NTRK Gene Fusion Overexpression

NTRK gene fusions represent a rare but critical genetic change that can drive cancer development across many different types of tumors, affecting both adults and children.

Table of contents

• What is NTRK gene fusion?
• How NTRK gene fusions occur
• How common are NTRK gene fusions?
• Cancer types affected
• Effects on tumor behavior
• Testing for NTRK gene fusions
• Treatment options

What is NTRK gene fusion?

The NTRK gene family includes three genes called NTRK1, NTRK2, and NTRK3. These genes produce proteins known as TRK proteins (TRKA, TRKB, and TRKC), which are normally found in nerve tissue and play important roles in the development and proper functioning of the nervous system.^[1][10]

An NTRK gene fusion is a type of genetic change where a piece of a chromosome containing an NTRK gene breaks off and connects to a different gene on another chromosome. This creates a new, abnormal hybrid gene that produces unusual proteins called TRK fusion proteins.^[5][10]

Unlike normal TRK proteins that only work when activated by specific signals, these fusion proteins are constantly active without needing any external trigger. This ongoing activity can cause cells to grow and multiply uncontrollably, leading to cancer.^[2]

How NTRK gene fusions occur

NTRK gene fusions happen through chromosomal changes including inversions (when a section of chromosome flips around), deletions (when part of a chromosome is lost), or translocations (when pieces of chromosomes swap places). These events bring together the portion of an NTRK gene that contains the active working part (called the kinase domain) with a portion of a completely different, unrelated gene.^[2]

The result is a chimeric or fusion protein that combines parts from both genes. The partner gene typically provides signals that keep the protein constantly turned on, while the NTRK portion sends continuous growth signals to the cell. This combination creates a powerful driver of cancer development.^[8]

These fusions work as independent cancer drivers. This means they typically do not occur together with other common cancer-causing mutations – they work alone to promote tumor growth.^[2]

How common are NTRK gene fusions?

NTRK gene fusions are quite rare in most cancers. Studies show they occur in fewer than 1% of solid tumors overall. In specific cancer types like non-small cell lung cancer and colorectal cancer, they appear in only about 0.1% to 0.2% of cases.^[1][5]

However, these fusions are much more common in certain rare tumor types. In some cancers, they are found in more than 90% of cases, making them a defining feature of these diseases. Examples include infantile fibrosarcoma, secretory breast carcinoma, and mammary analog secretory carcinoma of the salivary gland.^[8][12]

In colorectal cancers that show microsatellite instability (a specific genetic pattern abbreviated as MSI-High) and lack mutations in other common cancer genes like KRAS, NRAS, and BRAF, NTRK fusions can be found in 5% to 44% of cases.^[5]

Each year, approximately 5,000 patients receive a diagnosis of NTRK fusion-positive cancer.^[12]

Cancer types affected

NTRK fusions have been identified across a wide range of cancer types affecting both adults and children. They can occur in many solid tumor types throughout the body.^[1][8]

Common cancers where NTRK fusions occasionally appear include:

• Non-small cell lung cancer
• Colorectal cancer
• Breast cancer
• Pancreatic cancer
• Ovarian cancer
• Thyroid cancer (especially papillary thyroid cancer)
• Sarcomas (cancers of connective tissue)
• Brain tumors (gliomas)

Rare cancers where NTRK fusions are highly enriched or defining include:

• Infantile fibrosarcoma (more than 80% of cases)
• Secretory breast carcinoma (more than 90% of cases)
• Mammary analog secretory carcinoma of the salivary gland (more than 90% of cases)
• Congenital mesoblastic nephroma

Among the three NTRK genes, fusions involving NTRK1 and NTRK3 are more commonly found in cancers than NTRK2 fusions.^[2]

Effects on tumor behavior

Recent studies suggest that NTRK fusion-positive tumors may show increased ability to spread and invade surrounding tissues. Research has found an association between NTRK fusions and enhanced tumor migration and invasion capabilities in clinical settings.^[2]

This increased aggressiveness appears to be related to a process called epithelial-mesenchymal transition (EMT). This is a biological process where cells lose their normal connections to neighboring cells and gain the ability to move and spread more easily. Studies have shown that genes co-expressed with NTRKs, such as ECM1 and NOVA1, demonstrate significant association with EMT pathway activity.^[2]

These genes are often overexpressed in various cancers and are associated with more advanced clinical stages and increased tumor aggressiveness. However, the exact relationships between these genes and NTRK fusions, and how they work together to promote cancer spread, still require further research.^[2]

Testing for NTRK gene fusions

Testing for NTRK gene fusions is performed on a sample of tumor tissue obtained through a biopsy. Several laboratory methods can be used to detect these fusions, and they may be combined to provide more accurate and useful information.^[3][5]

Available testing methods include:

• Immunohistochemistry (IHC): Uses antibodies to detect TRK proteins in tissue samples
• Fluorescence in situ hybridization (FISH): Uses fluorescent markers to identify gene rearrangements
• Reverse transcriptase-polymerase chain reaction (RT-PCR): Detects specific fusion products
• Next-generation sequencing (NGS): Analyzes DNA and/or RNA to identify fusions and their specific partner genes

Next-generation sequencing is considered the most reliable method because it can detect fusion events, point mutations, and splicing variants involving NTRK1, NTRK2, and NTRK3 genes. It can also identify multiple genes at once and reveal the specific partner gene involved in the fusion.^[3][5]

Testing results will be reported as either “no fusion detected” or “fusion detected.” If a fusion is found, the report will specify which NTRK gene is involved and which partner gene it has fused with, such as “TPM3-NTRK1 fusion detected” or “ETV6-NTRK3 fusion detected.”^[5]

Some newer approaches also allow testing using blood samples through circulating tumor DNA (ctDNA) analysis, though tissue-based testing remains the standard approach.^[4]

Treatment options

The identification of NTRK fusions has led to the development of targeted drugs called TRK inhibitors. These medications specifically block the abnormal TRK fusion proteins, stopping their cancer-promoting signals.^[1]

Two first-generation TRK inhibitors have been approved by the U.S. Food and Drug Administration for treating NTRK fusion-positive cancers, regardless of where the tumor is located in the body:

• Larotrectinib (Vitrakvi)
• Entrectinib

These approvals were historic because they were based on the genetic characteristics of tumors (the presence of NTRK fusions) rather than the specific cancer type or location in the body. This approach is called tumor-agnostic or histology-agnostic treatment.^[3][8]

Clinical trials have shown that these TRK inhibitors produce high response rates, with more than 75% of patients responding to treatment across various cancer types. These responses are often durable, meaning they last for extended periods. The drugs are also generally well tolerated, with most patients experiencing manageable side effects.^[8][11]

Laboratory and clinical studies have demonstrated that TRK inhibitors can significantly reduce the migration and invasion capabilities of NTRK fusion-positive tumor cells.^[2]

Common side effects are typically mild and may include body aches, nausea, and neuropathy (nerve-related symptoms). Many patients can remain on treatment long-term as long as it continues to control their cancer.^[4][12]

Over time, some cancers may develop resistance to first-generation TRK inhibitors. This resistance is often caused by new mutations that develop in the NTRK kinase domain. To address this, second-generation TRK inhibitors such as LOXO-195 (also known as larotrectinib) and TPX-0005 are being studied in clinical trials. These newer drugs are designed to overcome resistance mutations.^[8]

The success of TRK inhibitor therapy highlights the critical importance of comprehensive molecular profiling for patients with metastatic cancers. Identifying an NTRK fusion can dramatically change treatment options and outcomes for patients who might otherwise have limited therapeutic choices.^[4]