Abstract
Thanks to the identification of crucial molecular pathways, the therapeutic landscape for advanced differentiated thyroid tumors (DTCs) has significantly improved during the last ten years. The therapeutic scenario has been greatly impacted by the discovery of mutually exclusive gene changes in the MAPK and PI3K/AKT pathways, such as RET or NTRK fusions and pathogenic mutations of the BRAF and RAS genes. Indeed, multi-kinase inhibitors and selective inhibitors have demonstrated outstanding efficacy for radioactive iodine-refractory (RAI-R) drug treatment, with overall response rates reaching up to 86%. Thus, for RAI-R DTCs, routine molecular testing for actionable gene alterations is now essential, for choosing the right therapy for the right patient. Additionally, tumor genotyping also allows to identify a subset of patients with worse prognosis disease, which may deserve a tailored clinical management. Thus, the right test should also include non-driver TERT, TP53, PIK3CA, and other mutations of aggressiveness, with the aim of a molecular-based risk stratification. Therefore, tumor genotyping should be considered in the diagnostic work-up of metastatic DTC patients or with highly aggressive histological features, in order to give the right drug for the right patient at the right time.