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

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.

Automated summary

This study investigated the molecular characteristics of pediatric papillary thyroid cancer (PTC) and identified different genetic drivers, including fusion oncogenes and point mutations. For patients with fusion oncogene PTC, fusion-directed therapy may lead to dramatic tumor responses.