Abstract
Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.
Highlights
Sarcomas are a heterogeneous group of malignancies that exhibit mesenchymal lineage differentiation
The emergence of NTRK gene fusions as clinically actionable biomarkers marks a new era in precision oncology, with the tumor-agnostic approvals of larotrectinib and entrectinib representing milestones in drug development
Integrating NTRK fusion testing into the current diagnostic workup of patients with sarcoma is challenging due to the rarity of this biomarker
Summary
Sarcomas are a heterogeneous group of malignancies that exhibit mesenchymal lineage differentiation. It has low to sub-nanomolar enzymatic activity against TRKA, TRKB, TRKC, ROS1, and ALK (IC50 values of 1.7, 0.1, 0.1, 0.2, and 1.6 nM, respectively).[44] Entrectinib is FDAapproved for use in adult and pediatric patients 12 years of age with solid tumors harboring an NTRK gene fusion who have disease that is metastatic or where surgery is likely to result in severe morbidity, and who have progressed following treatment or have no satisfactory alternative therapy. Progression-free survival, and overall survival were 10.3 (95% CI 4.6-15.0), 11.0 (95% CI 6.5-15.7), and 16.8 (95% CI 10.6-20.9) months, respectively (Table 2).[47]
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