From the Guidelines
The pathophysiology of RAI-Refractory Differentiated Thyroid Cancers (RAI-R DTCs) is characterized by the loss of iodine uptake and metabolism capabilities due to genetic alterations, epigenetic modifications, and tumor heterogeneity, leading to decreased or absent expression of the sodium-iodide symporter (NIS) and other thyroid-specific genes. The most recent and highest quality study on this topic is from 2022, which provides an update on the use of systemic therapy in advanced thyroid cancer 1. Key mechanisms involved in RAI-R DTCs include:
- Genetic alterations in the MAPK pathway, such as BRAF V600E mutations
- RET/PTC rearrangements and RAS mutations
- Epigenetic modifications, including hypermethylation of the NIS promoter
- Tumor heterogeneity, with some cells retaining iodine-concentrating ability while others lose it completely These changes lead to dedifferentiation of thyroid cancer cells, causing downregulation of thyroid-specific genes involved in iodine metabolism, including NIS, thyroid peroxidase (TPO), thyroglobulin (Tg), and the TSH receptor. Additionally, the PI3K/AKT/mTOR pathway activation contributes to RAI refractoriness by promoting cell proliferation and survival independent of iodine metabolism. Understanding these molecular mechanisms has led to targeted therapies like multikinase inhibitors (lenvatinib, sorafenib) and redifferentiation strategies using MEK inhibitors or BRAF inhibitors to restore iodine avidity in some patients with RAI-R DTCs, as supported by studies such as those referenced in 1, 1, 1, 1, 1, and 1.
From the FDA Drug Label
The FDA drug label does not answer the question.
From the Research
Pathophysiology of RAI-Refractory Differentiated Thyroid Cancers (RAI-R DTCs)
- RAI-R DTCs are a challenging malignancy with limited prognosis and treatment options 2
- The development and progression of DTC are associated with a series of consistent abnormalities in pathways such as MAPK/ERK and PI3/Akt, which govern cellular growth, proliferation, apoptosis, and angiogenesis 3
- Molecular mutations found in RAI-refractory thyroid cancer include BRAF V600E mutation, which can be targeted with BRAF inhibitors 2, 4
Treatment Options for RAI-R DTCs
- Targeted therapies, such as sorafenib and lenvatinib, have shown activity in RAI-R DTCs and are being used as first-line treatment 5, 6, 2, 4
- Other multi-targeted tyrosine kinase inhibitors, such as axitinib, motesanib, pazopanib, sunitinib, and vandetinib, are also being investigated for the treatment of RAI-R DTCs 4
- Inhibitors of BRAF, mammalian target of rapamycin, and MEK are also being considered for the treatment of RAI-R DTCs 4
Management of RAI-R DTCs
- Patient selection, initiation of therapy, follow-up, and management of adverse events are crucial in the management of RAI-R DTCs 6
- Tumor size and growth rate are the primary considerations for making treatment decisions 5
- Proactive management of side effects is also critical in optimizing the effectiveness of treatment 5
- A multidisciplinary approach, including patient education and engagement, is essential for the management of RAI-R DTCs 6