TRK Fusions Biomarker

NTRK genes (NTRK1/2/3) are responsible for tropomyosin receptor kinase proteins (TRKA/B/C). Normally, these proteins are found on the surface of cells in the nervous system and their expression is highly regulated. In some cases, one of the NTRK genes can become fused (or connected) to another unrelated gene, most commonly ETV6, LMNA, or TPM3. When these genes become fused, they result in the production of a new TRK fusion protein that is unregulated and expressed in cells outside of the nervous system. This fusion protein can result in uncontrolled cell growth and division, which may lead to cancer.  

The NTRK gene fusion, and the resulting fusion protein, are considered a biomarker in colorectal cancer. 

NTRK fusions are very rare in colorectal cancer, with less than 1% of colorectal cancers having a NTRK fusion. Therefore, testing for this biomarker is not generally recommended by guidelines.  

However, there are some cases in which testing for this biomarker may be recommended. NTRK fusion testing is most often limited to patients with metastatic colorectal cancer that is wild type (no mutations) in KRAS, BRAF, NRAS with cancer progression following chemotherapy. Alternatively, NTRK fusion testing may also be recommended for patients with metastatic colorectal cancer that is MSI-H/dMMR. Generally, next generation sequencing (NGS) is the preferred method for detecting NTRK fusions, as it allows for characterization of its fusion partner.

A report for your tumor’s NTRK fusion biomarker may be reported as “no fusion detected” if there was no NTRK fusion or “fusion detected” if there was a NTRK fusion present. If there is a NTRK gene fusion present, the report will often list the specific NTRK gene (e.g. NTRK1, NTRK2, NTRK3) and the other gene involved in the fusion (e.g. ETV6, LMNA, TPM3). For example, if you have a NTRK1 gene fusion with ETV6, your report may read something like “ETV6-NTRK1fusion detected.” 

NTRK fusions occur in less than 1% of colorectal cancers, meaning over 99% of colorectal cancers will not have a NTRK fusion. NTRK fusions are not hereditary. 

If your tumor has a NTRK fusion, your tumor’s NTRK gene is fused to an unrelated gene, leading to the production of a TRK fusion protein.  

• Patients with a NTRK fusion in their tumor may benefit from a TRK inhibitor. These therapies work by turning off the TRK fusion protein and blocking (or inhibiting) its downstream signals to stop or slow cancer cell growth and division.   

If your tumor does not have an NTRK fusion, there are several treatment options, including chemotherapy, targeted therapy, and/or immunotherapy. The status of your other biomarkers can help inform treatment decisions. 

There are currently two FDA-approved treatments for patients with metastatic CRC with an NTRK fusion: larotrectinib and entrectinib. These two treatments work by targeting TRK fusion proteins (produced from NTRK fusion genes) to turn off (inhibit) the fusion protein and its downstream signals to slow or stop cancer growth.  

The most effective treatment varies by individual. It is best to speak with your medical team to learn more about the best treatment options for you.

Drugs targeting TRK fusion proteins 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 insights.