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Ref Type Journal Article
PMID (28209747)
Authors Vanden Borre P, Schrock AB, Anderson PM, Morris JC, Heilmann AM, Holmes O, Wang K, Johnson A, Waguespack SG, Ou SI, Khan S, Fung KM, Stephens PJ, Erlich RL, Miller VA, Ross JS, Ali SM
Title Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions.
Journal Vol Issue Date Pages Journal Short Title
The oncologist 22 3 2017 Mar 255-263 Oncologist
URL
Abstract Text Thyroid carcinoma, which is rare in pediatric patients (age 0-18 years) but more common in adolescent and young adult (AYA) patients (age 15-39 years), carries the potential for morbidity and mortality.Hybrid-capture-based comprehensive genomic profiling (CGP) was performed prospectively on 512 consecutively submitted thyroid carcinomas, including 58 from pediatric and AYA (PAYA) patients, to identify genomic alterations (GAs), including base substitutions, insertions/deletions, copy number alterations, and rearrangements. This PAYA data series includes 41 patients with papillary thyroid carcinoma (PTC), 3 with anaplastic thyroid carcinoma (ATC), and 14 with medullary thyroid carcinoma (MTC).GAs were detected in 93% (54/58) of PAYA cases, with a mean of 1.4 GAs per case. In addition to BRAF V600E mutations, detected in 46% (19/41) of PAYA PTC cases and in 1 of 3 AYA ATC cases, oncogenic fusions involving RET, NTRK1, NTRK3, and ALK were detected in 37% (15/41) of PAYA PTC and 33% (1/3) of AYA ATC cases. Ninety-three percent (13/14) of MTC patients harbored RET alterations, including 3 novel insertions/deletions in exons 6 and 11. Two of these MTC patients with novel alterations in RET experienced clinical benefit from vandetanib treatment.CGP identified diverse clinically relevant GAs in PAYA patients with thyroid carcinoma, including 83% (34/41) of PTC cases harboring activating kinase mutations or activating kinase rearrangements. These genomic observations and index cases exhibiting clinical benefit from targeted therapy suggest that young patients with advanced thyroid carcinoma can benefit from CGP and rationally matched targeted therapy. The Oncologist 2017;22:255-263 IMPLICATIONS FOR PRACTICE: The detection of diverse clinically relevant genomic alterations in the majority of pediatric, adolescent, and young adult patients with thyroid carcinoma in this study suggests that comprehensive genomic profiling may be beneficial for young patients with papillary, anaplastic, or medullary thyroid carcinoma, particularly for advanced or refractory cases for which clinical trials involving molecularly targeted therapies may be appropriate.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
RET L633_A639del deletion unknown RET L633_A639del results in the deletion of seven amino acids in the extracellular domain of the Ret protein from amino acids 633 to 639 (UniProt.org). E633_A639del has been identified in the scientific literature (PMID: 28209747), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Jan 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
RET L633_A639del thyroid gland medullary carcinoma predicted - sensitive Vandetanib Case Reports/Case Series Actionable In a clinical case study, Caprelsa (vandetanib) treatment resulted in disease stabilization in a patient with metastatic medullary thyroid carcinoma harboring RET L633_A639del (PMID: 28209747). 28209747
RET D378_G385delinsE thyroid gland medullary carcinoma predicted - sensitive Vandetanib Case Reports/Case Series Actionable In a clinical case study, Caprelsa (vandetanib) treatment resulted in an ongoing biochemical response for more than 6 months in a pediatric patient 16 years old with metastatic medullary thyroid carcinoma harboring RET D378_G385delinsE (PMID: 28209747). 28209747