The Association Between Thyroid Differentiation Score and Survival Outcomes in Papillary Thyroid Carcinoma

Context: Thyroid differentiation score (TDS), calculated based on mRNA expression levels of 16 genes controlling thyroid metabolism and function, has been proposed as a measure to quantify differentiation in papillary thyroid carcinoma (PTC). Objective: The objective of this study is to determine whether TDS is associated with survival outcomes across patient cohorts. Methods: Two independent cohorts of patients with PTC were used: (1) The Cancer Genome Atlas (TCGA) thyroid cancer study (N = 372), (2) MD Anderson Cancer Center (MDACC) cohort (N = 111). The primary survival outcome of interest was progression-free interval (PFI). Association with overall survival (OS) was also explored. The Kaplan–Meier method and Cox proportional hazards models were used for survival analyses. Results: In both cohorts, TDS was associated with tumor and nodal stage at diagnosis as well as tumor driver mutation status. High TDS was associated with longer PFI on univariable analyses across cohorts. After adjusting for overall stage, TDS remained significantly associated with PFI in the MDACC cohort only (adjusted hazard ratio [aHR] 0.67, 95% CI 0.52-0.85). In subgroup analyses stratified by tumor driver mutation status, higher TDS was most consistently associated with longer PFI in BRAFV600E-mutated tumors in the MDACC cohort after adjusting for overall stage (TCGA: aHR 0.60, 95% CI 0.33-1.07; MDACC: aHR 0.59, 95% CI 0.42-0.82). For OS, increasing TDS was associated with longer OS in the overall MDACC cohort (aHR = 0.78, 95% CI 0.63-0.96), where the median duration of follow-up was 12.9 years. Conclusion: TDS quantifies the spectrum of differentiation status in PTC and may serve as a potential prognostic biomarker in PTC, mostly promisingly in BRAFV600E-mutated tumors.