# Association between clinical and pathological factors and risk of radioiodine refractory in patients with differentiated thyroid carcinoma

## TL;DR

This study identifies clinical and molecular factors linked to radioiodine resistance in thyroid cancer, helping improve patient risk assessment and treatment strategies.

## Contribution

The study reveals new insights into the combined role of clinical and molecular factors in predicting radioiodine resistance in differentiated thyroid carcinoma.

## Key findings

- RAIR-DTC patients more frequently underwent total thyroidectomy with radical lymph node dissection, indicating aggressive tumor behavior.
- Multivariate analysis identified total radiation dose, absence of distant metastases, and number of removed lymph nodes as significant risk factors for radioiodine resistance.
- The co-occurrence of BRAF and TERT mutations was associated with radioiodine resistance and may have prognostic value.

## Abstract

Currently, the therapeutic treatment of differentiated thyroid carcinoma (DTC) is based on the use of radioactive iodine; the effectiveness of treatment depends on the sensitivity of tumor cells to therapy. Factors associated with a high risk of radioactive iodine resistance of DTC (RAIR-DTC) are poorly understood in the current literature, but understanding their role may help optimize patient care. The aim of our study is to assess the relationship between the clinical and pathological characteristics of DTC and the risk of radioiodine resistance.

We conducted a case-control study involving a targeted sample of patients with differentiated thyroid carcinoma (DTC). The study included a total of 373 patients, of whom 60 were radioiodine-resistant and 313 were radioiodine-sensitive. For the molecular analysis, an additional sub-cohort was selected from the overall sample (n = 167), in which mutations in BRAF V600E, NRAS (codon 61) and pTERT (C228T/C250T) were determined using ddPCR.

In the group of patients with RAIR-DTC, total thyroidectomy with radical lymph node dissection was performed twice as often, which indicates more aggressive tumor invasion in this category of patients (p<0.001). The main risk factors for RAIR-DTC were female gender, total thyroidectomy with radical lymph node dissection, the presence of metastases in the lymph nodes, the total radiation dose, the absence of distant metastases, and the total number of lymph nodes removed, in the histological subcohort (n = 167), the presence of the double BRAF+pTERT mutation was also identified. Multivariate regression analysis showed that statistically significant risk factors for radioiodine resistance were the total radiation dose, the absence of distant metastases, and the total number of removed lymph nodes. These results were confirmed by ROC analysis; AUC was 0.796 (95% CI 0.726-0.865), p<0.0001.

The obtained data highlight the interplay between clinical and molecular factors in the development of radioiodine resistance in differentiated thyroid cancer (DTC). The co-occurrence of BRAF and TERT mutations has potential prognostic significance. These findings suggest that integrating clinical and molecular data enables more accurate risk stratification for radioiodine resistance and helps define the direction of future research.