Predictive biomarkers in thyroid cancer in the current molecular-morphology paradigm

Abstract

Abstract Thyroid cancer is one of the most common types of cancer worldwide. It is a spectrum of different diseases, ranging from very indolent to lethal tumors. Differentiated Thyroid Carcinoma (DTC), the most common thyroid malignancy, has often an excellent prognosis, but some patients develop metastatic Radioiodine-Refractory disease (RAIR) that cannot be controlled locally. In this setting, and for patients with metastatic Medullary Thyroid Carcinoma (MTC) and Anaplastic Thyroid Carcinoma (ATC), systemic treatment with non-selective Multikinase Inhibitors (MKIs) is often employed to improve survival rates and quality of life. The molecular characterization of thyroid cancer showed that the main drivers of thyroid carcinogenesis not only correlate with morphological and clinical features but can be targeted by some modern and highly selective Kinase Inhibitors: vemurafenib and dabrafenib for carcinomas with BRAF V600E mutation, including Papillary Thyroid Carcinoma (PTC) and its subtypes; dabrafenib in association with the MEK1/2 inhibitor trametinib for BRAF V600E-mutant ATC; larotrectinib and entrectinib for thyroid carcinomas with NTRK fusions and selpercatinib and pralsetinib for MTC with RET point mutations and DTC with RET-fusions. Apart of those markers, Microsatellite Instability status (MSI), Tumor Mutation Burden (TMB) and PD1/PD-L1 assessment have been explored in thyroid tumors, although immunotherapy for ATC has shown only modest results. Herein, we present a comprehensive review of the most relevant molecular markers with predictive value in thyroid pathology.