NTRK Fusion-Positive Thyroid Carcinoma: From Diagnosis to Targeted Therapy
Purpose: Neurotrophic tropomyosin receptor kinase (NTRK) fusions may act as oncogenic drivers in thyroid carcinomas. However, due to their low frequency, clinical, pathological, and molecular data on these patients and their responses to targeted therapies remain limited.
Methods: This observational, retrospective study was conducted at a high-volume cancer center in the United States. Data were collected retrospectively from medical records.
Results: A total of 65 patients (37 adults, 28 pediatric) with NTRK fusion-positive thyroid carcinoma were included (24 with NTRK1 fusions, 41 with NTRK3 fusions). The cohort consisted of 54 patients with papillary thyroid carcinoma (PTC), four with poorly differentiated thyroid carcinoma (PDTC), and seven with anaplastic thyroid carcinoma (ATC). In PTC, 22 (41%) patients exhibited an extensive follicular growth pattern. NTRK3 fusions were three times more frequent in adults (nine NTRK1, 28 NTRK3), while in pediatric patients, the frequencies of NTRK1 and NTRK3 fusions were similar (15 NTRK1, 13 NTRK3; P = .021). Among patients with PDTC/ATC treated with larotrectinib, four emergent solvent front mutations were identified (three NTRK3 G623R, one NTRK1 G595R), leading to drug resistance and disease progression. Three of these patients (two with ATC and one with PDTC) received second-line selitrectinib as part of a clinical trial. All three showed partial responses, but both patients with ATC progressed within a year.
Conclusion: NTRK1/3 fusions are present in PTC, PDTC, and ATC, with a high proportion of PTC cases exhibiting a follicular growth pattern. In patients treated with larotrectinib, solvent front mutations are the primary mechanism of resistance, particularly in PDTC and ATC. Responses to single-agent TRK inhibitors are generally short-lived in ATC patients,LOXO-195 suggesting that these drugs should be used with caution in this group.