Telomerase reverse transcriptase (TERT) promoter mutation has been reported to be associated with aggressive characteristics in differentiated thyroid cancer (DTC). This study examined the status of TERT mutation in distant metastatic DTC and evaluated the correlation between TERT mutation and radioiodine uptake, as well as that between TERT mutation and therapy response. Methods: TERT promoter and B-Raf proto-oncogene (BRAF) V600E mutation were retrospectively examined in primary tumors of 66 patients with distant metastatic DTC. Stimulated thyroglobulin (sTg) changes, radioiodine uptake status (avid or nonavid), and other imaging evidence were analyzed to evaluate therapy response. After a median follow-up of 46.5 mo (interquartile range, 29.0–70.5 mo), therapy response was classified as either disease control or refractory. Results: The prevalence of TERT mutations was 22.73% (15/66), of which C228T mutation was more prevalent (13/15) than C250T mutation (2/15). Rising sTg was noticed in 93.33% (14/15) of the TERT mutation group. Of cases negative for both mutations, 78.12% (25/32) presented with decreased sTg. TERT mutation closely correlated with a poor response to radioiodine therapy (P < 0.001), and all 15 patients were classified as refractory to radioiodine therapy, with a positive predictive value of 100% at the endpoint of follow-up. TERT mutation was associated with older mean age at diagnosis (P < 0.001), larger mean tumor diameter (P = 0.013), and greater likelihood of both BRAF mutation coexistence (P = 0.044) and radioiodine-refractory character (P < 0.001). In the 36 cases whose imaging results underwent semiquantitative analysis, TERT mutation significantly correlated with non–radioiodine avidity, with a much lower mean tumor-to-background ratio (obtained from postradioiodine whole-body scanning) than in TERT wild-type cases (P < 0.001). In addition, patients with distant metastatic DTC with TERT mutation were more likely to lose radioiodine avidity at the initial radioiodine therapy than were those with only BRAF mutation (8/8 vs. 5/11; Fisher exact test, P = 0.018). Conclusion: TERT mutation closely associates with non–radioiodine avidity in distant metastatic DTC, and when compared with BRAF mutation, TERT mutation manifested a greater negative influence on radioiodine uptake. TERT mutation could also be used as an early predictor of radioiodine-refractory cases.

The retained functionality of the sodium iodide symporter (NIS) expressed in differentiated thyroid cancer (DTC) cells allows the further utilization of post-surgical radioactive iodine (RAI) therapy, which is an effective treatment for reducing the risk of recurrence, and even the mortality, of DTC. Whereas, the dedifferentiation of DTC could influence the expression of functional NIS, thereby reducing the efficacy of RAI therapy in advanced DTC. Genetic alternations (such as BRAF and the rearranged during transfection [RET]/papillary thyroid cancer [PTC] rearrangement) have been widely reported to be prominently responsible for the onset, progression, and dedifferentiation of PTC, mainly through activating the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling cascades. These genetic alternations have been suggested to associate with the reduced expression of iodide-handling genes in thyroid cancer, especially the NIS gene, disabling iodine uptake and causing resistance to RAI therapy. Recently, novel and promising approaches aiming at various targets have been attempted to restore the expression of these iodine-metabolizing genes and enhance iodine uptake through in vitro studies and studies of RAI-refractory (RAIR)-DTC patients. In this review, we discuss the regulation of NIS, known mechanisms of dedifferentiation including the MAPK and PI3K pathways, and the current status of redifferentiation therapy for RAIR-DTC patients.

