Yoo Jungmin, Kim Mijin, Kim Hee Kyung, Shin Dong Yeob, Jeon Min Ji, Kim Bo Hyun, Kang Ho-Cheol, Lee Jaekyung, Lim Dong-Jun, Kim Won Gu
Endocr Relat Cancer. 2025 Jul 7;32(7). doi: 10.1530/ERC-25-0089. Print 2025 Jul 1.
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.
我们旨在确定放射性碘难治性甲状腺癌患者中可靶向基因融合的患病率及其临床意义。这项多中心回顾性队列研究纳入了来自五个三级医疗中心的111例患者，采用靶向新一代测序进行分子谱分析。分析显示，58例（52.3%）患者存在BRAFV600E突变，25例（22.5%）有RAS突变。在20例（18.0%）有基因融合的患者中，13例有RET融合，3例有NTRK融合，1例有BRAF融合，3例有非驱动基因融合。与BRAF或RAS突变患者相比，可靶向基因融合组患者明显更年轻（P<0.001），且主要为经典型乳头状甲状腺癌。此外，在野生型BRAF的难治性甲状腺癌患者中，30.8%检测到可靶向基因融合。超过一半的患者接受了全身酪氨酸激酶抑制剂治疗，3例确诊为RET或NTRK融合的患者使用选择性药物获得了有意义的临床获益。这些发现表明，一种逐步的分子检测策略——先进行BRAF单基因分析，然后进行新一代测序以评估可靶向基因融合——可能是一种合理的方法，特别是对于年轻的乳头状甲状腺癌患者，用于识别精准治疗的候选者。这支持将分子谱分析纳入放射性碘难治性甲状腺癌的常规临床实践，并强调了其在指导这一具有挑战性的疾病亚组的个性化治疗决策中的作用。
