as TMB-Low when the measured rate falls below a specific threshold. TMB-Low status is frequently defined as having fewer than 10 mutations per megabase, though the ideal cutoff can vary by cancer type and the assay utilized.
The Clinical Significance of Low TMB Status
The primary consequence of TMB-Low status relates directly to the expected effectiveness of immune checkpoint inhibitors (ICIs). TMB-L tumors are associated with a reduced chance of responding positively to these immunotherapies. Studies show that patients with TMB-Low tumors experience limited clinical benefit, such as shorter progression-free survival, when treated with single-agent ICIs compared to those with high TMB.
A TMB-Low result prompts the medical team to avoid immediately pursuing immunotherapy as the first or sole treatment option. For example, in trials involving non-small cell lung cancer, patients with TMB-Low disease showed similar outcomes whether they received immunotherapy or traditional chemotherapy. This finding helps prevent unnecessary exposure to the side effects and costs associated with a treatment that has a low probability of success.
The U.S. Food and Drug Administration (FDA) has granted tumor-agnostic approval for an ICI in tumors that meet a TMB-High threshold of 10 mutations per megabase. The TMB-Low classification represents the inverse of this approval, indicating the patient is unlikely to benefit from this specific treatment approach. Clinicians instead pivot to a stronger consideration of established treatments or molecularly guided therapies.
Biological Basis for Immunotherapy Resistance
The strong link between a low mutation rate and poor immunotherapy response is explained by the tumor’s visibility to the immune system. Genetic changes within cancer cells result in the production of abnormal proteins known as neoantigens. These unique proteins are processed and presented on the cell surface via major histocompatibility complex (MHC) molecules. Neoantigens act like foreign flags, allowing the immune system’s T-cells to recognize the tumor and mount an attack.
A TMB-Low tumor inherently possesses a reduced number of genetic errors, resulting in the generation of very few neoantigens. With fewer foreign flags displayed, the tumor is poorly recognized by the immune system, leading it to be characterized as immunologically “cold.” Immune checkpoint inhibitors function by removing the inhibitory signals from T-cells, allowing them to attack the cancer aggressively. However, if the T-cells cannot effectively detect the tumor, removing the brakes offers little therapeutic advantage.
Not every mutation results in a functional neoantigen that the immune system can recognize. The quality of the mutation matters as much as the quantity, as the protein must be properly processed and presented to the T-cells. TMB-Low tumors often lack the overall mutational load necessary to generate high-quality, recognizable neoantigens. This contrasts sharply with TMB-High tumors, which are generally “hot” due to their high neoantigen load, attracting a robust anti-tumor T-cell presence.
Treatment Approaches for TMB-Low Cancers
Since single-agent immune checkpoint blockade is frequently ineffective for TMB-Low cancers, treatment strategies focus on proven alternatives and innovative combinations. Traditional approaches remain the standard foundation of care, including cytotoxic chemotherapy, which directly kills rapidly dividing cancer cells. Radiation therapy, which uses targeted energy beams to destroy the tumor, is also a highly utilized method for localized disease. Surgical resection continues to be a primary method for achieving curative outcomes in TMB-L tumors when possible.
Targeted therapy is a preferred alternative when specific, actionable genetic drivers are identified through genomic testing. These treatments involve drugs designed to block particular proteins or pathways that fuel cancer growth, such as inhibitors for EGFR, ALK, or BRAF mutations. This molecularly guided approach offers a personalized strategy independent of the overall mutation burden.
Researchers are also actively investigating combination regimens to overcome the resistance seen in TMB-L tumors. These strategies aim to transform an immunologically “cold” tumor into a “hot” one by inducing T-cell infiltration. Combining ICIs with chemotherapy or specific targeted agents can cause cancer cell death, which releases tumor antigens and inflammatory signals. This potentially makes the tumor visible to the immune system and increases the likelihood of a response to the checkpoint blockade.