Preoperative Risk Stratification of Differentiated Thyroid Carcinoma Using a Molecular Cell Cycle Progression Score: Association with American Thyroid Association (ATA) Risk of Recurrence

Introduction

Alterations in cell cycle regulatory genes may lead to abnormal cellular proliferation, tumor development, and malignancy. At ENDO 2024, the development and molecular characterization of a cell cycle progression (CCP) transcriptomic activity score was presented showing that the highest CCP scores were correlated with worse clinical outcomes in a papillary thyroid carcinoma cohort from The Cancer Genome Atlas (TCGA) Thyroid and with higher risk molecular alterations such as TERT promoter mutations in an Afirma Genomic Sequencing Classifier (GSC) tested thyroid nodule cohort. The aim of this study was to analyze the correlation of CCP scores to the American Thyroid Association (ATA) risk of structural recurrence in a cohort of patients with differentiated thyroid carcinoma (DTC), in whom Afirma GSC testing was performed.

Methods

This retrospective study assessed a cohort of 170 patients with DTC from two medical centers. All included malignant thyroid nodules had either (B)ethesda III/IV cytology and were Afirma GSC-(S)uspicious or had B V/VI cytology. The CCP activity score was correlated with the Bethesda cytology and ATA risk of recurrence categories as well as the presence of BRAFp.V600E mutation using the Wilcoxon Rank-Sum Test.

Results

The cohort consisted of malignant thyroid nodules in the following Bethesda categories: 95 B III, 45 B IV, and 30 B V/VI. ATA risk categories included 149 ATA (L)ow, 20 ATA (I)ntermediate, and 1 ATA (H)igh DTC samples. ATA I and H groups were combined (ATA I-H) when comparing the CCP score against the ATA L group. The CCP score was significantly higher in ATA I-H than ATA (L) group (p = 0.03). There was no linear direct correlation between CCP score and Bethesda category. When B III/IV and B V/VI were grouped together, no significant difference in the CCP score was observed between the two groups (p = 0.14). Within B III/IV nodules, there was no difference in CCP score between ATA I-H and L (p = 0.55), but the CCP was significantly higher in B V/VI nodules with ATA I-H risk vs ATA L (p = 0.02). Finally, within BRAFp.V600E+ Bethesda V/VI nodules, the CCP was significantly higher in ATA I-H vs ATA L (p = 0.038).

Conclusion

This preliminary data suggests that the CCP activity score may have an added prognostic role in the pre-operative stratification of cytologically indeterminate – GSC-S and malignant thyroid nodules with regards to their ATA risk of recurrence classification. Importantly, this is evident even within BRAFV600E+ thyroid cancer, with higher CCP scores being associated with higher ATA risk of recurrence classification. Future studies with larger cohorts will be important to determine the broader utility of the CCP score as a preoperative prognostic tool.