NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake

초록

BACKGROUND. Molecular characterization in pediatric papillary thyroid cancer (PTC), distinct from adult PTC, is important for developing molecularly targeted therapies for progressive radioiodine-refractory (I-131-refractory) PTC. METHODS. PTC samples from 106 pediatric patients (age range: 4.3-19.8 years; n = 84 girls, n = 22 boys) who were admitted to SNUH (January 1983-March 2020) were available for genomic profiling. Previous transcriptomic data from 125 adult PTC samples were used for comparison. RESULTS. We identified genetic drivers in 80 tumors: 31 with fusion oncogenes (RET in 21 patients, ALK in 6 patients, and NTRK1/3 in 4 patients); 47 with point mutations (BRAF(V600E) in 41 patients, TERTC228T in 2 patients [1 of whom had a coexisting BRAF(V600E)], and DICER1 variants in 5 patients); and 2 with amplifications. Fusion oncogene PTCs, which are predominantly detected in younger patients, were at a more advanced stage and showed more recurrent or persistent disease compared with BRAF(V600E) PTCs, which are detected mostly in adolescents. Pediatric fusion PTCs (in patients <10 years of age) had lower expression of thyroid differentiation genes, including SLC5A5, than did adult fusion PTCs. Two girls with progressive I-131-refractory lung metastases harboring a TPR-NTRK1 or CCDC6-RET fusion oncogene received fusion-targeted therapy; larotrectinib and selpercatinib decreased the size of the tumor and restored I-125 radioiodine uptake. The girl with the CCDC6-RET fusion oncogene received I-131 therapy combined with selpercatinib, resulting in a tumor response. In vitro I-125 uptake and I-131 clonogenic assays showed that larotrectinib inhibited tumor growth and restored radioiodine avidity. CONCLUSIONS. In pediatric patients with fusion oncogene PTC who have I-131-refractory advanced disease, selective fusion-directed therapy may restore radioiodine avidity and lead to a dramatic tumor response, underscoring the importance of molecular testing in pediatric patients with PTC.

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