Restoring Radioiodine Avidity in Radioiodine-refractory Differentiated Thyroid Cancer With Genotype-guided MAPK Inhibition and Dosimetry-guided Radioiodine

BACKGROUND: To evaluate the real-world effectiveness and safety of short-course MAPK pathway inhibition, integrated with individualized dosimetry, as a redifferentiation strategy in patients with radioiodine-refractory differentiated thyroid cancer (RAIR-DTC). PATIENTS AND METHODS: This retrospective single-center cohort included 11 patients with RAIR-DTC who underwent genotype-directed redifferentiation therapy with trametinib (±BRAF inhibition) followed by dosimetry-guided radioiodine therapy. Redifferentiation success was defined on post-redifferentiation diagnostic 123 I SPECT/CT as either a ≥30% increase in iodine uptake compared with baseline or any lesion demonstrating activity ≥2 times the mean hepatic uptake. RECIST 1.1 assessments were anchored to the pre-RAI dosimetry time point to isolate the therapeutic contribution of 131 I Clinical, biochemical, and imaging outcomes, including repeat redifferentiation cycles, were recorded. RESULTS: Restoration of iodine avidity occurred in 10 of 11 patients (91%; exact 95% CI, 0.59-1.00). Two patients underwent a second redifferentiation-plus-RAI cycle, both achieving successful reinduction of uptake and durable disease control. Among the 10 patients who received 131 I, partial response was observed in 8 (80%), stable disease in 1 (10%), and progression in 1 (10%) at 6-month imaging. Serum thyroglobulin trends were generally concordant with structural responses, although interpretation was limited by anti-Tg interference in 3 cases. No grade ≥3 adverse events occurred during redifferentiation or subsequent RAI. Median follow-up was 39 months (IQR: 20-54). CONCLUSIONS: Short-course, genotype-directed MAPK inhibition effectively restored iodine avidity and enabled safe, dosimetry-guided radioiodine therapy in a real-world RAIR-DTC cohort. Early structural responses were frequent, toxicity was minimal, and selected patients benefited from repeat redifferentiation cycles. These findings support the use of redifferentiation as a practical bridge to effective RAI and underscore the value of individualized dosimetry in modern RAIR-DTC management.