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C Rodriguez-Antona, Hereditary Endocrine Cancer Group, Spanish National Cancer Center (CNIO), Madrid, 28029, Spain
J Pallares, Department of Pathology and Molecular Genetics, University of Lleida, Lleida, Spain
C Montero-Conde, Hereditary Endocrine Cancer Group, Spanish National Cancer Center (CNIO), Madrid, Spain
L Inglada-Perez, Hereditary Endocrine Cancer Group, Spanish National Cancer Center (CNIO), Madrid, Spain
E Castelblanco, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, Lleida, Spain
I Landa, Hereditary Endocrine Cancer Group, Spanish National Cancer Center (CNIO), Madrid, Spain
S Leskela, Hereditary Endocrine Cancer Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
L Leandro-Garcia, Hereditary Endocrine Cancer Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
E Lopez-Jimenez, Hereditary Endocrine Cancer Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
R Letón, Hereditary Endocrine Cancer Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
A Cascón, Hereditary Endocrine Cancer Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
E Lerma, Pathology Service, Santa Creu and Sant Pau Hospital, Barcelona, Spain
M Martin, Molecular Cytogenetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
M Carralero, Molecular Cytogenetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
D Mauricio, Department of Endocrinology, Hospital Universitari Arnau de Vilanova, University of Lleida, Lleida, Spain
J Cigudosa, Molecular Cytogenetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
X Matias-Guiu, Department of Pathology and Molecular Genetics, Hospital Universitari Arnau de Vilanova, University of Lleida, Lleida, Spain
M Robledo, Hereditary Endocrine Cancer Group, Spanish National Cancer Centre (CNIO), Madrid, Spain

Cristina Rodriguez-Antona, Email: crodriguez{at}cnio.es

Abstract

Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis, and to identify potential targets for therapy in MTC. Since EGFR seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/VEGFR2-targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs, however, EGFR polysomy and a strong EGFR expression was detected in 15% and 13 % of the tumors, respectively. Interestingly, EGFR was significantly over-expressed in metastases compared to primary tumors (35% versus 9%, P=0.002). We also studied whether specific RET mutations had an effect on EGFR, and found a decrease in EGFR polysomies (P=0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (P=2.8x10-8). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed.