No Need for Genetic Testing for Most Thyroid Cancers

Zosia Chustecka

April 11, 2013

In the majority of patients with papillary thyroid cancer, the most common form of thyroid cancer, there is no need for genetic testing. However, there might be a role for such testing in the 7% of patients who present with an aggressive form of the disease.

This finding comes from a study published in the April 10 issue of JAMA that explores the association between the BRAF V600E mutation and mortality in patients with papillary thyroid cancer.

"Genetic testing for these aggressive cases, but not for all cases, may help us match people's tumors with targeted treatments, when possible," said Anne Cappola, MD, ScM, associate professor of medicine at the Perelman School of Medicine, University of Pennsylvania in Philadelphia, who cowrote an accompanying editorial.

Papillary thyroid cancer accounts for 85% to 90% of all thyroid cancers, and has an excellent prognosis; 5-year survival rates are 98%, the editorialists explain. Usual treatment is surgery and/or radioiodine ablation.

However, for the 7% of patients with an aggressive form of the disease, the natural history is unpredictable. In these patients, there are few therapeutic options, they add.

How to identify the subset of patients who need aggressive treatment to reduce mortality is a "major clinical challenge," write the researchers, headed by Mingzhao Xing, MD, PhD, from the division of endocrinology and metabolism at Johns Hopkins University School of Medicine in Baltimore, Maryland.

 
This represents a widely controversial issue in thyroid cancer medicine. Dr. Mingzhao Xing
 

"This represents a widely controversial issue in thyroid cancer medicine, particularly because of the low overall mortality of this cancer," Dr. Xing and colleagues note.

Certain clinicopathologic factors are known to be associated with a higher risk for progression, such as older age at diagnosis, larger tumor size, and the presence of metastases (at both local and distant sites). However, these "often lack accuracy in helping tailor the extent of treatment of papillary thyroid cancer to balance treatment-associated benefits and risk," Dr. Xing and colleagues write.

Hence, the researchers set out to determine whether genetic testing is useful in this situation. They homed in on a prominent oncogenic mutation, BRAF V600E, which occurs in about 45% of all cases of papillary thyroid cancer, on average.

Huge Undertaking

The study was a huge undertaking. The team retrospectively tested tumor tissue removed from 1849 patients at 13 centers in 7 countries. They then analyzed the medical records of these patients to see if the presence of the mutation was prognostic.

They found a significant association between the presence of the BRAF V600E mutation and cancer-related mortality.

Overall mortality was higher in those who carried the mutation than in those who did not (5.3% vs 1.1%; P < .001). The same was true for the number of deaths per 1000 person-years (11.80 vs 2.25).

However, this association was not independent of tumor features, they note. When lymph node metastasis, extrathyroidal invasion, and distant metastasis were included in the analysis, the association between BRAF V600E and mortality for all papillary thyroid cancers was no longer significant.

In addition, overall mortality was very low. Of the 1849 patients studied, only 56 died — 45 with the mutation and 11 without.

Because overall mortality is so low and the association between the mutation and mortality is not independent of clinical features, it is "unclear" how to use BRAF V600E testing in patients with papillary thyroid, the researchers conclude.

Reassuring for the Majority of Patients

In their editorial, Dr. Cappola and coauthor Susan Mandel, MD, MPH, also from the University of Pennsylvania, offer a few suggestions on how to use the new information.

The findings are reassuring for patients with stage I and II disease, who account for the majority of patients with papillary thyroid cancer, they write.

In these patients, the mutation was found in 40% of tumors, but there was no difference in mortality between patients who had and did not have the mutation, and overall survival in this group was 99.8%.

"This is valuable information for the clinician," write Drs. Cappola and Mandel. "BRAF V600E testing is widely available, but there are no data to support improved outcomes from incorporating BRAF V600E testing into therapeutic decision making for thyroid cancer."

In fact, such testing could "lead to significant anxiety in otherwise low-risk patients," they warn.

There might be a place for such testing in patients with more advanced disease, they suggest. The accumulating data from this and previous studies show an increased prevalence of aggressive tumor behavior in people who carry the BRAF V600E mutation.

Currently, the small proportion of patients who present with papillary thyroid cancer and distant metastases, and who have the greatest risk of dying from the disease, are actively recruited to clinical trials with multikinase inhibitors.

For the somewhat larger proportion of patients who present with metastases in the neck region, but not at distant sites, the risk of dying is slightly lower but is still significant. It might be useful to test these patients for BRAF V600E mutations, Drs. Cappola and Mandel note. In fact, they suggest testing patients older than 45 years with stage III or IVa disease and cervical lymph node metastases.

In that subgroup, it might be worth considering aggressive therapy for patients carrying the mutation, perhaps before they develop distant metastases, they note.

Dr. Xing and coauthor David Sidransky, MD, also from Johns Hopkins University School of Medicine, report receiving royalties from a licensed US patent related to the BRAF V600E mutation in thyroid cancer. Some of the other coauthors report consultancy agreements with several pharmaceutical companies, as detailed in the paper. Dr. Cappola is a contributing editor to JAMA. Dr. Mandel reports serving on the scientific advisory board of Asuragen.

JAMA. 2013;309:1493-1501 and 1529-1530. Abstract, Editorial

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