NTRK Fusions, from the Diagnostic Algorithm to Innovative Treatment in the Era of Precision Medicine

Abstract

In the era of precision medicine, the identification of several predictive biomarkers and the development of innovative therapies have dramatically increased the request of tests to identify specific targets on cytological or histological samples, revolutionizing the management of the tumoral biomaterials. The Food and Drug Administration (FDA) has recently approved a selective neurotrophic tyrosine receptor kinase (NTRK) inhibitor, larotrectinib. Contemporarily, the development of multi-kinase inhibitors with activity in tumors carrying TRK fusions is ongoing. Chromosomal translocations involving the NTRK1, NTRK2, and NTRK3 genes result in constitutive activation and aberrant expression of TRK kinases in numerous cancer types. In this context, the identification of tumors harboring TRK fusions is crucial. Several methods of detection are currently available. We revise the advantages and disadvantages of different techniques used for identifying TRK alterations, including immunohistochemistry, fluorescence in situ hybridization, reverse transcriptase polymerase chain reaction, and next generation sequencing-based approaches. Finally, we propose a diagnostic algorithm based on histology and the relative frequency of TRK fusions in each specific tumor, considering also the economic feasibility in the clinical practice.

Genome-wide analysis identifies critical DNA methylations within NTRKs genes in colorectal cancer

“…In previous studies, NTRK3 has been demonstrated to be an oncogene or a tumor suppressor gene in different cancer types [ 11 , 28 – 31 , 50 , 51 ]. These conflicting findings from in vitro and in vivo studies is similar to the results of our cohort analyses on NTRK3 methylation.…”

Hacking Pancreatic Cancer: Present and Future of Personalized Medicine

“…The tropomyosin receptor kinase (TRK) family includes three transmembrane protein receptors (TrkA, TrkB, and TrkC, respectively encoded by NTRK1, NTRK2, and NTRK3 genes), which regulate many aspects of neuronal development and function [ 98 , 99 ]. Chromosomal translocations involving NTRK1/2/3 genes result in constitutive activation and aberrant expression of TRK kinases [ 100 ]. NTRK alterations are rarely found in tumors with high prevalence, such as PC, where they occur in less than 1% of patients [ 7 ].…”

Non‐rhabdomyosarcoma soft tissue sarcomas diagnosed in patients at a young age. An overview of clinical, pathological, and molecular findings

“…8 The importance of incorporating next-generation sequencing technologies in this population with the goal of finding actionable targets is highlighted by recent publications that have emphasized the increasing availability of molecular therapies such as larotrectinib, an agent that specifically targets the NTRK gene fusion in IFS (and other tumors). [26][27][28][29] The availability of such agents in formulations suitable for young children raises promise for the potential to de-escalate potentially morbid therapies for IFS, with a particular focus in reducing the long-term morbidity of complex surgical procedures and adopting alkylator-and anthracycline-free chemotherapy regimens. 19,[23][24][25][26][27]30 It is also interesting to note that the possibility of spontaneous regression of IFS has also been reported in at least two cases.…”