Redifferentiation therapy with selpercatinib in RET-fusion-positive advanced thyroid carcinoma: a case report and literature review

Radioiodine-refractory differentiated thyroid carcinoma (RAI-R-DTC) represents a major therapeutic challenge, and strategies aimed at restoring iodine avidity are of increasing clinical interest. We report the case of a 58 year old woman with metastatic papillary thyroid carcinoma harboring a CCDC6:RET fusion, who developed progressive RAI-refractory disease decades after initial surgery and multiple 131 I-treatments. After a first-line cycle with Lenvatinib characterized by limited efficacy and poor tolerability, a second-line therapy with the selective RET inhibitor Selpercatinib was initiated, resulting in a sustained partial radiological response. Notably, after 17 months of treatment, a diagnostic 131 I whole-body scan following rhTSH stimulation demonstrated radioiodine uptake restoration in distant metastases, enabling successful retreatment with 131 I. This was followed by a marked biochemical response and further reduction in tumor burden, with durable disease control under combined therapy. This case illustrates Selpercatinib-induced redifferentiation in RET fusion–positive RAI-R-DTC and supports the emerging role of genotype-driven targeted therapies to restore radioiodine sensitivity. A review of the available literature underscores the potential of selective RET inhibition as a redifferentiation strategy, although further prospective studies are needed to define optimal patient selection and treatment sequencing.