Association of Genetic Alterations With Disease Characteristics and Response to Treatment in Pediatric Differentiated Thyroid Cancer

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In a study reported in the Journal of Clinical Oncology, Franco et al found that RET and NTRK fusions were common somatic genetic alterations in pediatric patients with differentiated thyroid cancer and were associated with an increased risk of metastasis and poorer treatment outcome.

Study Details

The study involved somatic cancer gene panel analysis of differentiated thyroid cancer samples from 131 pediatric patients treated at The Children’s Hospital of Philadelphia. Differentiated thyroid cancers were categorized into RAS-mutant (H-K-NRAS), BRAF-mutant (BRAF V600E), and RET/NTRK fusion (RET, NTRK1, and NTRK3 fusions) to evaluate differences between subtype classification in risk of metastasis and response to therapy at 1 year after completion of initial treatment.

Key Findings

Among the 131 samples, one of the genetic alterations was identified in 78 (59.5%), including RAS mutation in 9 (6.9%), BRAF mutation in 26 (19.8%) and RET or NTRK fusion in 43 (32.8%); RAS mutation, BRAF mutation, and RET/NTRK fusions were mutually exclusive in every tumor analyzed.

The mutation-based subtype categories had significant correlations with most clinical/pathologic characteristics, including extrathyroidal extension, invasion, histology, remission, age, M stage, and N stage, but not sex or T stage. In analysis excluding RAS mutation, due to small sample size, significant correlations for BRAF mutation vs RET/NTRK fusions were observed for invasion, remission, age, M stage, and N stage.

Distant metastasis occurred in 39.5% of patients with RET/NTRK fusions, compared with 11.1% of those with a RAS mutation and 0% of those with a BRAF mutation (overall P < .001; P < .001 for RET/NTRK vs BRAF). N1b disease occurred in 69.8%, compared with 0% and 15.4% (overall P < .001; P < .001 for RET/NTRK vs BRAF). Remission at 1 year was achieved in 41.9% of patients, compared with 55.6% and 61.5% (overall P = .006; P = .030 for RET/NTRK vs BRAF).

The investigators concluded, “Our data support that genetic subtyping of pediatric differentiated thyroid cancer more accurately reflects clinical behavior than sole reliance on pathologic classification, with patients with RET/NTRK fusions having worse outcomes than those with BRAF-mutant disease. Future trials should consider inclusion of molecular subtype into risk stratification.”

Andrew J. Bauer, MD, of the Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the National Institutes of Health, The Children’s Hospital of Philadelphia Frontier Programs, and The Children’s Hospital of Philadelphia Foerderer Grant. For full disclosures of the study authors, visit

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