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Geisinger Offering Prophylactic Thyroidectomy to Patients with Cancer-Linked RET Variants

Endocrinologist examining throat of young woman in clinic

NEW YORK – Patients with genetic variants associated with a risk of a rare thyroid cancer and identified through a DNA sequencing program at Geisinger Health System are being referred for surgical consultations, even when they're asymptomatic.

While Geisinger sees value in identifying at-risk patients and removing their thyroid gland to treat and assess cancer early, some experts are concerned about overtreatment.

Seventy-five out of more than 184,200 patients who participated in Danville, Pennsylvania-based Geisinger's MyCode Community Health Initiative, a precision medicine and population genomic screening program, were found to have pathogenic or likely pathogenic variants in the RET gene, reported researchers in JAMA Otolaryngology–Head & Neck Surgery last month. These patients, who first learned they had a RET variant associated with medullary thyroid cancer through MyCode between June 2016 and May 2022, didn't have any other clinical evidence of the disease. Of those who completed a cascade of other tests, workups, and consultations, and ultimately decided to remove their entire thyroid gland via a thyroidectomy, 60 percent had medullary thyroid cancer. 

Most of these medullary thyroid cancer cases were diagnosed at stage I, allowing patients to be treated earlier, study authors wrote. "That is a high enough percentage to offer a low-morbidity surgery such as thyroidectomy," said Nicholas Purdy, director of head and neck surgery at Geisinger's department of otolaryngology and last author on the paper. In addition to the 60 percent of thyroidectomy patients who were found to have medullary thyroid cancer, 10 percent of patients who had the surgery were found to have papillary thyroid carcinoma and another 10 percent had C-cell hyperplasia, a precursor to medullary thyroid cancer.

Medullary thyroid cancer is rare, accounting for just 3 percent to 4 percent of all thyroid cancers, according to the National Cancer Institute. About one-quarter of medullary thyroid cancer cases are associated with a familial or inherited genetic risk, while three-quarters arise sporadically. The disease is typically diagnosed through imaging and tissue biopsy once patients develop a neck mass, trouble breathing, or other symptoms.

Patients who agree to partake in Geisinger's MyCode project are tested for variants in multiple genes. Those with medically actionable results are referred to genetic counselors to discuss their genetic risks and care recommendations. 

As such, outside of the context of the analysis done for this paper, patients with pathogenic or likely pathogenic RET variants identified through MyCode are continuing to be referred for follow-up care including possible surgical treatment. Follow-up care for these patients includes visits with endocrinology for additional testing and otorhinolaryngology for a surgical consultation, where they discuss their risk for developing medullary thyroid cancer and possible next steps — namely, thyroidectomy or lifelong surveillance with annual imaging and laboratory tests.

While surgical action based on preemptive genetic testing sounds futuristic, it's "not completely novel," Purdy said. The American Thyroid Association recommends considering thyroidectomy for children who have certain high-risk RET mutations and a family history of the disease in its guidelines for managing medullary thyroid cancer.

"The difference is the way we're picking up these patients," Purdy said. Traditionally, patients are offered genetic testing for such mutations if they have a family history of the disease or clinical symptoms. But, through MyCode, the health system can identify RET variants in patients before symptoms manifest and in those whose family history wouldn't have raised concern. That's a "relatively new situation," he said.

Of the 75 patients who were found to have RET variants through MyCode, only 20 opted to undergo total thyroidectomy.

"The overall rate was a little lower than I would have expected, but it highlights a couple things," like the need to improve patient education, said Adam Buchanan, chair of the genomic health department at Geisinger and a co-author on the paper. While patients who completed a surgical consultation tended to opt for surgery, there were lots of points along the care journey where a patient could drop off. They could decide to not schedule appointments with a genetic counselor or otorhinolaryngologist, for example.

The study didn't delve into reasons patients didn't undergo surgery, but study authors have some theories. Patients may be hesitant to undergo surgery for an issue that isn't causing any health problems, particularly if they aren't aware of a family history of thyroid cancer — which is understandable, Buchanan said.

"They [may] make a determination that it's not as big of a concern for them as we might believe based on what we know from the literature," he suggested. "But we really need to look at that more carefully," to uncover reasons behind patients' decisions.

Study authors concluded that while further research is needed to establish recommendations on how to manage care for patients with RET variants identified through population genomic screening programs like MyCode, "given the high rate of occult MTC in this cohort, early surgical intervention should be considered in all patients found to have a [pathogenic or likely pathogenic] RET variant."

