Tumor Profiling Identifies Potential Biomarkers for Vandetanib in MTC

W. Todd Penberthy, PhD
Published: Thursday, Oct 22, 2015

Researchers based at the Institute of Pathology, University Hospital Essen, Germany, identified molecular markers in medullary thyroid cancer (MTC) that were associated with response to vandetanib (Caprelsa) and the development of metastases.

The TKI vandetanib was approved in 2011 for the treatment of symptomatic or progressive MTC in patients with unresectable, locally advanced, or metastatic disease. The goal of the research, which was presented at the 2015 International Thyroid Congress, was to identify biomarkers that can be used to identify patients early in treatment who will derive a benefit from the drug.

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 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 versus 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 the RET mutational status.

Twenty-five percent of MTCs are caused by germline mutations in the RET gene. These are considered familial MTCs. While sporadic MTCs are not familial, they do most often possess acquired somatic RET mutations that are detectable in some cells of sporadic MTC.

Tiedje described the detection of RET mutations in 65% (21/32 samples) of patients. The RET918 mutation 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) and VEGFC (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.

Five of 10 patients treated with vandetanib showed a partial response. All of these responders had the RET918 mutation. Moreover, FLT1 (P  = .039), FLT4 (P = .025) and VEGFB (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 of FLT1, FLT4, and VEGFB may 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 for FGFR2, FGFR3, PDGFA, VEGFC, and BRAF. Of even more immediate practical significance, changes in the level of FLT1, FLT4, and VEGFB were seen in the patients that favorably responded to vandetanib therapy.

Tiedje V, Ting S, Walter R, et al. Tiedje V. Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients. Presented at: 2015 International Thyroid Congress; October 18-23, 2015; Orlando, FL. Abstract 492.

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