Tumor Mutational Burden Biomarker

Tumor mutational burden (TMB) is a measure of the mutation burden (or the number of genomic changes or mutations) present in cancer cells.

Cancers with a high number of mutations have a high mutational burden (TMB-High). Many of these cancers are also MSI-H/dMMR. A very small percentage (less than 10%) of cancers that are TMB-High are MSS. Cancer cells with very few mutations have a low mutational burden (TMB-Low).

TMB is considered a predictive biomarker in colorectal cancer and is used to predict how a cancer may respond to immune checkpoint inhibitors. It is also a prognostic biomarker and can be used to estimate the expected prognosis.

TMB is measured in patients with metastatic colorectal cancer using a primary or metastatic tumor biopsy. Alternatively, TMB status may be tested if your tumor is MSS to determine whether immunotherapy may be effective.

Currently the only test for TMB is a multigene, comprehensive biomarker panel using next generation sequencing (NGS). However, research is ongoing to assess the use of ctDNA in measuring TMB.

The best way to ensure you have been tested for TMB is to ask your medical care provider.

A report for TMB will be reported as high or low TMB. Less often, TMB may also be reported as intermediate.

Additionally, TMB may be reported as a number. This number represents the number of mutations per megabase of DNA (mut/Mb). A megabase is a measurement of the length of DNA.

Cutoffs for high and low TMB may vary by location. Generally, TMB is described as follows:

• TMB-Low: tumors with less than 10 mutations per megabase of DNA
• TMB-Intermediate: tumors with 10-20 mutations per megabase of DNA (in some cases, these may be combined with TMB-High)
• TMB-High: tumors with greater than 20 mutations per megabase of DNA

If you are TMB-Low, your tumor has a low mutational burden.

• Your treatment decisions may be guided by other biomarker testing results.
• Patients with TMB-Low tumors may not respond to immunotherapies unless they are MSI-H/dMMR.

If you are TMB-High, your tumor has a high mutational burden.

• Patients with TMB-High tumors often respond better to immune checkpoint inhibitors, regardless of MSI-H or MSS status.

Pembrolizumab, nivolumab, and ipilimumab are immune checkpoint inhibitors that are FDA-approved to treat colorectal cancer patients with MSI-H/dMMR. Pembrolizumab is also approved for use in patients with TMB-High and MSS colorectal cancer.

Treatments targeting TMB-High colorectal cancers are being tested in clinical trials. Talk to your medical team to determine if you may benefit from a clinical trial.

Check out Fight CRC’s Clinical Trial Finder to search for trials, and read our Clinical Trials Conversations blog for more insights.