Abstract 5776: Predictors of radioactive iodine refractoriness in papillary thyroid carcinomas

Abstract

Abstract Optimized surgery and radioactive iodine (131I, RAI) are the cornerstone of treatment for papillary thyroid carcinoma (PTC). Although standard treatment is curative for most, 5-20% of PTC patients develop RAI refractory disease – the main cause of thyroid cancer-related deaths. Early predictors indicating therapeutic response to RAI therapy in PTC are yet to be elucidated. We performed whole-exome sequencing (at a median depth of 198x) on 158 patient-matched primary PTCs and germline DNA. Clinical data was used to categorize RAI avidity in the PTC cohort. Whereby, 66 RAI refractory and 92 RAI avid tumors were identified. Clinical data and somatic variants were analyzed to compare the clinicopathological presentation, genomic landscape and mutational signatures between RAI refractory and avid PTCs. RAI refractory tumors were significantly associated with distinct aggressive clinicopathological features, including positive surgical margins (65.5% versus 26.7%; p=0.016) and the presence of lymph node metastases at primary diagnosis (62.5% versus 30.1%; p=0.012); higher nonsilent tumor mutation burden (p=0.011); and the enrichment of APOBEC-related single base substitution (SBS) COSMIC mutational signatures 2 (p=0.03) and 13 (p<0.001). APOBEC mutational signatures were not associated with BRAFV600E mutation. Notably, using multivariate logistic regression analysis only the SBS13 (odds ratio 13.01, 95% confidence intervals 1.20-140.94) APOBEC mutational signature was revealed to be an independent predictor of RAI refractoriness in PTC (p=0.035). Furthermore, using Cox proportional hazards SBS13-positive tumors (hazard ratio 3.52, 95% confidence intervals 1.79-6.91) were also significantly associated with poorer progression-free survival (p<0.001), albeit only in univariate analysis. This study highlights distinct clinical and genomic features in RAI refractory PTC, but above all proposes the APOBEC SBS13 mutational signature as an independent predictor of RAI refractoriness in a more aggressive subgroup of PTC. Where detection of RAI refractory disease following standard surgical PTC removal, and more suitable therapeutic interventions may potentially improve patient outcomes. Citation Format: Tariq Masoodi, Sarah Siraj, Abdul K. Siraj, Saud Azam, Zeeshan Qadri, Sandeep K. Parvathareddy, Khawla S. Al-Kuraya. Predictors of radioactive iodine refractoriness in papillary thyroid carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5776.