ORF12-05 - Association of Sodium Iodide Symporter (NIS) Expression with 2025 American Thyroid Association (ATA) Guidelines Estimated Risk of Structural Recurrence

The sodium iodide symporter (NIS) mediates active iodide transport into thyroid follicular cells and is encoded by the SLC5A5 gene. Functional NIS is required for radioiodine (RAI) uptake and NIS expression may serve as a marker for thyroid tumor differentiation status. Here, we retrospectively evaluated the expression of NIS in a cohort of Afirma Genomic Sequencing Classifier (GSC) tested thyroid nodules and correlated the level with the 2025 ATA estimated risk of structural recurrence based on the final histopathology of resected tumors from a single center. Samples were collected from 2018-2024 and 198 Afirma GSC-(S)uspicious samples were included. Of these, 125 samples had no ATA risk assigned due to either benign or NIFTP final histopathology. The median patient age was 55 and 70% were female. All had (B)ethesda III or IV cytology and 79% were BIII. ATA risk categories were 18% high, 19% intermediate-high (I-H), 11% intermediate-low (I-L), and 52% low risk. Relative to the median NIS expression in a cohort of Afirma GSC-(B)enign, there was no significant difference in NIS expression level in ATA low risk cancers and those lesions that were benign or NIFTP. NIS expression was significantly higher in ATA low risk versus all other categories combined (p < 0.01) and ATA high risk alone (p=0.046). A similar pattern was seen amongst the Afirma GSC-S samples with surgical resection. There was no discrimination of higher risk ATA categories by expressed variants or fusions. In a subset of samples tested from 2020-2024 with Afirma Genomic Resource for Intelligent Discovery (GRID – a resource of mRNA signatures) analysis, odds ratios were calculated using logistic regression to associate the top quartile versus the lowest quartile of expression by ATA risk category. When comparing ATA high, I-H, and I-L versus ATA low lesions, only lower NIS expression and the T cell accumulation signature were statistically significant (OR 0.11 and 0.24 respectively, p< 0.05) out of 31 data points. The same pattern was seen when comparing ATA high and I-H vs I-L and low (OR NIS – 0.2, T cell accumulation – 0.15, p< 0.05 for both). In summary, NIS mRNA expression in preoperative Afirma tested samples appears to inversely correlate with ATA estimated risk of recurrence category. This data suggests that NIS expression may serve as a prognostic tool to help risk stratify thyroid tumors with Afirma GSC-S results. Larger, multi-institutional, prospective, studies will be important to confirm that NIS expression can be confidently utilized in patient management for patients with molecularly tested thyroid nodules.