MTE5 - Medullary thyroid cancer: from genetics to clinic

Abstract

The current presentation consistently highlights that molecular profiling is central to modern management of medullary thyroid carcinoma (MTC). RET mutations drive nearly all hereditary cases and the majority of sporadic and advanced MTC, making germline testing mandatory in all patients and somatic testing essential in advanced disease for prognostic stratification and therapeutic decisions. Hereditary cases, particularly if MTC is driven by molecular alteration of the RET gene linked to the phenotype of type 2 Multiple Endocrine Neoplasia (MEN 2), need careful and specific management. It should be considered that the gene carriers, those still not affected by MTC but who carry the RET mutation, need to be followed up in a specific manner. From a clinical perspective, biochemical markers, calcitonin, and CEA, are key tools across the disease continuum. Calcitonin is crucial for early diagnosis and screening in selected thyroid nodules, while postoperative levels and doubling times are strong prognostic indicators and guide follow-up intensity. Imaging is used in a stepwise approach, escalating from ultrasound and CT scan, mainly total body with i.v. contrast medium, to functional imaging (ie, 18F-DOPA PET) in cases of biochemical or structural persistence. Management differs by risk:Low-risk or cases that are cured after surgery can often be managed with active surveillance and tailored follow-up based on biomarker trends.Advanced MTC cases require a more careful follow-up to identify those in which active therapy is needed. The progressive MTC cases, mainly according to progressions defined by a specific imaging, require systemic therapy, initiated based on tumor burden, progression rate, and symptoms rather than biochemical elevation alone. Therapeutically, multikinase inhibitors (vandetanib, cabozantinib) improve progression-free survival but are limited by toxicity and resistance. In contrast, highly selective RET inhibitors (selpercatinib) represent a major advance, offering higher response rates, better tolerability, and activity even after prior treatments—though restricted to RET-mutant disease and still challenged by resistance mechanisms. Overall, integrating molecular data, biomarkers, and imaging enables a personalized, risk-adapted approach that improves outcomes across both early and advanced MTC.