NTRK1-3 fusions in sarcomas: prevalence, significance, and clinical implications - a systematic review

Gene fusions involving Neurotrophic Receptor Tyrosine Kinase (NTRK) genes lead to Tropomyosin Receptor Kinases (TRK) overexpression. Detecting NTRK1-3 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 NTRK1-3 gene fusions, primarily involving NTRK1 and NTRK3 (~93%), with ETV6-NTRK3 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 NTRK1-3 fusions in sarcomas. TRK inhibitors show high efficacy in sarcomas, emphasizing the necessity of genomic testing in all cases.Protocol registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024563594.