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BRAF mutation signals thyroid ca risk.

COLORADO SPRINGS -- Papillary thyroid cancers positive for the BRAF V600E mutation behave markedly more aggressively than those that aren't, Dr. Electron Kebebew said at the annual meeting of the American Surgical Association.

"Future testing for this mutation could help us select how extensive our initial surgery should be, an appropriate adjuvant therapy, and how closely we monitor these patients in follow-up," added Dr. Kebebew of the University of California, San Francisco.

The incidence of thyroid cancer has nearly doubled during the past 3 decades. Most of this increase involves small papillary thyroid cancers, many of which are occult and detected only incidentally. Today papillary thyroid cancer accounts for roughly 85% of all thyroid cancers. Some series of occult papillary thyroid cancers smaller than 1.5 cm show a recurrence rate of less than 6% and near-normal life expectancy. But within the large group of generally favorable-prognosis papillary thyroid cancers is a subset that behaves aggressively.

The V600E missense mutation located on exon 15 of the BRAF gene--the most potent mitogen-activating gene--might have a valuable role to play in sorting out this higher-risk subset. The mutation occurs commonly in patients with anaplastic thyroid cancer, which is almost uniformly lethal, he noted.

To determine whether the BRAF mutation predicts tumor aggressiveness, Dr. Kebebew reported on 347 tumor samples obtained from 314 patients with thyroid cancer. Of these patients, 212 had classic or usual papillary thyroid cancer histologically, while 29 had the follicular variant of papillary thyroid cancer and 73 had follicular thyroid cancer. Most patients were in their fifth decade of life. Their tumors averaged slightly less than 3 cm. Most were well differentiated. Roughly one-third were multicentric tumors, one-quarter entailed extrathyroidal invasion, and one-third involved lymph node metastases. Just four patients had distant metastases. More than 80% had stage I or II disease, and 13% had high-risk thyroid cancer by the AMES (age, distant metastases, extent and size of tumor) criteria.

The prevalence of the BRAF V600E mutation was 51% in those with classic papillary thyroid cancer, 24% in patients with the follicular variant, and just 1% in those with follicular thyroid cancer.

In a multivariate analysis, there were only two independent predictors of recurrent or persistent disease at a mean follow-up of 6 years: lymph node metastases, which conferred a 7.7-fold increased risk, and BRAF V600E-positive status of the primary tumor, which was associated with a 4.2-fold increased risk.

Even when the analysis was restricted to the subgroup of patients with stage I localized disease and low-risk status by the AMES criteria, the BRAF mutation was associated with a highly significant nearly 2.5-fold increased risk of persistent or recurrent disease, Dr. Kebebew continued.

An intriguing finding was that 5 of 32 patients with lymph node metastases had discordance with regard to BRAF mutation status. That is, while 13 patients had the BRAF V600E mutation in both their primary tumor and nodal metastases and 14 didn't have the mutation at either site, there were 3 patients who were primary tumor mutation-positive but lymph node-negative and 2 others who were primary tumor-negative but lymph node-positive.

One possible explanation for this discordance, according to Dr. Kebebew, lies in the observation by other investigators that roughly one-third of multicentric papillary thyroid cancers are heterogeneous with regard to BRAF V600E; that is, one portion of the primary tumor is mutation positive while the other is negative.

Some surgeons have suggested observation might be an appropriate approach to small papillary thyroid cancers. BRAF mutation testing could be extremely useful in refining such a strategy.

All papers presented at the 127th annual meeting of the ASA are subsequently submitted to the Annals of Surgery.

BY BRUCE JANCIN

Denver Bureau
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Title Annotation:Endocrinology
Author:Jancin, Bruce
Publication:Internal Medicine News
Geographic Code:1USA
Date:Aug 15, 2007
Words:615
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