Next-generation sequencing of targetable gene fusions in radioiodine-refractory thyroid cancer: a multicenter study

We aimed to determine the prevalence and clinical significance of targetable gene fusions in patients with radioiodine-refractory thyroid cancer. This multicenter retrospective cohort study enrolled 111 patients from five tertiary medical centers, with molecular profiling performed using targeted next-generation sequencing. The analysis revealed that 58 (52.3%) patients possessed BRAFV600E mutation, while 25 (22.5%) had RAS mutations. Among the 20 (18.0%) patients with gene fusions, 13 had RET fusions, three had NTRK fusions, one had a BRAF fusion, and three had nondriver gene fusions. The group with targetable gene fusions was significantly younger compared to those with BRAF or RAS mutations (P < 0.001) and predominantly had classic papillary thyroid carcinoma. Furthermore, targetable gene fusions were detected in 30.8% of patients with refractory thyroid cancer harboring wild-type BRAF. More than half of the patients received systemic tyrosine kinase inhibitor therapy and three patients with confirmed RET or NTRK fusions achieved meaningful clinical benefit with selective agents. These findings suggest that a stepwise molecular testing strategy - initiating with BRAF single gene analysis followed by next-generation sequencing for assessing targetable gene fusions - may be a rational approach, particularly for younger patients with papillary thyroid carcinoma, for identifying candidates for precision therapy. This supports the integration of molecular profiling into routine clinical practice for radioiodine-refractory thyroid cancer and emphasizes its utility in guiding personalized treatment decisions in this challenging disease subset.