Risk assessment for distant metastasis in differentiated thyroid cancer using molecular profiling: A matched case‐control study

BACKGROUND: Risk stratification for patients with differentiated thyroid cancer (DTC) is based primarily on pathologic tumor characteristics. Accurate preoperative prognostication could allow for more informed initial surgical recommendations, particularly among patients at a higher risk for distant metastasis (DM). The objective of this study was to characterize the genetic profile of DTC with DM and to validate a molecular‐based risk stratification. METHODS: A case‐control study design was used to analyze patients who had DTC with DM (n = 62) and a propensity matched cohort of patients who had DTC without DM after at least 5 years of follow‐up using the ThyroSeq version 3 targeted next‐generation sequencing assay. The results were classified into high‐risk, intermediate‐risk, and low‐risk of aggressive disease. RESULTS: Most patients who had DTC with DM (66%) had a late‐hit mutation in TERT, TP53, or PIK3CA. After propensity matching by age, tumor size, and sex, the high‐risk molecular profile had strong association with DM (high‐risk vs intermediate‐risk: odds ratio, 25.1; 95% CI, 3.07‐204.4; P < .001; high‐risk vs low‐risk: odds ratio, 122.5; 95% CI, 14.5‐1038.4; P < .001). Overall, molecular risk categories were associated with DM risk, with a concordance index of 0.836 (95% CI, 0.759‐0.913), which remained consistent after internal validation. Within the range of 5% to 10% of DM observed in DTC, the expected probability of DM would be 0.2% to 0.4% for the low‐risk molecular profile, 4.7% to 9.4% for the intermediate‐risk molecular profile, and 19.3% to 33.5% for the high‐risk molecular profile. CONCLUSIONS: In this matched case‐control study, genetic profiling using an available molecular assay provided accurate and robust risk stratification for DM in patients with DTC. The availability of preoperative prognostication may allow tailoring treatment for patients with DTC.