BRAF V600E in thyroid cancer: navigating prognostic uncertainty and therapeutic opportunity

This review explores the role of BRAF V600E in thyroid cancer with emphasis on its debated prognostic value, notable molecular heterogeneity, and opportunities as a therapeutic target. BRAF V600E, the most common oncogenic driver in papillary thyroid carcinoma, activates the MAPK pathway and suppresses genes involved in iodine metabolism and differentiation. While linked to adverse features and outcomes such as extrathyroidal extension, lymph node metastasis, recurrence, and mortality, its utility as an independent prognostic marker remains controversial. In solitary intrathyroidal tumors (1-4 cm) and low-risk microcarcinomas, BRAF V600E testing may help refine surgical decisions, though evidence is inconsistent, particularly for tumors <2 cm. The mutation also contributes to radioactive iodine (RAI) refractoriness, but not all BRAF-mutant tumors behave similarly. Transcriptomic and genomic heterogeneity - including differences in thyroid differentiation score, genetic co-alterations and miRNA signatures - modulates treatment response. Targeting BRAF V600E has led to novel therapeutic strategies. Selective BRAF and MEK inhibitors - including vemurafenib, dabrafenib, and selumetinib - have demonstrated efficacy in advanced thyroid cancers. The combination of dabrafenib and trametinib is FDA approved for BRAF V600E-mutant anaplastic thyroid carcinoma based on its significant survival benefits. Moreover, due to its histology-agnostic approval for solid tumors with BRAF V600E mutations, this regimen is now also indicated for papillary and poorly differentiated thyroid cancers. In addition, redifferentiation strategies using MAPK inhibitors to restore RAI avidity have shown promise, particularly in selected patients. These advances highlight the need to contextualize BRAF mutation status within a broader molecular and clinical framework to guide personalized, effective treatment strategies.