What is NTRK?


NTRK refers to a family of genes—NTRK1, NTRK2, and NTRK3—that provide instructions for making proteins called Trk-A, Trk-B, and Trk-C. These proteins are located on the cell surface and play a crucial role in regulating essential processes, such as cell growth and survival. In early development, they help nerve cells grow and form connections. In adults, they continue to play a role in the nervous system, particularly in learning and memory.

Why is NTRK important in cancer?

In some cancers, a portion of the NTRK gene becomes fused to another gene. This abnormal fusion causes the NTRK protein to stay turned on all the time, leading to uncontrolled cell growth and cancer. These abnormal fusions are known as NTRK gene fusions, and they can act as “driver mutations”—genetic changes that fuel tumor development.

Detecting an NTRK fusion is important because patients with these tumors may benefit from special targeted treatments called TRK inhibitors, such as larotrectinib and entrectinib.

What types of tumors have NTRK fusions?

NTRK fusions are rare but can be found in both adult and pediatric tumors. They are especially common in certain tumor types:

  • Infantile fibrosarcoma – A soft tissue tumor that usually affects infants and young children. Most cases contain an ETV6::NTRK3 gene fusion and respond well to TRK inhibitors.
  • Secretory carcinoma of the breast and salivary glands – These tumors often have a similar genetic change (ETV6::NTRK3) and are typically low-grade, slow-growing cancers.
  • Congenital mesoblastic nephroma (cellular and mixed types) – A kidney tumor found in infants. NTRK fusions, particularly those involving NTRK3, are common in various cellular types.
  • Lipofibromatosis-like neural tumor – A rare pediatric soft tissue tumor that may resemble benign growths but has a characteristic NTRK1 fusion.
  • Uterine sarcomas with fibrosarcoma-like features – A rare group of uterine tumors that show NTRK fusions, most commonly involving NTRK1 or NTRK3.
  • Pediatric gliomas and thyroid cancers – NTRK fusions are more common in children than adults in these tumor types.
  • Other tumors – Although rare, some adult tumors may also harbor NTRK fusions. These include:

In general, NTRK fusions are more frequent in pediatric tumors and rare in common adult cancers. When found, they offer a chance for effective targeted treatment.

How do pathologists test for NTRK fusions?

Pathologists use several types of tests to look for NTRK fusions. The most common test is immunohistochemistry (IHC), which uses a pan-TRK antibody to detect the presence of Trk proteins in tumor cells. If the test is positive, the cells will show staining in the cytoplasm or nucleus, depending on the type of fusion. For example, tumors with NTRK1 or NTRK2 fusions typically show cytoplasmic staining, while NTRK3 fusions may show cytoplasmic or nuclear staining. This test is often used as a screening tool.

If the IHC test is positive or suspicious, a second test is usually done to confirm the result. This is often next-generation sequencing (NGS), which looks for the actual gene fusion at the DNA or RNA level. This test is more precise and can identify the specific genes involved in the fusion.

In some cases, fluorescence in situ hybridization (FISH) may be used to detect gene rearrangements involving NTRK genes. This method uses fluorescent probes to highlight gene abnormalities under a microscope.

Together, these tests help confirm whether a tumor contains an NTRK fusion, which is crucial for diagnosis and determining whether the patient may benefit from targeted treatment.

Why is NTRK important in a pathology report?

If your pathology report mentions NTRK, it means your doctor and pathologist are looking for an important genetic change that could affect treatment. Tumors with NTRK fusions may respond well to targeted TRK inhibitor therapy, even if the tumor is rare or advanced. Identifying this change can help guide treatment and improve outcomes.

Questions to ask your doctor

  • Was my tumor tested for NTRK fusions?
  • What were the results of the immunohistochemistry or genetic testing?
  • Could I benefit from treatment with a TRK inhibitor, such as larotrectinib or entrectinib?
  • Will additional genetic testing be done to confirm the results?
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