What is NTRK fusion?

NTRK fusion is a type of genetic change (mutation) involving the NTRK1, NTRK2, or NTRK3 genes that encode the TRK A, TRK B, and TRK C proteins. NTRK is also known as neurotrophic tyrosine receptor kinase or neurotrophic tropomyosin receptor kinase.

When a piece of a chromosome (the cell structure that carries genes) containing an NTRK gene breaks off and attaches to a gene on another chromosome, this is called an NTRK gene fusion. It is a combination of the NTRK gene and a fusion partner gene.

Genes give the instructions for your cells to make proteins, and when NTRK gene fusion occurs, your cells will make abnormal proteins called TRK fusion proteins. TRK fusion proteins are a combination of a TRK protein and a partner gene protein. Fusion proteins can lead to abnormal cell growth and survival, causing cancer. Genes, like NTRK, that can cause normal cells to become cancer cells are called oncogenes. Oncogene mutations that cause cancer are called oncogenic drivers.

NTRK gene fusion plays an oncogenic driver role in several solid tumor types, including colorectal cancer, sarcoma, papillary thyroid cancer, breast cancer, glioma brain tumors, and non-small cell lung cancer.  

NTRK fusion is rare in colorectal cancer (bowel cancer) overall. Fewer than 1% of CRCs have NTRK fusion. However, in patients whose cancers have microsatellite instability (MSI-High) and wild-type (non-mutant) KRAS, wild-type NRAS, and wild-type BRAF, the prevalence of NTRK fusion can be much higher, ranging from 5-44%. NTRK gene fusions are not hereditary.  

How is NTRK fusion tested?

NTRK fusion is tested with a biopsy sample of your tumor (tumour). There are several laboratory methods for detection of NTRK fusion and they may be combined to get more accurate and useful information. The methods include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), reverse transcriptase-polymerase chain reaction (RT-PCR), and next-generation sequencing (NGS) of DNA and/or RNA.

What do my NTRK fusion testing results mean?

Your NTRK fusion testing result will be reported as “no fusion detected” or as “fusion detected”. If an NTRK fusion is detected, the report will include the specific partner gene that is fused with NTRK, and the specific NTRK gene name, such as “TPM3-NTRK1 fusion detected” or “ETV6-NTRK3 fusion detected”.

How does my NTRK fusion status impact my treatment?

If your colorectal cancer does not have an NTRK fusion

• Your treatment options include conventional chemotherapy, targeted therapy, and immunotherapy as indicated by the results of your other biomarker testing, such as RAS mutation status or microsatellite instability. 

If your colorectal cancer has an NTRK gene fusion

• You may benefit from NTRK targeted therapy.
• NTRK fusion positive cancers are treated with inhibition of TRK fusion proteins.
• The TRK inhibitors used in colorectal cancer patients are larotrectinib (Vitrakvi) and entrectinib (Rozlytrek).
• There are ongoing clinical trials for treatments that are more effective against colorectal cancers with NTRK gene fusion. Talk to your oncology team about whether you could benefit from a clinical trial.

Who should be tested for NTRK fusion?

If you have stage IV / metastatic colorectal cancer (mCRC), and you do not have a mutation in KRAS, NRAS, and BRAF, and you are experiencing cancer progression while on chemotherapy, you should be tested for NTRK gene fusion.  

If your stage IV / metastatic colorectal cancer has microsatellite instability (MSI-High, also known as dMMR), talk to your oncology team about whether NTRK fusion testing could benefit you.