The global annual new cases of thyroid cancer were estimated at 567 000 based on the GLOBOCAN 2018 database, and China accounted for approximately 34% of all incident cases worldwide.^1,2 Differentiated thyroid cancer (DTC) is the most common type, accounting for more than 90% of all thyroid cancers, and is composed of papillary, follicular, Hürthle cell, and poorly differentiated cancers.³ Up to 30% of patients with DTC experience disease recurrence, and 30% of the cancers eventually become refractory to radioactive iodine therapy.^4-6 Patients with radioactive iodine–refractory DTC (RAIR-DTC) have a poor prognosis, with a 10-year survival rate of 10%.^6,7 Sorafenib and lenvatinib, angiogenesis inhibitors,⁸ were found to prolong progression-free survival (PFS) in patients with RAIR-DTC in the DECISION and SELECT trials.^9,10 However, no significant benefit on overall survival (OS) was observed, except for a subgroup of patients older than 65 years in the SELECT trial.¹¹ Sorafenib and lenvatinib were not available for treatment of thyroid cancer in China until 2017 (sorafenib) and 2020 (lenvatinib). In addition, a relatively high proportion of patients with advanced disease, especially for RAIR-DTC, might also lead to the poor prognosis in China.^1,2 A large number of unmet clinical needs and the limited treatment options warrant the exploration of alternative strategies for patients with RAIR-DTC.

Overwhelming rapid metabolic and structural response to apatinib in radioiodine refractory differentiated thyroid cancer

Purpose Radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) has become a challenge in clinical practice, particularly in China with a high incidence and undesirable survival outcome. Since the publication of first China consensus on the diagnosis and treatment of RAIR-DTC in 2019, significant and rapid advances have occurred in the field both in China and internationally. This guideline aims to inform Chinese clinicians, researchers, patients, and health policy makers on the latest evidence and recommendations, to further standardize the clinical diagnosis and treatment of RAIR-DTC. Methods The structured clinical questions addressed in this guideline were derived from clinical diagnostic and treatment processes, with references to study, prior guidelines, expert consensus, and systematic reviews, etc. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used for quantitative and qualitative evaluation of the evidence. The editorial process was completely independent of the guideline development group. Results The guideline addressed 26 clinical questions and formed 35 recommendations. In this guideline, the definition criteria for RAIR-DTC was optimized, prediction and identification was based on evidence including molecular testing, dynamic biochemical changes, and multimodal imaging. Comprehensive pre-treatment clinical evaluation was emphasized and tailored for individualized decision-making. The combination of systematic therapy and surgery, and the redifferentiation followed by RAI therapy were also reviewed and updated. Molecular imaging plays a unique role in the pre-assessing and therapeutic response evaluation for RAIR-DTC. Conclusions We have updated and developed evidence-based recommendations with the aim of providing scientific, rigorous, and comprehensive guidance for the clinical diagnosis and treatment of RAIR-DTC patients in China. We hope to share our guideline with colleagues out of China, with the expectation of further comments and suggestions.

Medullary thyroid carcinoma (MTC) can only be cured through the excision of all metastatic lesions, but current clinical practice fails to localize the disease in 29% to 60% of patients. Previously, we developed a fibroblast activation protein inhibitor (FAPI)-based covalent targeted radioligand (CTR) for improved detection sensitivity and accuracy. In this first-in-class clinical trial, we head-to-head compared [68Ga]Ga-CTR-FAPI PET-CT and [18F]fluorodeoxyglucose ([18F]FDG) PET-CT in 50 patients with MTC. The primary endpoint was the patient-based detection rate, with [68Ga]Ga-CTR-FAPI exhibiting higher detection than [18F]FDG (98% vs. 66%, P = 0.0002). This improved detection was attributed to increased tumor uptake (maximum standardized uptake value = 11.71 ± 9.16 vs. 2.55 ± 1.73, P < 0.0001). Diagnostic accuracy, validated on lesions with gold-standard pathology, was greater for [68Ga]Ga-CTR-FAPI compared with [18F]FDG (96.7% vs. 43.3%, P < 0.0001). Notably, the management of 32% of patients was altered following [68Ga]Ga-CTR-FAPI PET-CT, and the surgical plan was changed for 66.7% of patients. Overall, [68Ga]Ga-CTR-FAPI PET-CT provided superior detection and diagnostic accuracy compared with [18F]FDG PET-CT, enabling precision management of patients with MTC. Significance: In this first-in-class clinical trial of CTR, [68Ga]Ga-CTR-FAPI demonstrated an improved patient-based detection rate (98%), tumor uptake (maximum standardized uptake value = 11.71 ± 9.16), and pathology-validated diagnostic accuracy (96.7%) compared with the currently approved method in MTC treatment. It directly altered management in 32% of patients, enabling precision diagnosis and management of MTC. See related commentary by Witney, p. 264