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

Abstract

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.

Clinical detection of “extremely low‐risk” follicular thyroid carcinoma: A population‐based study of 7304 patients

“…However, most studies have attempted only to determine FTC patients with high metastatic risk 8,9 and poorer outcomes 4,5,10 . Very few studies have focused on how to stratify FTC patients with low metastatic risk 11 …”

“… 4 , 5 , 10 Very few studies have focused on how to stratify FTC patients with low metastatic risk. 11 …”

DIAGNOSIS OF ENDOCRINE DISEASE: Usefulness of genetic testing of fine-needle aspirations for diagnosis of thyroid cancer

“…Therefore, particularly for aggressive cancers, these data may improve treatment decision-making by informing the triage and extent of surgery only for prognostic markers (39), radioactive iodine administration, and for setting the frequency of follow-up, according to recurrence risk stratification by current criteria most likely complemented by mutations or gene expression classifiers (84). This has been shown in practice, with a recent matched case-control study showing accurate risk stratification of distant metastasis risk by molecular risk groups (76). Simpler methods for identifying prognostic biomarkers may be more efficient than use of a commercially available gene panel, such as single-gene sequencing of TERT or similar targeted approaches, particularly when some genomic information is already available which lessens the incremental value of a large gene panel.…”

Mutational status may supersede tumor size in predicting the presence of aggressive pathologic features in well differentiated thyroid cancer

“…Therefore, further longitudinal studies would be required to assess long-term oncological behavior associated with each of these mutations. Song et al [ 44 ] and Yip et al [ 41 ] displayed, respectively, higher recurrence rates and higher 5-year risk of distant metastasis with isolated BRAF V600E -positive tumors. Also, we chose to compare only patients with documented BRAF V600E and RAS -like mutations, thereby introducing a selection bias.…”

“…Furthermore, treatment planning, including choice of surveillance and the appropriate extent of thyroid surgery (i.e., hemithyroidectomy versus total thyroidectomy and prophylactic central neck dissection) and staging of thyroid cancer often heavily rely on tumor size [37]. However, over the past few years, multiple major studies have suggested a progressive shift towards a new pathological classification of thyroid lesions, accounting for genotypic differences and consideration of individualized management depending on mutational profile [39][40][41]. Our findings indeed support this point of view, in regard to the current role and interpretation of tumor size in the management of thyroid nodules.…”