Genetic Screening Program Identifies Unsuspected Thyroid Cancer

A population-based genetic screening program showed promise for detecting clinically occult thyroid cancer in patients with RET variants.

Among 20 patients who had surgery on the basis of a positive test, 14 had thyroid cancers that were previously unsuspected. Ten of 12 patients with medullary thyroid cancer had stage I disease and none had stage IV cancer. Postoperative surveillance, including imaging and laboratory testing, suggested that all of the detected cancers were curable, reported Nicholas C. Purdy, DO, of the Geisinger Medical Center in Danville, Pennsylvania, and coauthors in JAMA Otolaryngology–Head & Neck Surgery.

"This initial cross-sectional investigation found benefit of identifying P/LP [pathogenic/likely pathogenic] RET variants via population genomic screening, namely, the ability to enable relevant, early MTC [medullary thyroid cancer] diagnosis," the authors concluded. "While additional data are needed to shape recommendations in individuals identified via population screening, given the high rate of occult MTC in this cohort, early surgical intervention should be considered in all patients found to have a P/LP RET variant."

"We hope that this process will lead to the identification of a broad range of RET variants associated with MTC in patients who are otherwise asymptomatic and do not have knowledge of their risk for malignancy," they added. "With population genomic screening, we hope to reaffirm our initial findings, develop protocols that will support appropriate, interventive measures for patients, and ultimately improve treatment of patients with and at risk for MTC."

Population-based genetic screening makes sense for a disease that is relatively common, treatable, and confers a significant risk of morbidity and mortality that can be reduced by early detection, argued Louise Davies, MD, of the Geisel School of Medicine at Dartmouth in Hanover, New Hampshire, and Peter Angelos, MD, PhD, of the University of Chicago, in an accompanying editorial. However, because MTC is so rare, the benefits of screening would be accompanied by a "large opportunity cost."

The study reported by Purdy's group involved nearly 185,000 participants, of whom 85 were found to have RET variants, noted Davies and Angelos. Of those 85, only 20 opted to have surgery in response to a positive test

"This small number of people who seemed to benefit from this early knowledge of genetic results calls into question the entire concept of genetic testing as a means of earlier diagnosis and treatment of cancers," wrote Davies and Angelos. "If people are not prepared to take on the risks of surgery to treat potential cancers, then the role of genetic testing as a beneficial widespread public health measure is suspect. These data suggest the need for greater patient education about why genetic testing is being done and the implications for long-term health."

Patients who refused surgery should be followed as closely as those who had surgery in order to gather information about the natural history of RET variants and cancer risks associated with each variant, they added.

"Failure to follow this group over time would be an important missed opportunity to better understand how genetic variants manifest in different diseases in the future," Davies and Angelos concluded.

In current clinical practice, identification of genomic risk for MTC usually occurs after the disease has been diagnosed in a patient or family member, Purdy and coauthors noted. In 2015 the Geisinger Clinic, an integrated healthcare system, launched the MyCode Community Health Initiative Genomic Screening and Counseling Program, a population-based genomic screening program. The program encompasses P/LP variants associated with about 30 Mendelian medically actionable diseases, with screening results reported to primary care clinicians and patients.

As of May 31, 2022, the MyCode cohort comprised 184,293 participants, and identification of P/LP RET variants had been reported to 85 adults participating in the screening program. Ten of the 85 had prior knowledge of their RET variants and were excluded from the analysis. Subsequently, 20 of the 75 remaining participants with RET variants underwent thyroidectomy a median of 4 months after disclosure of RET variant status.

The 20 patients who underwent surgery consisted of 11 women and nine men who had a median age of 48. The 55 patients who did not have surgery (including 13 who could not be reached to discuss the results) consisted of 27 women and 28 men who had a median age of 58.

Three of the 20 patients who had surgery did not meet preoperative criteria for fine-needle aspiration biopsy on the basis of American Thyroid Association guidelines, noted Purdy and coauthors. Preoperatively, 12 patients had elevated preoperative calcitonin levels and 10 had elevated carcinoembryonic antigen.

All 20 operative patients underwent total thyroidectomy and 13 also had central neck dissection. Pathology reports showed that 12 of the 20 patients had MTC and two had papillary thyroid carcinoma. In addition to the 10 patients with stage I MTC, one patient had stage II disease and one had stage III disease.

"This [study] suggests that genomic screening may provide opportunities for early detection and treatment of MTC, with the potential for improved patient outcomes," the authors concluded.

Comment