VICTORIA, British Columbia — A multicenter, double-blind clinical study on the latest-generation ThyroSeq version 3 (University of Pittsburg/CBLPath) gene-classifier test validates its high negative predictive values (NPV) in identifying thyroid nodules of indeterminate cytology, potentially sparing patients from unnecessary surgeries.
“In this prospective, blinded, multicenter study, ThyroSeq V3 showed very high sensitivity and negative predictive value, with robust NPV in populations with different disease prevalence,” said lead investigator Yuri Nikiforov, MD, PhD, a professor of pathology at University of Pittsburgh Medical Center, in presenting the findings here at the 2017 Annual Meeting of the American Thyroid Association.
“The test showed high specificity and positive predictive value (PPV) that may allow for diagnostic surgery to be avoided in more than 60% of patients with cytologically indeterminate Bethesda III and IV nodules,” he added.
In commenting on the research, Bryan McIver, MD, deputy physician in chief and senior member of endocrinology at the Moffitt Cancer Center, in Tampa, Florida, said the study was “done the way science is supposed to be.”
“This study is unlike just about any other [gene-classifier] study out there,” he told Medscape Medical News.
“What the researchers did was to get a large-enough group of patients with a high-enough rate of indeterminate biopsies who were naïve to molecular testing, and the pathologists were blinded, so that’s critical,” he said.
“Another critical issue that makes this superior to [other research] was in refusing to eliminate any patients after the analysis was complete.”
Indeterminate Thyroid Nodules: Clinical Challenge Usually Resolved With Surgery
An indeterminate evaluation of a thyroid nodule, as opposed to a more definitive benign or cancerous assessment, presents a clinical challenge that is typically only resolved with surgery.
However, with histology turning out to be benign in as many as 70% of cases, there is a significant need for improved diagnostic tools to prevent such unnecessary surgeries.
The latest version of the ThyroSeq classifier (version 3) expands on previous versions, utilizing next-generation sequencing of DNA and RNA samples, with genomic classification of mutations, fusions, and gene-expression and copy-number variations (CNV), a new class of diagnostic markers, covering 112 thyroid-related genes.
In this pivotal, prospective, international validation study for the classifier, 805 patients were initially enrolled at 10 medical centers with thyroid nodule of Bethesda III through V cytology and whose surgical outcomes were known. There were no significant differences in patient characteristics or nodule size.
The surgical pathology slides were reviewed by a blinded panel of expert pathologists, with the primary outcome of the study being diagnostic accuracy of the test for Bethesda III and Bethesda IV nodules.
After exclusions, the study set included assessment of 234 patients and 257 cytologically indeterminate, excised nodules.
Overall, the prevalence of malignancy was 30%.
Of the samples, 154 (60%) were Bethesda III, 93 (36%) were Bethesda IV, and 10 (4%) were Bethesda V.
For Bethesda III nodules, the gene-classifier test had a sensitivity of 91%, a specificity of 85%, a negative predictive value (NPV) of 97%, and PPV of 64%.
There was a 23% prevalence of malignant nodules, which included nodules classified as having noninvasive follicular thyroid neoplasms with papillarylike nuclear features (NIFTP).
Among Bethesda IV nodules, final pathology showed a prevalence of 35%, while ThyroSeq had a sensitivity of 97%, specificity of 75%, an NPV of 98%, and PPV of 68%.
In a combination of Bethesda III and IV nodules (247 cases), which was the main focus of the study, the prevalence of malignancy was 28%, and ThyroSeq had a sensitivity of 94%, specificity of 82%, an NPV of 97%, and PPV of 66%.
Overall, 61% of Bethesda III and IV nodules were assessed on ThyroSeq as being negative (benign) and 39% positive (likely malignant).
“To put this data into perspective, with a hypothetic 100 patients with Bethesda III and IV, 61 nodules would be called negative and two would be false negatives using the test, and out of 39 called positive, 13 would be a false positive and 26 would be true positive for cancer,” Dr Nikiforov explained.
Clinical Validation of Thyroseq Version 3 Suggests Advantages Over Competitor
Four cases in the Bethesda III and IV groups and one case in the Bethesda V group were false negatives, including three papillary thyroid cancers and one follicular carcinoma, and 33 were false positives.
In the false negatives, the cancers were intrathyroidal and of low stage, with no aggressive histology, Dr Nikiforov said.
Of the false positives, 68% were diagnosed on pathology as Hurthle-cell or follicular adenomas, and 10% were initially diagnosed by a pathologist as cancer or NIFTP.
Importantly, 94% of the false positives had clonal oncogenic molecular alterations, including mutation, gene fusion, or CNV, suggesting they were clonal tumors and not hyperplasia.
In an assessment of the difficult-to-diagnose Hurthle-cell nodules, which have been underrepresented in diagnostic tests, the study looked at 49 nodules and all the 10 that were carcinomas were detected with ThyroSeq V3, for a sensitivity of 100% and specificity of 66.7%, with a benign call rate of 53.1%.
“The study provides clinical validation of ThyroSeq version 3, performed in a large prospective, double-blind, multicenter, international study,” the researchers concluded.
Dr McIver said that while competitor Veracyte’s Afirma gene expression classifier has dominated the market on indeterminate-nodule classification, these new findings from this rigorous clinical validation study suggest important advantages of the version 3 ThyroSeq.
“This was a rigorously validated test showing an excellent negative predictive value, a manageable positive predictive value, and nuanced set of data that allows for individual precision-medicine approaches for nodules that are cytologically indeterminate,” he concluded.
Dr Nikiforov is the owner of intellectual property related to ThyroSeq. Dr McIver has no relevant financial relationships to ThyroSeq. He receives research support from GenePro Dx, which is performing a clinical study of a different molecular marker in thyroid nodules.
2017 Annual Meeting of the American Thyroid Association. October 21, 2017; Vancouver, British Columbia. Abstract 5.
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