Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients.
Medullary thyroid carcinoma (MTC) occurs sporadically in 75% of patients. Metastatic disease is associated with significantly poorer survival. The aim of this study was to identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy.



Clinical courses of 32 patients with sporadic MTC (n=10 pN0cM0, n=8 pN1cM0, n=14 pN1cM1) were compared with genetic profiles of the patients' primary tumour tissue. Analysis for RET proto-oncogene mutations was performed by Sanger sequencing and next-generation sequencing (NGS). The mRNA expression (mRNA count) of 33 targets was measured by nCounter NanoString analysis.



Somatic RET mutations occurred in 21/32 patients. The RET918 mutation was found in 8/14 pN1cM1 patients. BRAF (P=0.019), FGFR2 (P=0.007), FGFR3 (P=0.044) and VEGFC (P=0.042) mRNA expression was significantly lower in pN1cM0/pN1cM1 compared with pN0cM0 patients, whereas PDGFRA (P=0.026) mRNA expression was significantly higher in pN1cM0/pN1cM1 when compared with pN0cM0 patients. Among the 10/32 vandetanib-treated patients, 5 showed partial response (PR), all harbouring the RET918 mutation. mRNA expression of FLT1 (P=0.039), FLT4 (P=0.025) and VEGFB (P=0.042) was significantly higher in therapy responders.



In this study, we identified molecular markers in primary tumour tissue of sporadic MTC associated with the development of metastasis (both lymph node and organ metastasis) as well as response to vandetanib therapy.
Department of Endocrinology and Metabolism vera.tiedje@uk-essen.de.
Vera
V
Tiedje
Institute of Pathology.
Saskia
S
Ting
Institute of Pathology Department of Interventional PneumologyRuhrlandklinik, West German Lung Centre, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
Robert Fred
RF
Walter
Institute of Pathology German Cancer Consortium (DKTK)German Cancer Research Center (DKFZ), Heidelberg, Germany.
Thomas
T
Herold
Institute of Pathology.
Karl
K
Worm
Department of Endocrinology and Metabolism.
Julia
J
Badziong
Department of Endocrinology and Metabolism.
Denise
D
Zwanziger
Institute of Pathology.
Kurt Werner
KW
Schmid
Department of Endocrinology and Metabolism.
Dagmar
0000-0003-0357-4192
D
Führer
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010880:Piperidines / Q000627:therapeutic use*; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics*; D011799:Quinazolines / Q000627:therapeutic use*; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011799:Quinazolines; D051096:Proto-Oncogene Proteins c-ret; C099282:RET protein, human; C452423:vandetanib