The Association Between Radioiodine Refractory in Papillary Thyroid Carcinoma, Sodium/Iodide Symporter Expression, and BRAFV600E Mutation

Abstract

Objective To study the association between radioiodine refractory papillary thyroid carcinoma, sodium/iodide symporter (NIS) expression, and the BRAF V600E mutation. Methods A study was conducted on 30 radioiodine refractory papillary thyroid carcinoma patients and 30 radioiodine-avid papillary thyroid carcinoma patients. The expressions of sodium/iodide symporter and BRAF V600E mutated protein were determined by immunohistochemistry using formalin-fixed, paraffin-embedded tissue. Results The mutated BRAF V600E protein was identified in 26 radioiodine refractory papillary thyroid carcinoma subjects (86.7%) and 22 radioiodine-avid papillary thyroid carcinoma subjects (73.3%), with no significant difference between the 2 groups ( P = 0.3). Sodium/iodide symporter expression was detected in 4 of 30 cases (13.3%) from the radioiodine-avid papillary thyroid carcinoma group but was negative for all radioiodine refractory cases. There was no association between sodium/iodide symporter expression and radioiodine refractory papillary thyroid carcinoma ( P = 0.11). Cases with positive NIS expression were likely negative for BRAF V600E mutation (3/4; P = 0.02). Conclusion Papillary thyroid carcinomas with BRAF V600E mutation were more likely to be negative for NIS expression. BRAF V600E mutation and NIS expressions cannot be used to predict radioiodine sensitivity.

Strategies for Radioiodine Treatment: What’s New

“…The BRAF mutation causes the uncontrolled activation of the MAPK pathway and is associated with a more aggressive phenotype and a less favorable outcome [ 182 ]. Moreover, BRAF mutated tumors have a less-differentiated phenotype with the downregulation of iodine metabolism genes, such as NIS and thyroperoxidase (TPO) [ 183 , 184 ] resulting in a decreased or absent radioiodine uptake and the loss of RAI sensitivity [ 92 ]. TERT promoter mutations are considered to be a late event in DTC carcinogenesis and are often found in more aggressive histological types, such as PDTC [ 185 ] and anaplastic thyroid cancer [ 186 ].…”

“…The main breakthrough in this framework was provided by the finding of MAPK signaling as the pathway that was the most frequently involved in the refractoriness process [ 196 , 197 ]. The major trigger of the MAPK pathway is represented by BRAF-V600E [ 181 , 185 , 197 ], a leading mutation that, by activating the downstream kinases MEK and ERK, produces an uncontrolled stimulation, resulting in a downregulation of iodine metabolism genes, such as NIS and TPO [ 183 , 184 , 196 , 197 , 198 ]. The more recent attempts to stimulate the redifferentiation process have been built around these molecular steps, finding through the selective BRAF and MEK inhibitors the pivotal therapeutic agents [ 196 , 197 ].…”

Blood Profiles in the Prediction of Radioiodine Refractory Papillary Thyroid Cancer: A Case–Control Study

“…Although other studies in this field also confirmed the relationship between these two mutations and RAIR, the predictive accuracy varied in different studies. 6 , 12 , 14 , 58 The discrepancy might be explained by different patient selection and sequencing techniques. Since targeted sequencing is costly in most medical institutions, other researchers tried to use clinicopathological and ultrasound examination characteristics to predict the RAIR.…”

Add-on radioiodine during long-term BRAF/MEK inhibition in patients with RAI-refractory thyroid cancers: a reasonable option?

“…Owing to heterogenous methodologies, including different therapeutic targets and redifferentiation procedures, results have varied significantly. Overall, success rate for redifferentiation in larger studies (>8 patients) have varied from 33 and 95% with reported response rates to 131 I between 33 and 100% [ 12 , 14 , 15 , 17 – 19 ]. Results from a phase II randomized trial comparing dabrafenib monotherapy to dabrafenib + trametinib in patients with BRAF-mutated radioactive iodine refractory DTC have reported an objective response rate of 48% (modified RECIST) in dabrafenib + trametinib arm versus 42% in dabrafenib arm, respectively [ 20 ].…”