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Molecular Profile of Advanced Radioiodine-refractory Thyroid Cancer and Response to Lenvatinib Treatment

Elisa Minaldi1, Teresa Ramone1, Raffaele Ciampi1

  • 1Department of Clinical and Experimental Medicine, Endocrinology Unit, University of Pisa, Pisa 56124, Italy.

The Journal of Clinical Endocrinology and Metabolism
|March 27, 2026
PubMed
Abstract

Insights

Molecular profiling of radioiodine-refractory thyroid cancer (RAIR-TC) treated with lenvatinib reveals TERT mutations are common. Patients with a single driver mutation showed improved survival, while those with no mutations or TERT co-mutations responded poorly.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • The predictive value of genetic mutations for lenvatinib response in advanced radioiodine-refractory thyroid cancer (RAIR-TC) remains unclear.
  • Understanding the molecular landscape of RAIR-TC is crucial for optimizing treatment strategies.

Purpose of the Study:

  • To define a molecular signature in RAIR-TC patients treated with lenvatinib.
  • To investigate the impact of this molecular signature on clinical outcomes and lenvatinib response.

Main Methods:

  • Retrospective analysis of 49 RAIR-TC patients receiving first-line lenvatinib.
  • Next-generation sequencing (NGS) of tumor tissues to identify genetic alterations.
  • Median follow-up of 9.2 years.

Main Results:

  • BRAF (38.7%) and RAS (22.4%) were the most frequent driver mutations; TERT mutations occurred in 57.1%.
  • Patients with any mutation had significantly longer progression-free survival (PFS) than mutation-negative cases (P = .004).
  • A single driver mutation correlated with longer overall survival (OS) compared to no driver mutations or driver mutations co-occurring with TERT/TP53.

Conclusions:

  • RAIR-TC exhibits a heterogeneous molecular profile, with TERT mutations being the most prevalent.
  • Lack of mutations or co-occurrence of TERT with driver mutations predicted a worse response to lenvatinib.
  • The presence of a single driver mutation was associated with a better clinical response to lenvatinib.
Keywords:
BRAFRASlenvatinibradioiodine-refractory thyroid cancerthyroid carcinoma

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