Cancer treatment increasingly focuses on personalized medicine, moving beyond the tumor’s location to examine its unique biological characteristics. This approach requires identifying specific molecular biomarkers to guide treatment decisions. Tumor Mutational Burden (TMB) is one such biomarker, emerging as a significant predictor in the field of cancer immunotherapy. TMB provides a quantifiable measure derived from the tumor’s genetic profile, offering valuable insight into how the cancer interacts with the patient’s immune system.
Defining Tumor Mutational Burden
Tumor Mutational Burden (TMB) quantifies the total number of genetic changes, or somatic mutations, found within a tumor’s DNA. These mutations are acquired during a person’s lifetime and are not inherited. As cancer cells divide, their DNA replication machinery often makes mistakes, leading to a build-up of these alterations.
Tumors with defects in DNA repair mechanisms or those exposed to high levels of mutagens, such as tobacco smoke or ultraviolet light, acquire a high number of mutations. This high mutation rate results in a higher TMB score, making the tumor genetically distinct from surrounding healthy tissue.
Measuring TMB in the Laboratory
To determine a tumor’s TMB score, a tissue sample is analyzed using Next-Generation Sequencing (NGS). This technology sequences millions of DNA fragments from the tumor, allowing scientists to count the number of somatic mutations. The measurement can be performed on a biopsy sample from the primary tumor or a metastatic site.
The TMB result is reported as the number of mutations per megabase (mut/Mb) of DNA sequenced, providing a standardized score. The “gold standard” for TMB calculation is whole exome sequencing, which sequences all coding regions of the DNA. However, clinical practice often uses targeted NGS panels that sequence a selected set of genes, and the results are then extrapolated to estimate the total mutational burden.
TMB, Neoantigens, and the Immune System
The significance of a high TMB score is its direct link to the production of abnormal proteins called neoantigens. Each somatic mutation alters the protein structure, creating these unique, non-self peptides. A tumor with a high mutational burden generates a larger number of these protein fragments, which are displayed on the cancer cell surface.
The immune system, specifically T-cells, recognizes these neoantigens as foreign. When TMB is high, the abundance of neoantigens increases the likelihood of triggering a robust anti-tumor immune response. This heightened visibility to the immune system makes TMB a relevant biomarker, reflecting the tumor’s “immunogenic potential.”
Using TMB to Guide Treatment Decisions
The primary clinical application of the TMB score is predicting a patient’s potential response to immune checkpoint inhibitors (ICIs). ICIs are a type of immunotherapy that releases the “brakes” on the immune system, allowing T-cells to attack cancer cells. TMB-High tumors are generally more susceptible to ICIs because of their high neoantigen load and visibility to the immune system.
A high TMB score, often defined as 10 mutations per megabase (mut/Mb) or greater, is associated with a greater likelihood of clinical benefit from ICIs across many advanced solid tumors. The US Food and Drug Administration (FDA) used this threshold to approve a specific ICI therapy for any unresectable or metastatic solid tumor identified as TMB-High. This pan-cancer approval highlights TMB’s utility as a predictive biomarker, independent of the tumor’s site of origin.
The optimal cutoff for defining a “TMB-High” tumor can vary depending on the cancer type and testing platform used. Patients with TMB-High tumors typically experience longer progression-free and overall survival when treated with ICIs compared to those with TMB-Low tumors.
TMB in Context with Other Biomarkers
Tumor Mutational Burden is rarely used in isolation; it is considered alongside other molecular characteristics to create a comprehensive tumor profile. Two other important biomarkers often evaluated are PD-L1 expression and Microsatellite Instability (MSI) status.
PD-L1 is a protein on the surface of some cancer cells that helps them evade the immune system, and its presence is measured via immunohistochemistry. Microsatellite Instability results from defects in the DNA mismatch repair system, leading to a high number of short, repetitive DNA sequence errors. Tumors that are MSI-High (MSI-H) almost always have a very high TMB, making the two biomarkers closely related in cancers like colorectal cancer. Clinicians use the combination of TMB, PD-L1, and MSI to tailor treatment, especially when one marker is inconclusive.