Prognostic markers and response to vandetanib therapy in sporadic medullary thyroid cancer patients

Abstract

Objective: 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. Design and methods: 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. Results: 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. Conclusions: 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.

Clinical significance of RET and RAS mutations in sporadic medullary thyroid carcinoma: a meta-analysis

“…After reading full-texts, we further excluded 35 studies and the remaining 23 studies, comprising 964 sporadic MTCs were included for final analyses (Fig. 1) (Zedenius et al 1994, 1995, Romei et al 1996, Frisk et al 2000, Schilling et al 2001, Cho et al 2005, Dvorakova et al 2008, Elisei et al 2008, Goutas et al 2008, Moura et al 2009, Mian et al 2011, Pasquali et al 2011, Schulten et al 2011, Ciampi et al 2013, Lyra et al 2014, Simbolo et al 2014, Chuang et al 2016, Grubbs et al 2016, Nascimento et al 2016, Tiedje et al 2016, Cavedon et al 2017. The characteristics of all included studies are shown in Table 1.…”

“…Pertinent data for RET mutations from 12 studies were included for analysis (Zedenius et al 1994, Schilling et al 2001, Dvorakova et al 2008, Elisei et al 2008, Moura et al 2009, Mian et al 2011, Schulten et al 2011, Simbolo et al 2014, Chuang et al 2016, Grubbs et al 2016, Nascimento et al 2016, Tiedje et al 2016). There was a statistical difference in male proportion between two groups ( Supplementary Fig.…”

“…Eligible data for RET and RAS mutations were available to extract from 11 studies (Zedenius et al 1994, Schilling et al 2001, Dvorakova et al 2008, Elisei et al 2008 Endocrine-Related Cancer Moura et al 2009, Mian et al 2011, Schulten et al 2011, Simbolo et al 2014, Grubbs et al 2016, Nascimento et al 2016, Tiedje et al 2016 and five studies (Moura et al 2011, Ciampi et al 2013, Lyra et al 2014, Simbolo et al 2014, Nascimento et al 2016, respectively. Patients with RET-mutated (RET-mut) tumors showed a significantly younger age compared with RET-wild type (RET-wt) tumors (MD = −7.19; 95% CI = −12.47 to −1.90; I 2 = 83%) ( Supplementary Fig.…”

NGS based identification of mutational hotspots for targeted therapy in anaplastic thyroid carcinoma

“…Hereditary medullary thyroid carcinoma (MTC) is characterized by germline RET mutations [38] and in 40–60% of sporadic MTC somatic RET mutations are present [39, 40], which cause constitutive activation of the RET tyrosinkinase and in consequence MAPK/ERK and PI3K pathway activation. In follicular-cell derived thyroid carcinoma RET mutations are generally rare events [41].…”

Expression based biomarkers and models to classify early and late-stage samples of Papillary Thyroid Carcinoma

“…The various types of features in this signature reveal the role of various non-coding transcripts along with protein-coding transcripts in the progression of cancer. Out of 28 protein-coding, five genes; TERT [68], FLT4 [69], DUSP6 [70], USP10 [71] and POMC [72] have already been implicated in thyroid cancer. miR-3196 has also been found to be downregulated in PTC nonmetastasized patients [73].…”