A new test designed to identify benign thyroid nodules that were originally diagnosed inconclusive might spare tens of thousands of patients unnecessary invasive surgery each year, according to two recent research studies.
The studies published in the New England Journal of Medicine (NEJM) and Thyroid investigated a diagnostic test known as the Afirma Gene Expression Classifier (GEC), a genomic test developed by Veracyte, Inc. located in South San Francisco, California. Both studies were funded by research grants from the molecular diagnostics company.
The American Cancer Society (ACS) estimates that 56,460 new cases of thyroid cancer will be diagnosed in the United States in 2012, and the chance of being diagnosed is more than twice what it was in 1990. According to the ACS, most thyroid nodules that develop in patients are benign, but 1 in 20 is cancerous.
The simplest way to diagnose whether or not a thyroid nodule is malignant is with a fine-needle aspiration (FNA), and about 450,000 nodule FNAs are performed each year in the U.S. In about 30 percent of cases, the results are ambiguous and current guidelines recommend surgery for most of these patients to remove all or part of their thyroid for final diagnosis—an invasive option that may result in lifelong thyroid hormone therapy for the patient.
The goal of the new gene-expression test, which became available to endocrinologists in early 2011, is to help reduce thyroid surgeries due to inconclusive nodules by using cutting-edge diagnostic techniques. The Afirma procedure begins with a cytopathology review of thyroid nodule FNA samples. If the results are inconclusive, Veracyte follows up with its gene expression classifier. At the company’s laboratory, technicians extract RNA from the sample. The RNA is then affixed to a microarray embedded with 142 genes known to be specifically expressed in either benign or malignant thyroid tissue. The gene chip also includes another 25 genes expressed in rare cancers. A computer scan of the microarray shows which genes the sample RNA binds to; a proprietary algorithm then classifies the sample as either benign or suspicious for cancer. Doctors typically receive genomic test results within two weeks.
265 Indeterminate Samples
In the NEJM study published in the August issue, researchers enrolled 3,789 patients and collected 4,812 thyroid FNA samples from nodules at least 1.0 cm in size over a two-year period. Forty-nine academic and community sites participated around the country. Samples were simultaneously collected for local cytopathology analysis and for the study. If the local cytopathology result was indeterminate, the study sample was then analyzed using the GEC test. Researchers analyzed 265 cytologically indeterminate thyroid FNA samples from patients who had undergone surgical thyroidectomy. The findings showed that the genomic test could reclassify the inconclusive samples as “benign” with a high degree of accuracy.
When applied to the major categories of indeterminate samples (those with cytology labeled: “atypical of an undetermined significance” or “follicular neoplasm”), the genomic test reclassified most as benign and demonstrated a negative predictive value (NPV) of 95 percent and 94 percent, respectively, for a population that demonstrated a 32 percent prevalence of malignancy. Overall, the NPV was 93 percent, based on the study’s cancer prevalence rate of 32 percent.
“Presently, patients with cytologically indeterminate thyroid nodules are usually referred for thyroid surgery to ensure that thyroid cancer is not present,” said co-author Erik K. Alexander, M.D., of Brigham and Women’s Hospital and Harvard Medical School. “The gene expression test, when benign, should now enable physicians to consider recommending against surgery, given the low risk of carcinoma conveyed by a negative GEC results, and confidently monitor patients in a more conservative fashion.”
Surgery Rates Plummet
In the second study, appearing online in July in Thyroid, investigators aimed to answer whether endocrinologists would accept the GEC results and avoid surgery for their patients.
Researchers collected data from 51 endocrinologists at 21 community practices and academic settings on 368 adult patients (ages 21–86 years) who underwent a combined total of 395 biopsies. The participating practices all had three or more benign GEC readings in nodules of at least 1.0 cm with indeterminate FNA cytology readings. Information about the patients’ conditions and the decision to operate was obtained from the practice records.
The study’s findings showed that the surgery rate for patients with indeterminate thyroid cytology fell from the previously reported rate of 74 percent to 7.6 percent among patients whose GEC test results were classified as benign. The results illustrated that the use of the GEC reduced surgery rates by 90 percent—a drop that was larger than expected, even to investigators.
“We anticipated that the use of the test would lead to a significant reduction in surgery, though not to the extent that we actually found,” said co-author Bryan McIver, M.B., Ph.D., in the Division of Endocrinology at Mayo Clinic in Rochester, Minnesota.
Were any of the physicians participating in the study hesitant about trusting the classifier’s results?
“It is important to emphasize that the study, by its nature, included physicians who were ‘early adopters’ of this new technology,” explained McIver. “That level of enthusiasm could, of course, mean that these physicians were more likely to be ‘true believers’ in the technology, so more likely to encourage their patients to avoid surgery.”
McIver added that the NEJM study would likely “cement” substantial trust in the GEC and lead more physicians to adopt the test, thereby, expanding the number of patients who are recommended to avoid surgery.
In an accompanying editorial in NEJM, J. Larry Jameson, M.D., Ph.D., pointed out that “5 to 10 % of nodules classified as benign (false negative) are likely to be malignant.” For such high-risk patients, “it might be reasonable to repeat the fine-needle aspiration biopsy or perform a diagnostic hemithyroidectomy even when the gene expression classifier indicates a benign profile,” he suggested.
Study Projects Big Savings
Leonard Wartofsky, M.D., chairman of the Department of Medicine at Washington Hospital Center in Washington, D.C. has taken a waitand-see stance regarding the GEC’s impressive results. “Longer term follow-up of these patients will be important in regard to how many ultimately went to surgery irrespective of the GEC result,” he said. “It is important to stress that non-operated patients still need to be followed long-term and monitored.
“The cost savings of not doing surgery needs to be balanced against the costs of follow-up for the patient, physician visits, potential repeat ultrasonography, and fine needle aspiration cytology,” he cautioned.
A team of researchers from Johns Hopkins University conducted a statistical modeling study of the cost-effectiveness of routine use of the GEC. In results published last November in The Journal of Clinical Endocrinology & Metabolism, the researchers demonstrated that mean discounted-cost estimates were $12,172 for current practice and $10,719 with the molecular test during a modeled five-year follow-up for an average per-person savings of more than $1,400. Afirma GEC’s developer, Veracyte, reported that these numbers would create a savings to the U.S. health care system of more than $600 million in direct costs over five years.
McIver added that he hopes the detailed cost-effectiveness analysis, based on real-world experience rather than a statistical model, will ultimately confirm the expectation that a reduced number of surgeries leads both to improved quality of life for patients and a reduction in overall health care expenditures.