What is the tumor mutational burden (TMB) biomarker?

TMB is a measurement of how many genetic changes (mutations) are found in the genome of your tumor cells in a specific amount of DNA (a megabase). These non-inherited mutations can be in any genes present in your tumor cells. TMB is sometimes called tumor mutational load.

Tumor mutational burden is a useful biomarker in several solid tumor cancer types, including colorectal cancer, melanoma, and non-small cell lung cancer (NSCLC).  

Cancer research suggests that an increased TMB is associated with increased production of abnormal tumor proteins. Specialized white blood cells of the immune system (T-cells) are then able to recognize these new and abnormal proteins (neoantigens). T-cells then kill the tumor cells that express neoantigens. Tumor cells that do not express abnormal proteins may not be recognized or killed by T-cells.

Tumor mutational burden is both a prognostic and a predictive biomarker. It gives information about the normal course and expected outcome of the disease (prognosis). And TMB is a predictor of whether a cancer will respond to a particular treatment, such as immunotherapy.

How is tumor mutational burden tested?

TMB is tested in a biopsy sample of your tumor (tumour) using NGS (next-generation sequencing). It can be tested in primary tumor cells or metastatic tumor cells, although metastatic tumor may have a higher TMB than the primary colorectal tumor. There are ongoing studies using blood samples to test tumor mutational burden by analyzing circulating tumor DNA (ctDNA), which is DNA released by tumor cells into the blood. This method is not used outside the cancer research setting right now, but may be in the near future.

TMB is sometimes measured in a targeted gene panel while profiling other genetic mutation biomarkers. Tumor mutational burden is also tested with whole exome sequencing, which is genetic analysis of only the parts of the tumor DNA that encode proteins, or with whole genome sequencing, which is analysis of all parts of the tumor DNA.

What do my TMB results mean?

Your TMB biomarker results will be reported as TMB-Low / Low TMB or TMB-High / High TMB. Some cancer centers and laboratories also include a category called TMB-Intermediate / Intermediate TMB.  

The result may also be reported as the number of mutations per megabase (mut/Mb) of tumor DNA. The cut-off numbers defining low TMB, intermediate TMB, and high TMB are different for different tumor types. Even in colorectal cancer, these cut-offs may vary by cancer center or laboratory. For colorectal cancer, TMB-Low usually describes tumors with fewer than 10 mutations per megabase (mut/Mb) of tumor DNA. TMB-Intermediate colorectal cancers usually have 10-20 mutations per megabase (mut/Mb) of tumor DNA. And TMB-High colorectal tumors usually have more than 20 mutations per megabase (mut/Mb) of tumor DNA. Sometimes, TMB-Intermediate and TMB-High categories are combined within TMB-High. These tumors have more than 10 mut/Mb of tumor DNA.  

How does my tumor mutational burden impact my treatment?

If your cancer has low tumor mutational burden

• Your treatment will be guided by other biomarker testing and clinical response.
• Immunotherapy may not work against TMB-Low colorectal cancers unless they also have microsatellite instability (MSI), which is also known as deficient mismatch repair (dMMR).  

If your cancer has intermediate tumor mutational burden, your treatment will be similar to the treatment of colorectal cancer with high TMB.

If your colorectal cancer has high tumor mutational burden

• You may benefit from immunotherapy, even if your colorectal cancer is microsatellite stable.
• Immunotherapy with immune checkpoint inhibitors, such as pembrolizumab (Keytruda), nivolumab (Opdivo), and ipilimumab (Yervoy), may be effective against colorectal cancers with TMB-High even if they have MSS (microsatellite stability).
• Cancer immunotherapy uses your own immune system to kill tumor cells by promoting stronger responses against cancer cells from white blood cells in your tumor (tumor-infiltrating lymphocytes).  
• In colorectal cancers with microsatellite instability (MSI), TMB-High is associated with a better response rate to immunotherapy.
• In colorectal cancers with MSS, TMB-High is associated with better overall survival.
• There are ongoing clinical trials for treatments targeting colorectal cancers with high TMB. Talk to your oncology team about whether you could benefit from a clinical trial.  

Who should be tested for TMB?

Guidelines for the testing of tumor mutational burden in colorectal cancer (bowel cancer) vary around the world. Talk to your oncologist and healthcare team about whether TMB testing could benefit you.  

If your tumor has microsatellite stability (MSS) you should have TMB testing to find out if you could be a candidate for immunotherapy.