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Shedding Light on the Role of NTRK Gene Fusions in Cancer

By: Lauren Harrison, MS
Posted: Monday, March 7, 2022

A review article published by Noah Federman, MD, of the University of California, Los Angeles, and his colleagues highlights the role of NTRK gene fusions in cancer and discusses how the identification of these mutations can be used for targeted therapy. This work was published in the American Journal of Managed Care and provides recommendations for NTRK gene testing in both pediatric and adult patients.

NTRK genes encode the TRK family of proteins, and NTRK gene fusions have been identified in a variety of cancer types. The gene fusions constitutively activate NTRK and drive cell and tumor development. NTRK mutations are rare in solid tumors, occurring in just 0.3% of colorectal cancers and 0.2% of lung cancers. However, they are common in many rare tumor types including infantile fibrosarcoma (90.6%), secretory breast carcinoma (92.9%), salivary gland carcinoma (79.7%), and congenital mesoblastic nephroma (21.5%). In general, NTRK gene fusions occur more frequently in pediatric tumors than adult tumors.

These mutations can be detected using immunohistochemistry, fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), and next-generation sequencing (NGS) of RNA or DNA. The authors describe various advantages and drawbacks of each of these methods, but they report that the optimal approach is likely DNA-based next-generation sequencing.

For tumors in which NTRK fusions are common, the European Society for Medical Oncology recommends testing for these mutations using FISH, PCR, or RNA-based NGS. RNA-based NGS screening followed by sequencing is appropriate for identifying these mutations in cancers in which the fusions are uncommon.

Two first-generation TRK inhibitors, larotrectinib and entrectinib, have been approved for treatment of cancers with TRK fusion, and several other TRK inhibitors are in clinical development. Larotrectinib has an estimated objective response rate of 75%, whereas entrectinib has an estimated objective response rate of 61%, according to the authors. Both treatments are relatively well tolerated.

Disclosure: For a full list of authors’ disclosures, visit ajmc.com.


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