Risk of Structural Disease Recurrence Reclassification of Differentiated Thyroid Cancer from 2015 to 2025 American Thyroid Association (ATA) Guidelines

Introduction

• The 2025 American Thyroid Association (ATA) Thyroid Cancer guidelines¹ subdivided the 2015 intermediate risk of recurrence group into low-intermediate (L-I) and intermediate-high (I-H) groups and incorporated histologic specific categories.
• Thyroid cancers in a 2015 risk category may be assigned to a different 2025 category based on these changes.
• The Afirma Genomic Sequencing Classifier (GSC) utilizes whole-transcriptome-derived RNA sequencing as the test platform providing a wealth of mRNA data for every sample analyzed.

Methods

• A retrospective, single-center study of thyroid cancer cases that underwent Afirma Genomic Sequencing Classifier testing as part of routine clinical care.
• Each case was assigned 2015 and 2025 ATA risk of recurrence labels.
• Cases that shifted categories were compared with those that remained stable.
  • Most shifts were from the 2015 ATA low risk category; therefore, it was used as the reference for demographic and molecular differences.
  • ATA 2025 I-H and high samples were combined for analysis.
• Expressed molecular variants and fusions and differences in Afirma Genomic Resource for Intelligent Discovery (GRID) data were evaluated.
• Statistical analyses utilized the Mann-Whitney U Test for three pairwise group comparisons across 35 GRID signature pathways: 2015/2025 ATA low vs. 2025 L-I, 2015/2025 ATA low vs. 2025 I-H, and 2025 I-L vs. 2025 I-H. Fisher’s exact test was used to assess differences in categorical demographic variables, while the Kruskal-Wallis test was used for continuous variables.

Results

• Seventy-two cases were classified using ATA 2025 criteria: 26 low, 19 L-I, 16 I-H, and 11 high (Table 1):
  • Of the 3 cancers that were 2015 ATA high risk, all 3 remained high risk by 2025 classification (Figure 1).
  • Of 45 ATA 2015 low risk cancers, only 25 remained low risk in 2025, while 15 shifted to L-I, 3 to I-H, and 2 to high risk (Figure 1).
• Average tumor size increased across 2025 risk strata (p=NS, Table 2):
  • Low (1.7 cm) to L-I (2.05 cm) to I-H/high (3.02 cm).
  • No significant differences were seen in age, sex, or Bethesda category between groups.
• There were no significant differences in the proportion of expressed variants and fusions (by Afirma Xpression Atlas (XA)) between cancers that remained low risk from 2015–>2025 and those that were reclassified to a higher risk category in 2025 (Table 3).
• Analysis of Afirma GRID molecular hallmarks of cancer showed a trend for linear decreases in Immunomodulatory signature signaling and Apical surface hallmark while there was a linear increase in Angiogenesis hallmark signaling from 2025 ATA low to ATA I-H/high groups (p = 0.1, Figure 2).