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Tumor Mutational Burden (TMB)

Tumor Mutational Burden (TMB)

Tumor mutational burden (TMB) refers to the number of gene mutations found in a patient’s cancer cells. Why is this number important? Cancers with high TMB are more likely to respond to treatment types such as immunotherapy or targeted therapies. However, tumors with low TMB are less likely to respond to these treatment types. Doctors and researchers use TMB as an individual type of biomarker.

Mutations in tumors count towards the TMB when they alter the protein that is made from a gene. Each mutation results in a protein, which is an antigen that can be recognized by the immune system to attack the tumor cells. The more antigens that are produced, the more likely it is that the immune system will recognize them as foreign. Therefore, treatments that activate the immune system such as immunotherapies are effective when treating tumors with a high TMB.

Treating High TMB Cancers

Treatment for tumors with high mutational burden depends on multiple factors like the cancer type, patient’s overall health, and the exact score for TMB. Last year in 2020, the FDA approved the first drug for the treatment of cancer with high TMB. Pembrolizumab (Keytruda) is an immune checkpoint inhibitor that helps the immune system recognize the cancer cells and attack them. Not all cancer patients with high TMB will see results from immunotherapies such as Keytruda. Standard treatments such as chemotherapy or radiation therapy are always available for patients with low or high TMB. However, those with rare cancer types may have limited options for alternative therapies or clinical trials. Other immune checkpoint inhibitors are being evaluated by the FDA in clinical trials to treat cancers with high TMB tumors.

Testing for TMB

To determine a tumor’s mutational burden there are two options. Next Generation Sequencing (NGS), which analyzes someone’s entire genomic makeup, or a test on a smaller gene panel will be performed to analyze the tumor cells. These tests involve taking a sample of the tumor tissue and sending it to a laboratory to analyze it under a microscope. Then, it is determined how many mutations are found in the sample per megabase. A megabase is a unit of length for DNA fragments. 1 megabase is roughly 1 million nucleotides, or 1 centimorgan. The following are the potential results for the test:

  • Low: Less than or equal to 5 mutations per megabase 
  • Intermediate: Between 5 and 20 mutations per megabase 
  • High: Between 20 and 50 mutations per megabase 
  • Very high: More than 50 mutations per megabase 

Those with a high or very high score should strongly consider treatments targeting the mutations in their cancer. For those with low TMB, they are less likely to respond to immunotherapies and should talk with your doctor to see if standard therapies would be more beneficial for your case. Every type of cancer has the potential of a low or very high TMB. However, some cancer types have a high or low TMB more often than not. For example, lung cancer results in a high TMB more often than any other cancer type and myeloproliferative disorders (group of chronic blood disorders) often have low TMB.


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