Redifferentiation with selpercatinib in radioactive iodine-refractory differentiated thyroid carcinoma harboring RET fusions: A mini review and case report

Rearranged during transfection (RET) fusions are the significantly oncogenic drivers of thyroid cancer, frequently identified in pediatric patients and adolescents, and associated with aggressive clinicopathologic features. These fusions drive tumor cell proliferation and dedifferentiation by inducing abnormal activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling pathways. Furthermore, they downregulate the expression of the sodium iodide symporter (NIS), thereby contributing to radioactive iodine refractory (RAIR). It is worth noting that differentiated thyroid cancer (DTC) with RET fusions frequently manifests a unique clinical paradox, characterized by radioactive iodine (RAI) avidity despite disease progression. This RAI uptake manifestation usually misguides clinical decision-making, resulting in redundant repetition of RAI treatment (RAIT) with suboptimal therapeutic response. Fortunately, over the past five years, there has been significant progress in the treatment of progressive or symptomatic RAIR-DTC patients with RET fusions. These patients can now be treated with the selective RET inhibitors, such as selpercatinib, which demonstrate favorable therapeutic efficacy and safety profile. Furthermore, these inhibitors have the potential to restore RAI uptake through redifferentiation. This article first addresses the oncogenic mechanism, distinctive RAI uptake features of DTC with RET fusions, and the promising therapeutic redifferentiation strategy combining selective RET inhibitors with RAIT. The subsequent presentation of a RAIR-DTC case with RET fusion demonstrated redifferentiation in response to selpercatinib, which enabled subsequent RAIT. The partial response (PR) was maintained thereafter for 15 months, despite a reduction in the dose of selpercatinib to two-thirds of the initial level.