Precision Thyroid Oncology Using Genetic-Based Therapies: A Narrative Review

Most thyroid malignancies harbor a limited set of well-characterized mutations driving tumor initiation and determining phenotype. This relatively direct genotype-phenotype association, bringing insights into molecular mechanisms of progression and drug resistance, makes advanced thyroid cancers suitable for genetic-based therapies. Personalized cancer treatment by targeting actionable tumor mutations represents one of the most innovative frontiers in oncology.

The present narrative review focuses on actionable mutations occurring in thyroid cancers and provides a state-of-the-art overview of genetic-based treatments that have received regulatory approval worldwide. These include two selective RET inhibitors (sRET-Is) (selpercatinib and pralsetinib), three NTRK inhibitors (NTRK-Is) (larotrectinib, entrectinib, and repotrectinib), and two dual BRAF/MEK inhibitor regimens (dabrafenib plus trametinib and encorafenib plus binimetinib). The most significant impact has been observed in the management of RET-mutant medullary thyroid cancer. Selpercatinib, available in many countries, demonstrated superiority over standard multikinase inhibitors (MKIs) in a head-to-head comparison. It currently represents the best first-line treatment option. In BRAF^V600E-positive anaplastic thyroid cancer, both dabrafenib plus trametinib and encorafenib plus binimetinib showed efficacy that appeared to exceed that historically observed with standard approaches. However, their approval is currently limited to a few countries. In radioiodine-refractory differentiated thyroid cancer (DTC), sRET-Is and NTRK-Is are effective in molecularly selected patients and are approved in many countries. However, their applicability is limited by the low prevalence of the corresponding actionable alterations. In BRAF^V600E-positive radioiodine-refractory DTC, dabrafenib plus trametinib has emerged as a useful option after MKI failure, although a tumor-specific approval has been granted only in Europe.

Precision oncology is increasingly being integrated into the management of advanced thyroid cancer. However, its impact varies widely across different tumor settings, and its real-world use is strongly influenced by country-specific drug regulations.