Prognostic significance of TERT promoter and BRAF mutations in TIR-4 and TIR-5 thyroid cytology

Abstract

Objective Follicular-derived thyroid cancers generally have a good prognosis, but in a minority of cases, they have an aggressive behavior and develop distant metastases, with an increase in the associated mortality. None of the prognostic markers currently available prior to surgery can identify such cases. Methods TERT promoter and BRAF gene mutations were examined in a series of 436 consecutive TIR-4 and TIR-5 nodes referred for surgery. Follow-up (median: 59 months, range: 7–293 months) was available for 384/423 patients with malignant nodes. Results TERT promoter and BRAF mutations were detected in 20/436 (4.6%) and 257/434 thyroid nodules (59.2%), respectively. At the end of the follow-up, 318/384 patients (82.8%) had an excellent outcome, 48/384 (12.5%) had indeterminate response or biochemical persistence, 18/384 (4.7%) had a structural persistence or died from thyroid cancer. TERT promoter mutations correlated with older age (P < 0.0001), larger tumor size (P = 0.0002), oxyntic and aggressive PTC variants (P = 0.01), higher tumor stages (P < 0.0001), distant metastases (<0.0001) and disease outcome (P < 0.0001). At multivariate analysis, TERT promoter mutation was not an independent predictor of disease outcome. TERT promoter mutation- (OR: 40.58; 95% CI: 3.06–539.04), and N1b lymph node metastases (OR: 40.16, 95% CI: 3.48–463.04) were independent predictors of distant metastases. BRAF mutation did not predict the outcome, and it correlated with a lower incidence of distant metastases (P = 0.0201). Conclusions TERT promoter mutation proved an independent predictor of distant metastases, giving clinicians the chance to identify many of the patients who warranted more aggressive initial treatment and closer follow-up.

Incremental utility of expanded mutation panel when used in combination with microRNA classification in indeterminate thyroid nodules

“…[16][17][18][19]21 They are also considered an independent risk factor for persistent disease, distant metastases, and mortality for well differentiated thyroid cancer. 16,20 Given this prognostic information, inclusion of TERT promoter mutation testing in the expanded panel may provide enhanced clinical utility. In our study, nodules with strong drivers, such as TERT, typically had positive microRNA results consistent with high risk of malignancy, the majority of which were strong positive microRNA results that are highly specific for malignancy.…”

“…[10][11][12] BRAF-related fusion transcripts have also been associated with BRAFV600E-like properties, although they are more commonly found in pediatric thyroid cancer populations 11,[13][14][15] TERT promoter mutations have been strongly correlated to persistent disease, aggressive forms of cancer, distant metastasis, and mortality. [16][17][18][19][20][21] Other oncogenic drivers can present a challenge to guiding patient management when they alone are used to assess malignancy risk.…”

Multiplatform molecular test performance in indeterminate thyroid nodules

“…4,5 Strong driver mutations that are highly predictive of malignancy, such as BRAF V600E mutations, RET fusions, and TERT promoter mutations, have proven useful in surgical decision making. [6][7][8][9][10][11][12][13] However, the most common mutations in indeterminate nodules are RAS, which are weak driver mutations with a lower PPV. In recent studies of RAS mutations, the PPV ranged from only 10% to 37% across multiple institutions.…”

“…4,21,22 The expanded mutation panel includes NTRK and ALK fusions that have targeted therapies, as well as TERT and RET protooncogene mutations that are markers of aggressive disease. 6,[23][24][25][26][27][28] In MPTX testing, samples with no detectable mutational change and those that have weak driver mutations are further risk stratified using the microRNA classifier, which incorporates two thresholds for malignancy risk. 29 The first threshold was designed to optimize sensitivity for malignancy while the second threshold was designed to maximize specificity.…”

“…All and RET mutations and BRAF and RET related fusions are categorized as strong oncogenic drivers based on their established high PPV for malignancy, BRAF V600E-like signatures, and/or association with aggressive disease. [6][7][8][9][11][12][13]25,34 In MPTX, all other mutations and fusions are categorized as weak oncogenic drivers based on literature supporting their presence in both benign and malignant thyroid nodules, their RAS-like signatures, and/or the lack of literature supporting their high PPV for malignancy or aggressive behavior. Test performance was also examined after results of the study cohort were prevalence-adjusted to reflect the proportions of distinct histopathologic subtypes observed in a different study.…”