Clinical impact of testing for mutations and microRNAs in thyroid nodules

Abstract

Background We report results of a multicenter clinical experience study examining the likelihood of patients with indeterminate thyroid nodules to undergo surgery or have malignant outcome based on multiplatform combination mutation and microRNA testing (MPT). Methods MPT assessed mutations in BRAF, HRAS, KRAS, NRAS, and PIK3CA genes, PAX8/PPARγ, RET/PTC1, and RET/PTC3 gene rearrangements, and the expression of 10 microRNAs. Baseline clinical information at the time of MPT and clinical follow‐up records were reviewed for 337 patients, of which 80% had negative MPT results. Kaplan Meier analysis for cumulative probability of survival without having a surgical procedure or malignant diagnosis over the course of patient follow‐up was determined for MPT results of 180 patients, among which only 14% had malignancy. Results A negative MPT result in nodules with Bethesda III or IV cytology (2009) conferred a high probability of non‐surgical treatment, with only 11% expected to undergo surgery and a high probability of survival without malignancy (92%) for up to 2 years follow up. A positive MPT result conferred a 57% probability of malignancy and was an independent risk factor for undergoing surgical treatment (Hazard Ratio [HR] 9.2, 95% confidence intervals 5.4‐15.9, P < .0001) and for malignancy (HR 13.4, 95% confidence intervals 4.8‐37.2, P < .0001). For nodules with weak driver mutations, positive microRNA test results supported high risk of cancer while negative results downgraded cancer risk. Conclusion MPT results are predictive of real‐world decisions to surgically treat indeterminate thyroid nodules, with those decisions being appropriately aligned with a patient's risk of malignancy over time.

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

“…[7][8][9] Our results support that microRNA testing can help to overcome limitations in assessing malignancy risk in the absence of detectable mutations and fusions. 52 Although combination mutation and microRNA testing has been validated in patients with surgically confirmed outcomes, 51 51 Our results demonstrate that strong positive microRNA results that are highly specific for malignancy 8 and prevalent in nodules with strong drivers can also be found in a subset of patients who lack any detectable mutations and fusions even when a more expanded mutation panel is used.…”

“…8 Consistently, results of a large multicenter study examining the outcomes of patients who underwent clinically prescribed combination mutation and microRNA testing concluded that more aggressive surgical management options are warranted in patients with weak drivers and positive microRNA results given confirmed high risk of malignancy. 52 A small, but nonetheless significant, minority of thyroid follicular cancers will lack detectable mutations and fusions. 7 to either mechanism, the lack of detectable oncogenic change cannot provide complete assurance that a nodule is benign and as such those nodules have a residual cancer risk of 5% to 25%.…”

“…Positive microRNA results and even more so strong positive results favor elevated concern for malignancy 8. Consistently, results of a large multicenter study examining the outcomes of patients who underwent clinically prescribed combination mutation and microRNA testing concluded that more aggressive surgical management options are warranted in patients with weak drivers and positive microRNA results given confirmed high risk of malignancy 52. A small, but nonetheless significant, minority of thyroid follicular cancers will lack detectable mutations and fusions 7.…”

“…28,[31][32][33][34][35][36][37][38][39][40][41][42] Furthermore, PPARG-and THADA-related fusion transcripts can have RAS-like properties, 15 while other fusions such as those related to NTRK and ALK have properties that are neither RAS-like nor BRAFV600E-like. 6,51,52 Furthermore, microRNA risk classification has been shown to help to reclassify cancer risk in both the absence of mutational change and the presence of mutations that have lower positive predictive values for malignancy, with strong positive microRNA classifier results offering extremely high specificity for malignancy. 28,29,33,[43][44][45] microRNA risk classifier testing has been used to help resolve diagnostic dilemmas encountered with the use of mutation panels alone.…”

“…[46][47][48][49][50] A multiplatform approach using a combination of a mutation panel and a microRNA risk classifier has been shown to effectively "rule-in" and "rule-out" high risk of malignancy with results being predictive of surgical treatment decisions that are appropriately aligned with cancer risk. 6,51,52 Furthermore, microRNA risk classification has been shown to help to reclassify cancer risk in both the absence of mutational change and the presence of mutations that have lower positive predictive values for malignancy, with strong positive microRNA classifier results offering extremely high specificity for malignancy. 8 We aimed to better understand the incremental utility in using expanded mutation panels and how microRNA classifier testing can provide additional diagnostic information to expanded panel test results.…”