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Pediatric, adolescent and young adult (PAYA) thyroid carcinoma harbors frequent and diverse targetable genomic alterations including kinase fusions

Date

10 Oct 2016

Session

Endocrine and neuroendocrine tumours

Presenters

Pierre Vanden Borre

Citation

Annals of Oncology (2016) 27 (6): 136-148. 10.1093/annonc/mdw369

Authors

P. Vanden Borre1, A.B. Schrock2, P. Anderson3, A.M. Heilmann4, O. Holmes4, K. Wang5, S. Khan6, J.C. Morris7, S.I. Ou8, S. Waguespack9, P. Stephens10, R.L. Erlich4, V. Miller11, J.S. Ross12, S. Ali12

Author affiliations

  • 1 Biomedical Informatics, Foundation Medicine, Inc., 02141 - Cambridge/US
  • 2 Clinical Development, Foundation Medicine, Inc., Cambridge/US
  • 3 Pediatric Hematology Oncology And Blood And Marrow Transplantation, Cleveland Clinic Foundation, Cleveland/US
  • 4 Biomedical Informatics, Foundation Medicine, Inc., Cambridge/US
  • 5 Computational Biology, Foundation Medicine, Inc., Cambridge/US
  • 6 Department Of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, Dallas/US
  • 7 Division Of Endocrinology, Diabetes, Metabolism, And Nutrition, Mayo Clinic, Rochester/US
  • 8 Hematology/oncology, Chao Family Comprehensive Cancer Center, Irvine/US
  • 9 The University Of Texas Md Anderson Cancer Center, Department of Endocrine Neoplasia and Hormonal Disorders, Houston/US
  • 10 Research And Product Development, Foundation Medicine, Inc., Cambridge/US
  • 11 Medical Affairs, Foundation Medicine, Inc., Cambridge/US
  • 12 Pathology, Foundation Medicine, Inc., Cambridge/US
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Background

Thyroid carcinoma in children and young adults is rare but carries the potential for morbidity and mortality. A series of advanced pediatric, adolescent and young adult (PAYA) thyroid carcinoma cases were assayed in the course of clinical care to identify genomic alterations (GAs) linked to potential benefit from targeted therapy.

Methods

Hybrid-capture based comprehensive genomic profiling (CGP) was performed prospectively on 58 consecutively submitted PAYA thyroid carcinomas.

Results

All patients were 39 years old or younger including 41 patients with papillary thyroid carcinoma (PTC) (median age: 26 years, range: 7-39 years), 3 with anaplastic thyroid carcinoma (ATC) (median age: 33 years, range 25-33 years), and 14 with medullary thyroid carcinoma (MTC) (median age: 33 years, range 15-39). 64% (37/58) of the patients were female. GAs were detected in 93% (54/58) of cases, with a mean of 1.4 GAs per case. Clinically relevant GAs, defined as GAs associated with at least one actively recruiting clinical trial or an FDA-approved therapy, were identified in 91% (53/58) of cases. BRAF V600E was present in 46% (19/41) of PTCs and in 1/3 ATCs. Oncogenic fusions were identified in 37% (15/41) and 33% (1/3) of PTC and ATC cases, respectively. In addition to fusions previously observed in PAYA thyroid carcinoma involving RET, NTRK1, and NTRK3, 3 ALK fusions (EML4-ALK, STRN-ALK, and GTF2IRD1-ALK) were detected in pediatric patients with PTC. In PAYA patients with MTC, RET mutation occurred in 93% (13/14) of cases, including the predominant RET M918T mutation and 3 insertion/deletions in exons 6 and 11. Two patients with MTC harboring in-frame deletions in RET exons 6 and 11 experienced clinical benefit from vandetanib treatment.

Conclusions

CGP identified diverse targetable genomic alterations in PAYA patients with thyroid carcinoma. 83% of PTC cases harbored either activating kinase mutations or rearrangements, including three cases with ALK fusions. Genomic alteration data and our clinical observations suggest that young patients with advanced thyroid carcinoma can often benefit from CGP to identify matched targeted therapies.

Clinical trial identification

Legal entity responsible for the study

Foundation Medicine

Funding

Foundation Medicine

Disclosure

P. Vanden Borre, A.B. Schrock, A.M. Heilmann, O. Holmes, K. Wang, P. Stephens, R.L. Erlich, V. Miller, J.S. Ross, S. Ali: Employee and has stock ownership in Foundation Medicine.

All other authors have declared no conflicts of interest.

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