DOI: 10.6084/m9.figshare.30893221
title: <i>NTRK1-3</i> fusions in sarcomas: prevalence, significance, and clinical implications – a systematic review

description: Gene fusions involving Neurotrophic Receptor Tyrosine Kinase (<i>NTRK</i>) genes lead to Tropomyosin Receptor Kinases (TRK) overexpression. Detecting <i>NTRK1-3</i> fusions through advanced molecular techniques has revolutionized cancer care through personalized medicine, such as TRK inhibitors. We conducted a comprehensive search of databases (PubMed/MEDLINE, SCOPUS, Web of Science) and extracted data on study characteristics, molecular characteristics, and clinical outcomes. Data synthesis involved narrative and thematic analysis and study quality assessment using the Methodological Standard for Epidemiological Research (MASTER) scale. We included 136 studies with 18,077 patients. The most common tumor categories were unclassified soft tissue sarcomas (11.09%), gynecological sarcomas (5.64%), and liposarcomas (3.37%). Most tumors were gynecologic (5.64%), followed by the limbs (1.45%). Genomic sequencing was the predominant diagnostic method used in 110 studies. Overall, 551 patients with sarcoma tested positive for <i>NTRK1-3</i> gene fusions, primarily involving <i>NTRK1</i> and <i>NTRK3</i> (~93%), with <i>ETV6-NTRK3</i> fusion being the most frequently reported fusion. Larotrectinib was used in 142 patients, demonstrating an 83.80% response rate, with low mortality (2.82%) and recurrence (2.11%) rates. Entrectinib had a lower response rate of 63.64%. We confirm the rarity of <i>NTRK1-3</i> fusions in sarcomas. TRK inhibitors show high efficacy in sarcomas, emphasizing the necessity of genomic testing in all cases. <b>Protocol registration</b>: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024563594. Understanding <i>NTRK1-3</i> Change In Sarcoma And How New Medicines Help Sarcomas are rare cancers that can grow in soft tissues, muscle, fat, or bone. In a small number of these cancers, a change in genes, called Neurotrophic Receptor Tyrosine Kinases (<i>NTRK1-3</i>), occurs. The change is called fusion, in which a part of one gene joins the part of another gene. This change keeps a signal in the body switched on that tells the cancer to grow. Doctors now use a group of medicines called TRK inhibitors for cancers with <i>NTRK1-3</i> fusions. These drugs are different from chemotherapy. Instead of affecting the whole body, they target cancer cells with this gene change, which means they often cause fewer side effects. In this review, we looked at all published studies to learn how often <i>NTRK1-3</i> fusions appear in sarcomas and how patients respond to TRK inhibitors. We found that <i>NTRK1-3</i> fusions are rare in sarcomas, but when they are present, patients often respond well to medicines like larotrectinib and entrectinib. Many patients had their tumors shrink, and some had no sign of cancer after treatment. Most patients handled the medicines well, with only mild side effects. Some patients had the cancer come back because the tumor developed new changes that made the drug not work. This review shows that testing for <i>NTRK1-3</i> gene fusions is important. If we find this change, patients can receive targeted treatment that may be more effective and easier to tolerate than standard treatment. More studies are still needed to understand how long these benefits last.