NTRK1-3 Fusions in Sarcomas: Prevalence, Significance, and Clinical Implications – A Systematic Review

Purpose Gene fusions involving Neurotrophic Receptor Tyrosine Kinase ( NTRK ) genes lead to Tropomyosin Receptor Kinase (TRK) overexpression, an oncogenic mechanism rarely prevalent in soft tissue tumors. Detecting NTRK1-3 fusions through advanced molecular techniques has revolutionized cancer care through personalized medicine, such as TRK inhibitors (e.g., larotrectinib, entrectinib). In this systematic review, we examined the prevalence and types of NTRK1-3 gene fusions in soft tissue sarcomas. Design Using terms related to NTRK1-3 and sarcomas, we conducted a comprehensive search of databases (PubMed/MEDLINE, SCOPUS, Web of Science). We screened titles and abstracts, followed by a full-text assessment. We extracted data on study characteristics, molecular characteristics, and clinical outcomes. Data synthesis involved narrative and thematic analysis and study quality assessment using the MASTER scale. Results We included 136 studies (n = 18,077 patients). The most common tumor categories were unclassified soft tissue sarcomas (2,004 patients, 11.09%), gynecological sarcomas (1,019 patients, 5.64%), and liposarcomas (609 patients, 3.37%). Most tumors were gynecological in origin (1,019 patients, 5.64%), followed by the limbs (262 patients, 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 (174/551). 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% (21/33). Conclusions This systematic review highlights the rarity of NTRK1-3 fusions in sarcomas. TRK inhibitors show high efficacy in sarcomas, emphasizing the necessity of genomic testing in all cases.