Buchanan also stressed that such RET variant screening would have to take place as part of a broader program that screens patients for multiple disease risk variants. "It's not a stand-alone [test]," he said.

Geisinger's study demonstrates how pathogenic or likely pathogenic RET variants identified as part of broad DNA sequencing efforts can inform care management, said Leslie Biesecker, director of the National Human Genome Research Institute's Center for Precision Health Research in the National Institutes of Health, who was not involved in the MyCode study. "These people really benefited from this having been found early," he said of the 12 patients who underwent thyroidectomy and were found to have medullary thyroid cancer.

However, not everyone in the study cohort had cancer, so offering everyone with a pathogenic or likely pathogenic variant a thyroidectomy could lead to overtreatment, he cautioned. It's critical "not to leap from a genomic finding to action, [but] to move thoughtfully from a genomic finding to a thorough evaluation, and then, if that's positive, to a therapeutic action," Biesecker said.

In a commentary accompanying the paper in JAMA Otolaryngology–Head & Neck Surgery, two surgeons raised concerns about the utility of population screening for RET variants, noting that much is still unknown about how aggressively medullary thyroid cancer develops and that some patients in the study appeared hesitant to have surgery based on knowledge of RET variants. Different types of RET variants have different risk profiles for how aggressive the cancer is likely to be; patients in the study at Geisinger all had RET variants deemed moderate risk by the American Thyroid Association's guidelines.

"Mass screening makes sense when a disease is relatively common, when meaningful treatment is available, when the disease has high morbidity or mortality if identified late, and if identifying it early will confidently result in decreased morbidity and mortality," Louise Davies, chief of otolaryngology-head and neck surgery at the White River Junction VA Medical Center in Vermont, and Peter Angelos, chief of endocrine surgery and associate director of the MacLean Center for Clinical Medical Ethics at UChicago Medicine, wrote in their commentary. They noted that the significant costs of setting up processes for screening and return of results for RET variants may not yield comparable benefits when weighed against the rarity of medullary thyroid cancer and the inherent risks of surgical intervention. Not to mention, after total thyroidectomy, patients will need to take lifelong thyroid hormone replacement medication.

At Geisinger, the costs of identifying RET variants were minimal since the study was part of the larger MyCode program. Regeneron Genetics Center, an R&D subsidiary of drugmaker Regeneron, covers MyCode's research exome sequencing costs and Geisinger funds the Genomic Screening and Counseling Program, including clinical confirmatory testing for pathogenic and likely pathogenic variants. Other healthcare systems may not have the industry partnerships and internal resources to set up a population screening program, however.

Patients at Geisinger are responsible for the cost of follow-up care including visits with specialists, surveillance testing, and surgery. Individuals with pathogenic or likely pathogenic RET variants who chose thyroidectomy have had the procedure covered by insurance, according to Purdy. He added that it's important to weigh the risks of surgery against the risk of developing medullary thyroid cancer and the inconvenience and cost of the non-surgical approach to care, which is lifelong surveillance. Moreover, he noted that surgeries are less extensive and have fewer risks when patients have them at an earlier stage of disease or at the pre-cancerous stage.

None of the 20 patients who underwent thyroidectomy in the study had complications or signs of disease after surgery, based on postoperative surveillance imaging and laboratory testing. Still, concerns about clinical utility and cost-effectiveness are compounded by the relatively few patients who elected for surgery.

"The aim of screening is to identify conditions early, so that people can consider intervention," wrote Davies in an email. If patients aren't willing to take such steps, then she questions the entire approach to using genetic testing for early diagnosis and treatment in this way.

Purdy, on the other hand, believes that performing thyroidectomy for asymptomatic patients with pathogenic or likely pathogenic RET variants could become part of standard care — at least in situations where patients are screened in broad genomic screening programs like MyCode. Screening for only RET variants would be inefficient, given the low occurrence of such variants, he said.

Future research at Geisinger will involve following patients who opted for thyroidectomy as well as those who opted for surveillance to see what their long-term outcomes are. Studying patients who elected for surveillance will help to establish a picture of the lifetime risk of developing medullary thyroid cancer for different types of RET variants. Purdy is also interested in whether patients who opted for surveillance later change their mind and decide to undergo surgery.

"We're setting the groundwork for further studies," Purdy said. "Twenty patients is great, and we can see our initial experience, but that's by no means a large enough number to make absolute, definitive recommendations on how every single patient should be handled."