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TRK Mutations: How to Find Them and Target Therapy for Select Solid Tumors

By: Lauren Harrison, MS
Posted: Monday, May 9, 2022

Jaclyn F. Hechtman, MD, a molecular and gastrointestinal pathologist from Fort Myers, Florida, published a review article focusing on the biology of tropomyosin receptor kinase (TRK) and its role in malignant cells. In addition, this article in Modern Pathology reviewed the currently used testing methods and proposed algorithms for how testing should be used in the clinical environment.

TRK receptors normally bind to a neurotrophin ligand, leading to kinase domain activation, dimerization, and autophosphorylation of intercellular tyrosine residues. This leads to downstream activation of signaling pathways, which promote neuron growth, differentiation, and survival.

Mutations in the NTRK gene are rare among many tumor types, and estimates suggest between 0.26% and 0.28% of patients with cancer harbor these mutations. However, for a few rare tumor types—including secretory carcinomas of the breast and salivary gland, infantile fibrosarcomas, pleomorphic adenomas, and pediatric thyroid carcinomas—NTRK mutations are present in more than 20% of patients or are even pathognomonic.

Two different drugs have been developed to target NTRK fusions: larotrectinib and entrectinib, with others in the pipeline. Patients receiving these medications must have an NTRK fusion, metastatic or unresectable disease, and disease progression on prior therapy. Larotrectinib yields an estimated objective response rate of 78%, whereas entrectinib yields an objective response rate of 63.5%. Treatment resistance can develop over time to these medications, which has led to investigation of the second-generation TRK inhibitors selitrectinib and repotrectinib to overcome this resistance.

There are several methods to test for NTRK fusions, and multiple testing algorithms have been proposed; however, the prevailing theme is testing should be influenced by tumor type and available resources. Some suggest testing based on histology, in which case those with histology suggesting a high probability of harboring an NTRK mutation should be tested. Another suggestion is genomic-based triage, in which patients who lack other oncogenic driver mutations should be screened.

Disclosure: For Dr. Hechtman’s disclosures, visit ncbi.nlm.nih.gov.


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