Redifferentiation Therapies in Thyroid Oncology: Molecular and Clinical Aspects

Abstract

Since the 1940s, 131-I radioiodine therapy (RIT) has been the primary treatment for metastatic differentiated thyroid cancer (DTC). Approximately half of these patients respond favorably to RIT, achieving partial or complete remission or maintaining long-term stable disease, while the other half develop radioiodine-refractory DTC (RAI-R DTC). The main genomic alteration involved in radioiodine resistance is the activated mitogen-activated protein kinase (MAPK) pathway, which results in the loss of sodium iodide symporters (NIS). Therefore, RAI-R DTC requires alternative treatment options such as tyrosine kinase inhibitors. Over the past decade, several studies have investigated pharmacological induction or enhancement of NIS expression through "redifferentiation" therapies, mainly targeting the MAPK pathway. These novel approaches can restore radioiodine sensitivity in previously refractory patients and, therefore, potentially reestablish the efficacy of RIT. This review discusses various redifferentiation strategies, including their molecular mechanisms and clinical implications.

Keywords: BRAF; MEK; NTRK; RET; differentiated thyroid cancer; radioactive iodine refractory; redifferentiation; tyrosine kinase inhibitors.

Figure 1

Patient with negative post-treatment whole-body radioiodine scintigraphy (A) and multiple [¹⁸F]FDG-avid lesions (B). Legend: male, 67 years, affected by papillary thyroid carcinoma with increasing thyroglobulin level 2 years after thyroidectomy and radioiodine therapy [4.4 GBq]. (A) Post-treatment whole-body scintigraphy [7.4 GBq] showing no radioiodine-avid lesions. (B) [¹⁸F]FDG PET/CT: multiple [¹⁸F]FDG-avid lesions in the mediastinum and lung, with an associated [¹⁸F]FDG-active pleural effusion (right side), and [¹⁸F]FDG-avid lesions in the retroperitoneal region. A biopsy on an abdominal lesion confirmed metastasis of papillary thyroid carcinoma.

Figure 2

Mixed metabolic features in patient with metastatic follicular thyroid carcinoma. Multiple [¹⁸F]FDG avid (A) and radioiodine avid lesions (Ba, anterior; Bp posterior). Legend: male, 48 years, referred to the emergency room for intense pain corresponding to the right scapula. Multiple bone, lymph node, lung, liver, and renal metastasis at computed tomography. Bone biopsy (right scapula): follicular thyroid carcinoma. (A) preoperative [¹⁸F]FDG PET/CT: gross involvement of the thyroid gland and multiple intensely [¹⁸F]FDG-avid metastasis. Post-treatment whole body scan (Ba, anterior; Bp, posterior): intense radioiodine-avidity of most [¹⁸F]FDG-avid metastases.

Figure 3

Redifferentiation of radioiodine-refractory disease. Legend: Male, 63 years, affected by a papillary thyroid carcinoma [pT3a(m), pN1b, pMx] developed multiple lung and bone metastasis without iodine-uptake whole-body scintigraphy 5 days after administration of 7.4 GBq I-131 (Aa, anterior; Ap, posterior). An off-label treatment with dabrafenib (150 mg/2xday) and trametinib (2 mg/day) was started after approval from the insurance company. Two months later, 7.4 GBq of I-131 were administered, and the post-treatment whole-body scintigraphy (Ba, anterior, Bp, posterior) showed multiple, intensely radioiodine-avid lesions at the level of the lymph nodes, lungs, and musculoskeletal metastases. Six months after treatment, a partial biochemical response was recorded with a thyroglobulin decrease from 2276 to 825 μg/L.

Figure 4

Clinical flowchart in redifferentiation therapies. Legend: FTC, follicular thyroid carcinoma; Tg, thyroglobulin; TgA, thyroglobulin antibodies; T4, thyroxine, rhTSH, recombinant human thyroid-stimulating hormone; PET/CT, positron-emission tomography.