Markers in Medullary Thyroid Cancer May Signal Metastasis, Vandetanib Response

Researchers in Germany appear to have identified a gene-expression signature associated with metastasis in sporadic medullary thyroid cancer (MTC) and prognostic molecular tumor markers of MTC response to vandetanib therapy. They reported these findings this week at the 15th International Thyroid Congress (ITC) and 85th Annual Meeting of the American Thyroid Association (ATA) in Lake Buena Vista, Florida.

“We identified a different expression pattern of tyrosine kinases-FGFR2, FGFR3, PDGFRA, VEGFC, and BRAF-in the primary tumor tissue of patients with and without development of metastatic MTC during follow-up, and an upregulation of FLT1, FLT4, and VEGFB in patients who showed partial responses to vandetanib at initial staging,” reported lead study author Vera Tiedje, of the department of endocrinology and metabolism at University Hospital Essen, in Essen, Germany.

MTC occurs sporadically in 75% of patients, and advanced-stage MTC is associated with poor prognosis, she noted. Vandetanib is one of two tyrosine kinase inhibitors that has been approved by the US Food and Drug Administration (FDA) for treating progressive, metastatic MTC in adult patients who are not candidates for surgery.

“To identify prognostic markers for progressive MTC and oncogenic factors associated with response to vandetanib therapy, the clinical courses of 32 patients with sporadic MTC of different tumor stages were compared with genetic profiles of the patients’ primary tumor tissues,” Tiedje said.

Ten of the patients were diagnosed with pN0cM0-stage MTC, nine patients with pN1cM0, and fourteen with pN1p/cM1. Ten of the patients with pN1p/cM1 MTC were administered vandetanib.

“Analysis for RET-proto-oncogene mutations was performed by Sanger and next generation sequencing,” Tiedje explained. “The mRNA expression (mRNA count) of 33 tyrosine kinases was measured by nCounter NanoString analysis.”

Somatic RET mutations were found in 21 of 32 MTCs analyzed, she reported. “The high-risk RET918 mutation was found in 8 of 14 MTCs of pN1p/cM1 patients and moderate-risk mutations (codon 620, 630, and 768, respectively) were found in primary tumor tissues of two pN0cM0, one pN1cM0, and one pN1p/cM1 patient. “Among the ten vandetanib treated patients, five showed partial response-all harboring the RET918 mutation.”

“PDGFRA mRNA expression was significantly higher in MTC of pN1cM0/pN1pcM1 compared to pN0cM0 patients [P = .026],” she reported. mRNA expression was significantly lower in pN1cM0/pn1pcM1 than pN0cM0 patients for BRAF (P = .019), FGFR2 (P = .007), FGFR3 (P =.044), and VEGFC (P = .042).