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NTRK Fusion – Genetics, Diagnosis and Treatment

An NTRK fusion is a genetic alteration in which NTRK genes merge with other genes, creating an abnormal protein that can drive uncontrolled tumor growth.

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Things worth knowing about "NTRK Fusion"

An NTRK fusion is a genetic alteration in which NTRK genes merge with other genes, creating an abnormal protein that can drive uncontrolled tumor growth.

What is an NTRK Fusion?

An NTRK fusion (also called an NTRK gene fusion) is a specific genetic alteration found in cancer cells. It occurs when one of the three NTRK genes – NTRK1, NTRK2, or NTRK3 – abnormally joins with another unrelated gene. This produces a fusion protein that is permanently activated, stimulating uncontrolled cell growth and tumor development.

NTRK fusions can occur across a wide variety of tumor types and are considered a tumor-agnostic biomarker, meaning their therapeutic relevance is independent of where the tumor originates in the body.

Causes and Origin

NTRK fusions arise from chromosomal rearrangements in which segments of different genes become joined together. These alterations are somatic, meaning they develop during a person's lifetime in individual body cells and are generally not inherited.

NTRK1 fusions are frequently described in papillary thyroid carcinoma and colorectal cancer.
NTRK2 fusions occur in gliomas and other brain tumors, among others.
NTRK3 fusions are characteristic of secretory breast carcinoma and infantile fibrosarcoma.

Overall, NTRK fusions are rare in the general cancer population (below 1%), but can be very common in certain rare tumor types (up to 90%).

Affected Tumor Types

NTRK fusions have been detected in more than 20 different tumor types, including:

Thyroid carcinoma
Colorectal carcinoma
Non-small cell lung cancer (NSCLC)
Salivary gland carcinoma
Infantile fibrosarcoma
Secretory breast carcinoma
Gliomas and other CNS tumors
Congenital mesoblastic nephroma

Diagnosis

The presence of an NTRK fusion is detected through molecular testing of tumor tissue. The following methods are used:

Next-Generation Sequencing (NGS): Comprehensive genomic profiling that can simultaneously detect many genetic alterations – considered the gold standard for fusion detection.
Fluorescence In Situ Hybridization (FISH): Detects gene rearrangements at the chromosomal level.
Immunohistochemistry (IHC): Can be used as a screening method, as NTRK fusion proteins are often overexpressed; however, confirmation by NGS or FISH is required.
Reverse Transcriptase PCR (RT-PCR): A targeted method for detecting known fusion variants.

Early testing is important, as the presence of an NTRK fusion determines eligibility for highly effective targeted therapies.

Treatment – TRK Inhibitors

The discovery of NTRK fusions has led to the development of targeted therapies known as TRK inhibitors (tropomyosin receptor kinase inhibitors). These drugs block the overactive fusion protein generated by the gene rearrangement, thereby inhibiting tumor growth.

Approved TRK Inhibitors

Larotrectinib (Vitrakvi®): The first tumor-agnostically approved TRK inhibitor. It is approved for adults and children with solid tumors harboring an NTRK gene fusion for whom no adequate standard therapy is available, or who have progressed following standard therapy.
Entrectinib (Rozlytrek®): Another TRK inhibitor that also targets ROS1 and ALK fusions. It is approved in adults with NTRK fusion-positive solid tumors.

Efficacy

Clinical trials have demonstrated remarkably high response rates of 57–79% in NTRK fusion-positive tumors treated with TRK inhibitors, consistently across different tumor entities. Many patients achieve durable remissions.

Resistance and Secondary Mutations

During treatment, secondary mutations in the NTRK gene can emerge, leading to resistance against first-generation TRK inhibitors. Second-generation TRK inhibitors, such as selitrectinib and repotrectinib, are being investigated in clinical trials to overcome these resistance mechanisms.

Significance in Oncology

NTRK fusions serve as a prime example of precision oncology: therapeutic decisions are based not on the location of the tumor, but on its molecular profile. This makes NTRK fusions a landmark example of tumor-agnostic treatment concepts and highlights the growing importance of molecular diagnostics in modern cancer medicine.

References

Drilon A. et al. – Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. New England Journal of Medicine, 2018.
Doebele R.C. et al. – Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours. The Lancet Oncology, 2020.
European Medicines Agency (EMA) – Product Information for Vitrakvi (Larotrectinib) and Rozlytrek (Entrectinib), www.ema.europa.eu.

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