Molecular Profiling of Medullary Thyroid Cancer Identifies Prognostic Markers for Vandetanib

While medullary thyroid cancer (MTC) is not nearly as common as papillary or follicular thyroid cancer, progressive metastatic MTC prognosis does have a poorer prognosis than these more common forms of metastatic thyroid cancer.

One out of four MTCs are caused by germline mutations in theRETgene. These are considered familial MTCs. While sporadic MTCs are not familial, they do most often possess acquired somaticRETmutations that are detectable in some cells of sporadic MTC. Two tyrosine kinase inhibitors (TKIs) are currently approved and used for treatment of metastatic MTC. Still, prognosis remains poor for TKI-treated progressive metastatic MTC.

With the continuing development of diagnostic and prognostic molecular technologies, researchers based at the Institute of Pathology, University Hospital Essen, Essen, Germany are characterizing the molecular profile of the progressive metastatic MTC disease state and the desired vandetanib-responsive therapy state. The hope is to identify biomarkers that can be used to parse out patients early in the treatment phase. An early determination of likely drug responsiveness may assist in decisions to avoid unnecessary serious adverse events (AEs) associated with TKIs and inform medical oncologists that another drug should be considered. Alternatively, with a favorable early-response molecular profile, the therapeutic course would be maintained.

Presenting at the 15th annual International Thyroid Congress, University Hospital Essen physician Vera Tiedje, MD, described molecular profiling from 32 patients with MTC at different tumor stages (n = 10 pN0cM0; n = 9 pN1cM0; n=14 pN1p/cM1) with a median age of 56 years and a follow-up time of 42 months. Nine of the patients died over this observation period. Ten of the patients were started on vandetanib treatment due to progressive disease, based on RECIST criteria.

Molecular profiling comparisons were made between the patients’ own primary vs more progressive tumor tissues. Tiedje et al examined the mRNA expression level of 33 different tyrosine kinase genes using nCounter NanoString. Next-generation sequencing was used to determine theRETmutational status.

Tiedje described the detection ofRETmutations in 65% (21/32 samples) of patients. TheRET918mutation is the highest risk mutation, and it was also the most common mutation detected, at 57% (8/14) of patients in the pN1p/cM1 MTC arm.

BRAF(P= .019),FGFR2(P= .007),FGFR3(P= .044) andVEGFC(P= .042) mRNA expression was significantly lower in MTC of the pN1cM0/pN1pcM1 arm compared with the pN0cM0 arm. By contrast,PDGFRA(P= .026) mRNA expression was significantly higher in MTC of the pN1cM0/pN1pcM1 arm compared with the pN0cM0 arm.

Out of 10 patients treated with vandetanib, just 5 showed a partial response. All of these responders had theRET918mutation. Moreover,FLT1(P= .039),FLT4 (P= .025) andVEGFB(P=.042) mRNA expression was distinctly higher in primary tumor tissues of patients responding to vandetanib therapy.

Together these are encouraging results, which suggest that molecular profiling may be useful to determine the likelihood of progressive metastatic MTC development. Most significantly, the early determination of whether or not the cancer is responding to vandetanib therapy. Data indicates that the early monitoring ofFLT1, FLT4,andVEGFBmay offer early hints about whether or not the patient should stay on vandetanib therapy.

Tiedje et al identified distinct characteristic changes in the levels of tyrosine kinases associated with progression from primary tumor to metastatic progression encoding mRNAs forFGFR2,FGFR3,PDGFA,VEGFC, andBRAF.Of even more immediate practical significance, changes in the level ofFLT1, FLT4,andVEGFBwere seen in the patients that favorably responded to vandetanib therapy.

Tiedje V. Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients. Presented at the 15th International Thyroid Congress: October 21, 2015. Abstract #492.