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Novel genomic sequence classifier improves detection of benign thyroid nodules

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May 29, 2018

A new genomic sequencing classifier accurately classified more thyroid nodules with indeterminate cytology as benign vs. its predecessor, the gene expression classifier, potentially eliminating unnecessary surgery for some patients, according to findings from a masked validation study published in JAMA Surgery.

“Approximately one-third of thyroid nodule cytology findings today are cytologically indeterminate, with estimated risks of malignancy ranging from 5% to 30%,” Kepal N. Patel, MD, a head and neck surgeon in the division of endocrine surgery at New York University Langone Medical Center, and colleagues wrote in the study background. “Consequently, approximately three-quarters of patients with cytologically indeterminate thyroid nodules have been referred for surgery, even though 80% ultimately prove to have benign nodules.”

During an interview with Endocrine Today, Patel said: “This test improves our specificity over the old test, and still maintains a really high negative predictive value. We know that when we do a biopsy on a thyroid nodule and it comes back indeterminate, that most them are still benign. What this test is doing is taking out even more benign nodules from the indeterminate category, thus avoiding unnecessary surgery even more so than before.”

Using a prospective and masked protocol, Patel and colleagues analyzed data from 183 cytologically indeterminate thyroid nodules with adequate residual RNA for validation, collected by fine-needle aspiration biopsy between June 2009 and December 2010 from 49 academic and community centers in the U.S. (77.6% women; mean age, 52 years). All patients underwent surgery without genomic information and were assigned a histopathology diagnosis by an expert panel masked to all genomic information. Nodules were samples with Bethesda III and IV indeterminate cytopathology from a cohort previously used to validate the gene expression classifier (Afirma, Veracyte). Independent validation occurred between August 2016 and May 2017. Primary endpoint was the measurement of genomic sequencing classifier sensitivity, specificity and negative and positive predictive values in biopsies from Bethesda III and IV nodules. The secondary endpoint was measurement of classifier performance in biopsies from Bethesda II, V and VI nodules.

Researchers found that the genomic sequencing classifier correctly identified 41 of 45 malignant samples, for a sensitivity of 91.1% (95% CI, 79-98), as well as 99 of 145 nonmalignant samples, for a specificity of 68.3% (95% CI, 60-76). Additionally, at 24% cancer prevalence, the negative predictive value was 96.1% (95% CI, 90-99) and the positive predictive value was 47.1% (95% CI, 36-58). There were no observed differences in performance between Bethesda II and IV category nodules, according to researchers.

The researchers noted that a wide variety of malignant subtypes were correctly classified as suspicious, and four false-negative cases occurred.

“This study demonstrates high test sensitivity and [negative predictive value] among Bethesda III and IV cytologically indeterminate thyroid nodules across a broad range of nodule sizes,” the researchers wrote. “As an adjunct to clinical judgment, the [genomic sequencing classifier] is expected to reduce unnecessary diagnostic surgery, improve patient safety, reduce health care costs and improve patient quality of life.”

Patel told Endocrine Today: “We will hopefully be taking less patients to the operating room for indeterminate cytology and be able to diagnose more of these nodules as benign and potentially avoid surgery.” – by Regina Schaffer

Disclosures: Veracyte funded this study. Patel reports he has received speaker honoraria from Veracyte. Please see the study for all other authors’ relevant financial disclosures.

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Stephanie Lee

What the researchers did in this paper is use the same sample published in The New England Journal of Medicine (Alexander EK, at al. N Eng J Med. 2012;doi:10.1056/NEJMoa1203208) and re-ran the test with the new assay — this is not a new collection of patients. In doing that, they had 89% agreement between the gene expression classifier and the genomic sequencing classifier. The advantage in doing that is that because it was part of the prospective trial for the gene expression classifier, all of those patients went to surgery. So, they actually have surgical truth, which is important.

In the past, when you had a gene expression classifier-suspicious result, the risk for cancer was 38% in patients. That meant that, in patients with Bethesda III and IV nodules or suspicious fine-needle aspiration, we ran the gene expression classifier and 62% of the samples were actually benign. So, you’re still sending benign patients to surgery with their prior test.

The 30% increase that they’re talking about is that with the new genomic sequencing classifier, instead of 38% of nodules being cancerous, 47% of nodules are cancerous. So, that’s a 10% increase. You still have suspicious Afirma tests where one or two of those patients will not have cancer. So, their statement is true: 30% less of the suspicious patients on Afirma testing will be going to surgery. If you take a step back and ask, “How many patients will you send to surgery without disease?” Still, one in two. It is better than one in five without the test. This new test definitely reduces the number of patients who go to surgery, but we still have more work to do. For every one patient with cancer, we’re still sending one patient with benign disease to surgery.

Stephanie L. Lee, MD, PhD, ECNU

Associate Professor of Medicine and Director of Thyroid Health
Section of Endocrinology, Diabetes and Nutrition
Boston Medical Center

Disclosure: Lee reports no relevant financial disclosures.