Molecular markers predict metastases, therapy response in medullary thyroid cancer

Issue: November 25, 2015

LAKE BUENA VISTA, Fla. — Certain molecular markers in primary tumor tissue appeared associated with lymph node and organ metastases in patients with sporadic medullary thyroid cancer, according to study results presented at the International Thyroid Congress.

Perspective from Miriam N. Lango, MD

Further, these markers may predict patient response to treatment with vandetanib (Caprelsa, AstraZeneca), the researchers also reported.

“In sporadic medullary thyroid cancer, we do not have such genotype and phenotype correlation as we see in MEN2 disease,” Vera Tiedje, MD, of the department of endocrinology and metabolism at University Hospital Essen in Germany, told HemOnc Today. “The aim was to identify oncogenic factors in medullary thyroid cancer. The other aim was to understand the mechanisms behind patients who were resistant to vandetanib therapy. We want to know which patients might respond to vandetanib so that we can make good treatment decisions.”

Medullary thyroid cancer occurs sporadically in approximately 75% of patients, according to study background. Metastatic disease is associated with a significant OS reduction.

Currently, two tyrosine kinase inhibitors are approved for treatment of metastatic, progressive medullary thyroid cancer. Thus, Tiedje and colleagues sought to identify prognostic markers for progressive medullary thyroid cancer, as well as oncogenic factors associated with vandetanib therapy response.

The study included data from 32 patients with different tumor stages (pN0cM0, n = 10; pN1cM0, n = 9; pN1p/cM1, n = 14). The researchers compared the patients’ clinical courses with genetic profiles of their primary tumor tissues.

Of the entire cohort, 10 patients underwent vandetanib treatment.

Twenty-one patients harbored somatic RET mutations, eight of whom (all pN1p/cM1) harbored the high-risk RET918 mutation. Further, moderate-risk mutations were found in the primary tumor tissue of two patients with pN0cM0 (codon 620), one patient with pN1cM0 (codon 630) and one pN1p/cM1 patient (codon 768).

BRAF (P = .019), FGFR2 (P = .007), FGFR3 (P = .044) and VEGFC (P = .042) mRNA expression appeared significantly lower in patients with pN1cM0/pN1pcM1 stages compared to patients with pN0cM0 disease, whereas PDGFRA (P = .026) mRNA expression was significantly higher in patients with pN1cM0/pN1pcM1.

Among the 10 patients treated with vandetanib, five achieved partial response, all of whom harbored the RET918 mutation. Further, researchers observed significantly higher mRNA expression of FTL1 (P = .039), FTL4 (P = .025) and VEGFB (P = .042) in the primary tumor tissue of the responding patients.

“We have identified some interesting candidate genes that have to be validated in a bigger cohort of patients,” Tiedje said. “However, I think this is a nice starting place to identify who could be treated with vandetanib and who might be better suited by another drug.” – by Cameron Kelsall

For more information:

Vera Tiedje, MD, can be reached at University Hospital Essen, Hufelandstasse 55, 45147, Essen, Germany; email: vera.tiedje@uk-essen.de.

Reference:

Tiedje V, et al. Short Oral Communication 492. Presented at: International Thyroid Congress; Oct. 18-23, 2015; Lake Buena Vista, Fla.

Disclosure: The researchers report no relevant financial disclosures.

Perspective

Miriam N. Lango, MD

Medullary thyroid cancer comprises 2% to 3% of all thyroid cancers, most of which are sporadic. Of sporadic medullary thyroid cancers. at least 50% are associated with an activating mutation of the RET proto-oncogene; 85% of these are RET918 mutations.

Vandetanib (Caprelsa, AstraZeneca) — the small-molecule inhibitor of RET, vascular endothelial growth factor receptor 2 (VEGFR2) and epidermal growth factor receptor — is approved for use in patients with locally advanced or metastatic medullary thyroid cancer. FDA approval was based on a phase 3 randomized clinical trial that showed improved PFS relative to placebo (30.5 months vs. 19.3 months; P < 0.001). However, the FDA approved vandetanib with Risk Evaluation and Mitigation Strategies (REMS) due to toxicity. Predictors of response to treatment with vandetanib have not been well defined.

In a study by Tiedje and colleagues, investigators characterized the somatic mutations of 32 sporadic medullary thyroid cancers. In all, 21 of the 32 tumors had somatic RET mutations. Mutations were identified using Sanger and next-generation sequencing. In addition, mRNA expression of 33 tyrosine kinases was quantified. Over half of all metastatic tumors had RET918 mutations; metastatic tumors also had higher mRNA expression of some tyrosine kinases — BRAF, FGFR2, FGFR3, VEGFC — than non-metastatic tumors, but lower mRNA expression of others (PDGFRA). Of the 10 patients treated with vandetanib, five responders all had RET918 mutations, also exhibiting higher baseline mRNA expression of FLT1, FLT4, VEGFB.

The investigators, thus, characterize factors associated with metastasis and response to treatment with vandetanib. The markers associated with metastasis are also markers for response to therapy. The study provides evidence to support treating sporadic medullary thyroid cancers with the RET918 mutation with vandetanib.

Miriam N. Lango, MD

Fox Chase Cancer Center

Disclosures: Lango reports no relevant financial disclosures.