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

Q: Why is BRAF V600E prognostic value considered controversial?

Although it correlates with adverse features and worse outcomes, its utility as an independent prognostic marker remains contested, and evidence is inconsistent for risk stratification in certain tumor sizes.

Q: How does BRAF V600E influence treatment opportunities?

It contributes to radioactive iodine refractoriness and drives novel therapeutic strategies, including selective BRAF and MEK inhibitors, with combination therapy approved for BRAF V600E-mutant anaplastic thyroid carcinoma and indications extended to other thyroid cancers based on tumor-agnostic evidence.

Sep 23, 2026

Uploaded by OmBimo

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. BRAFV600E activates the MAPK pathway and suppresses genes involved in iodine metabolism and differentiation. Although associated with adverse clinicopathological features and outcomes such as extrathyroidal extension, metastasis, recurrence, and mortality, its role as an independent prognostic marker remains controversial. Evidence is inconsistent for risk refinement across tumor sizes, and the mutation contributes to radioactive iodine refractoriness. Genomic and transcriptomic heterogeneity shape treatment response. Targeted BRAFV600E therapies, including selective BRAF/MEK inhibitors and redifferentiation strategies to restore RAI avidity, support increasingly personalized management.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages14

Reading Time35 min

AccessFree to download

Abstract

Introduction

European Thyroid Journal (2025) 14 e250225 [https://doi.org/10.1530/ETJ-25-0225](https://doi.org/10.1530/ETJ-25-0225) REVIEW Received 24 July 2025 Accepted 9 December 2025 Available online 10 December 2025 Version of Record published 23 December 2025 | BRAF V600E in thyroid cancer: navigating prognostic uncertainty and therapeutic opportunity
Garcilaso Riesco-Eizaguirre􀀁1,2
1Department of Endocrinology and Nutrition, Hospital Universitario de Móstoles, Madrid, Spain
2Molecular Endocrinology Group, Faculty of Medicine, Universidad Francisco de Vitoria, Madrid, Spain
Correspondence should be addressed to G Riesco-Eizaguirre: [g.riesco.prof@ufv.es](g.riesco.prof@ufv.es)
This article forms part of a special collection titled ‘ Novel Insights in Advanced Thyroid Carcinoma: From Mechanisms to Treatments’. The editors of this collection are Dr Iñigo Landa (Group Leader, Institut Gustave Roussy in Villejuif, Grand Paris, France), Professor Iwao Sugitani (Graduate School Professor & Chairman, Department of Endocrine Surgery, Nippon Medical School, Tokyo, Japan) and Professor Eﬁsio Puxeddu (Associate Professor of Endocrinology, Department of Medicine and Surgery, University of Perugia, Italy) . | | --- | | Abstract
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. BRAFV600E, 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 BRAFV600E 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 BRAFV600E-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.
Keywords: thyroid cancer; BRAF V600E; risk stratiﬁcation; heterogeneity; therapeutic target | Introduction BRAF mutations are found in approximately 4–8% of all cancers, with the highest prevalence in melanoma, thyroid cancer, colorectal cancer (CRC), and non-small cell lung cancer (NSCLC) (1, 2) . The most common mutation is V600E, which accounts for over half of all BRAF mutations. The BRAF V600E mutation was ﬁrst Published by Bioscientiﬁca Ltd. [https://etj.bioscienti](https://etj.bioscienti)ﬁ[ca.com](ca.com) © 2025 the author(s) This work is licensed under a Creative Commons Attribution 4 .0 International License. G Riesco-Eizaguirre European Thyroid Journal (2025) 14 e250225 [https://doi.org/10.1530/ETJ-25-0225](https://doi.org/10.1530/ETJ-25-0225) identiﬁed in thyroid cancer in 2003, showing a

FAQs

What biological effects does BRAFV600E have in thyroid cancer?

BRAFV600E activates the MAPK pathway and suppresses genes involved in iodine metabolism and differentiation, lowering the thyroid differentiation state.

Why is BRAF V600E prognostic value considered controversial?

Although it correlates with adverse features and worse outcomes, its utility as an independent prognostic marker remains contested, and evidence is inconsistent for risk stratification in certain tumor sizes.

How does BRAF V600E influence treatment opportunities?

It contributes to radioactive iodine refractoriness and drives novel therapeutic strategies, including selective BRAF and MEK inhibitors, with combination therapy approved for BRAF V600E-mutant anaplastic thyroid carcinoma and indications extended to other thyroid cancers based on tumor-agnostic evidence.

Sep 23, 2026

Uploaded by OmBimo