Redifferentiation in Radioiodine-Refractory Thyroid Cancer: Is Restoring Iodine Uptake Enough?

Abstract

Radioiodine (RAI) refractoriness represents a major turning point in the natural history of differentiated thyroid cancer (DTC). Loss of iodine avidity may reflect suppression of the molecular machinery responsible for iodine transport and metabolism, frequently driven by constitutive activation of the MAPK pathway. Pharmacologic inhibition of this pathway has therefore generated considerable interest as a strategy to restore thyroid differentiation and potentially re-enable treatment with RAI. The systematic review and meta-analysis published in this issue offers a useful opportunity to reconsider what redifferentiation has actually achieved so far and what remains uncertain. In the present meta-analysis, short-term MAPK inhibition restored detectable RAI uptake in 62.3% of patients, although the proportion decreased when a more stringent therapeutic dosimetric threshold was applied (1). Across prospective studies, depending on the molecular context, treatment regimen, imaging methodology, and definition of successful redifferentiation, restoration of iodine uptake has ranged from approximately 60% to more than 90%. In the phase II MERAIODE trial, for example, abnormal uptake was observed in 95% of post-treatment scans following dabrafenib plus trametinib in patients with BRAF V600E-mutated DTC.

However, restoring iodine uptake and restoring RAI sensitivity are not necessarily equivalent. This distinction is probably the central question surrounding redifferentiation today. Structural responses are consistently less frequent than restoration of iodine avidity. In prospective studies, objective responses after subsequent RAI therapy have been variable and generally less frequent than restoration of iodine uptake (2-4). In MERAIODE, the 6-month partial response rate was 38% in BRAF V600E-mutated tumors and 20% in the RAS-mutated cohort.