The multigene classifier test ThyroSeq Version 3 (University of Pittsburg/CBLPath) shows high accuracy in diagnosing indeterminate thyroid nodules, allowing for more than 60% of patients with such nodules to avoid diagnostic surgery, according to the final results of a multicenter, double-blinded study.
"Our study showed ThyroSeq can help avoid surgery in the vast majority of patients with benign nodules where the initial biopsy returns an ambiguous result," senior author Yuri Nikiforov, MD, PhD, professor of pathology and director, Division of Molecular and Genomic Pathology, University of Pittsburgh School of Medicine, Pennsylvania, said in a press statement from his institution.
"With such a high proportion of preventable surgeries, this test should practically resolve the decades-long struggle and inefficiency of medical care for patients with indeterminate cytology thyroid nodules," he added.
All False Negatives Were Low-Risk Cancers
Although fine-needle aspiration (FNA) biopsy is highly effective in classifying most nodules as being either benign or malignant, approximately 20% of nodules remain indeterminate and require surgery to confirm a diagnosis.
Molecular testing of the nodules with genetic classifiers has emerged in the past decade and has improved the diagnostic accuracy of FNA. However, such tests have relatively low specificity and positive predictive value (PPV), provide limited clinical validation, or are limited in their capacity to provide specific molecular information, the researchers explain.
In the prospective evaluation of the ThyroSeq V3 genetic classifier, which is designed to detect up to 112 genes, a total of 286 nodules from 256 patients were subjected to blinded molecular analysis at 10 medical centers.
Of 257 indeterminate nodules that could be analyzed by ThyroSeq as well as by diagnostic surgery, 154 were classified as Bethesda category III, 93 as Bethesda IV, and 10 as Bethesda V.
For the primary outcome of accuracy in diagnosing Bethesda III and IV nodules, the ThyroSeq test showed high sensitivity, with a PPV of 94%, as well as high specificity, with a negative predictive value (NPV) of 82%. For 61% nodules, test results were negative.
Of the 28% of nodules that were malignant (24%) or noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP; 4%), the ThyroSeq test had an NPV of 97% and a PPV of 66%.
The false negative rate was 3%, which is similar to that of FNA for benign nodules. All of the cancers that were incorrectly diagnosed as negative were low-risk tumors, the authors note.
"Although no test has perfect accuracy, it is reassuring that all false-negative cases in the study were low-stage and low-risk cancers by the American Thyroid Association criteria," the investigators write.
ThyroSeq Provides Detailed Genetic Profile of the Malignant Nodules
Of the nodules that did test positive, the genetic alterations were associated with probabilities of malignancies ranging from 59% to 100%.
The test's capability of diagnosing all types of thyroid cancer, particularly Hurthle cell nodules, for which existing molecular tests typically have low specificity, is highly important, said first author David Steward, MD, professor of otolaryngology at the University of Cincinnati College of Medicine and director of head and neck surgery at UC Health, in Ohio, in the press statement.
"Beyond simply differentiating benign and malignant nodules, the study shows that ThyroSeq also provides a detailed genetic profile of the positive nodules," he said.
"Since thyroid cancer is known to progress differently based on the mutation involved, ThyroSeq potentially allows physicians to employ a precision medicine approach, modifying treatment for each patient based on the mutations present."
The test's benefit in reducing unnecessary surgeries could have far-reaching implications, the authors underscore.
"This indicates that ThyroSeq V3...can prevent diagnostic surgeries for up to 61% of all of indeterminate Bethesda III to IV cytology nodules and as many as 82% of all benign nodules that yielded indeterminate cytology diagnosis," they point out.
"This should maximize the effect of molecular testing on the avoidance of surgery, reduction of health care costs, and improvement of patient quality of life.
"This is particularly important during what is widely considered as the era of thyroid cancer overdiagnosis and overtreatment," they write.
The study received funding from a Head and Neck Cancer SPORE grant to University of Pittsburgh and a Thyroid Cancer SPORE grant to the Ohio State University. The authors' relevant financial relationships are listed in the original article.
JAMA Oncol. Published November 8, 2018. Abstract