Promises and Pitfalls of Genetic Screening for Rare Thyroid Cancer

Asymptomatic patients identified as being at risk for medullary thyroid cancer (MTC) through population-based genomic testing show successful outcomes with this potentially fatal cancer when opting for surgical treatment (eg, a thyroidectomy), new research shows.

“[The study] suggests that genomic screening may provide opportunities for early detection and treatment of MTC, with the potential for improved patient outcomes,” report the authors of the research, published online January 5 in JAMA Otolaryngology–Head and Neck Surgery.

A key caveat, however, as demonstrated in the study’s relative low proportion of patients agreeing to the surgery, is the potential reluctance among those who are asymptomatic, note the authors of an editorial published along with the study.

“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,” editorial authors Louise Davies, MD, and Peter Angelos, MD, PhD, assert.

“These data suggest the need for greater patient education of why genetic testing is being done and the implications for long-term health.”

MTC: Rare but Requiring Aggressive Treatment

Though accounting for only 2%–5% of all thyroid cancers, MTC represents 13.4% of thyroid cancer fatalities, and it is commonly treated with more aggressive measures than the other thyroid cancers.

The cancer is usually diagnosed after discovery of a thyroid nodule or neck mass, and although only about 25% of cases are inherited forms, those cases can, importantly, be detected earlier with testing for a mutation in the rearranged during transfection (RET) proto-oncogene.

To investigate the benefits of extending genomic screening to broader populations, the authors, from Geisinger Medical Center in Danville, Pennsylvania, evaluated data from the MyCode Community Health Initiative’s Genomic Screening and Counseling Program, a population-based genomic screening research program launched at the center in 2015 that includes testing of more than 30 conditions, including MTC.

In the study cohort of 184,293 participants, 85 adult patients (.046%) were identified as carriers of the RET mutation.

Ten of the patients had prior knowledge of their RET mutation status and were therefore excluded from the analysis, and among the remaining 75 patients, 20 (27%) opted to undergo total thyroidectomy upon being informed of the results, including 13 who also had a central neck dissection.

The patients had a mean age of 48 years and were 55% female, and none had any clinical symptoms of disease at the time of surgery.

Pathological results following surgery confirmed that 12 of the patients had an MTC malignancy and 2 had papillary thyroid cancer. Of note, only half (6) of those with MTC malignancies showed preoperative ultrasonographic findings of nodules.

Of those with MTC, 83% (10 of 12) had stage I disease, one participant each had stage II and III, and none of the patients had advanced disease (stage IV).

With a mean postsurgical follow-up of 22.4 months (range 2-76 months), none of the patients had evidence of recurrence or persistent disease.

The authors underscore that, with no symptoms, none of the patients would likely have had their cancers detected until a later stage without the genomic testing.

“With no clinical evidence of disease, none of the patients had indications for a workup of a thyroid nodule aside from identification of a P/LP RET variant,” they write.

“Therefore, the MyCode program led to the detection of occult MTC in 60% of our study population, suggesting that genomic screening may lead to early diagnoses of MTC in patients with P/LP RET variants.”

The Findings Support Prophylactic Surgery

With research showing that once regional lymph node metastasis occurs with MTC, total thyroidectomy and neck dissection are no longer curative; thus, the findings underscore the benefits of early surgery, the authors add.

“While further studies are needed, we believe that surgical intervention may be advisable once a P/LP RET variant has been detected to optimize outcomes,” they write.

Senior author Nicolas C. Purdy, DO, of Geisinger’s Department of Otolaryngology–Head and Neck noted that, in general, prophylactic surgery should be considered when malignancy risks are 20% or greater, hence the 60% malignancy rate found with their genomic testing program used in the study supports the benefits of prophylactic surgery.

Furthermore, even if a malignancy isn’t initially found, “the psychological effect of a RET variant diagnosis [on the patient] is an important component to consider when deciding on surgery,” he told Medscape Medical News.

The fact that only 20 patients in the study opted for the surgery was a surprise, Purdy added, noting that the reasons for opting out were multifactorial.

“There were patients that did not follow through with initial management recommendations, including the surgical consultation, [and], of patients that had the initial management recommendations, some elected for observation as opposed to surgery,” he explained.

“It will be important for us to further identify barriers to care and make sure all patients receive adequate information to make an informed decision with their care,” he added. 

Uncertainties on Natural History of MTC Cloud Issue

In the editorial, authors Davies, of the Department of Veterans Affairs Medical Center in White River Junction, Vermont, and Angelos, of the University of Chicago, further caution that other factors may give pause regarding decisions for prophylactic surgery, including that much is still unclear regarding the natural history of MTC.

For instance, like papillary thyroid cancer or breast cancer, there could be “a subclinical reservoir of clinically inactive disease that may never become active or may grow extremely slowly, with low risks to the patient’s health,” they explain.

The most aggressive genetic variants “may still require other drivers to become fully active, and there may be variable penetrance of the more moderate variants identified in this group of patients, meaning that the presence of the variant may not always result in the development of a cancer,” they add.

Ultimately, the relatively small proportion of patients benefiting from the early testing results and agreeing to surgery “calls into question the entire concept of genetic testing as a means of earlier diagnosis and treatment of cancers,” the editorialists assert.

Purdy disagreed with that suggestion, noting that while isolated RET testing of the entire US population would indeed be “costly and inefficient,” the study’s testing was performed as part of a comprehensive genetic screening test at no cost to the patient.

Although similar programs are offered at other centers, including the Kaiser Permanente Center for Health Research and University of Alabama at Birmingham, Purdy said that, to his knowledge, “the MyCode program is the largest.”

“To date, we have disclosed actionable results to nearly 4000 patients,” he said.

Purdy added that results from other tests have indicated that the extent of an intervention may be associated with the likelihood of performing it, and “it is not unexpected that a surgical intervention would be less likely to be performed than biochemical surveillance.”

He noted that Geisinger has previously reported higher performance of recommended management strategies with other conditions.

The study was supported by internal grant funding from Geisinger Clinic and Regeneron. The study authors and editorialists report no relevant financial relationships.

JAMA Otolaryngology–Head and Neck Surgery. Published online January 5, 2023. Abstract, Editorial

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