BRAF MUTATION AND PAPILLARY THYROID CANCER

May 14, 2009 — A new study indicates that preoperative testing for a BRAF oncogene mutation could optimize surgical management of papillary thyroid carcinoma (PTC). Because BRAF-positive PTC is typically aggressive and invasive, total thyroidectomy is indicated for patients with this mutation.

First author Linwah Yip, MD, a surgical oncologist at the Multidisciplinary Thyroid Center, University of Pittsburgh Medical Center, Pennsylvania, presented the results May 5 at the annual meeting of the American Association of Endocrine Surgeons in Madison, Wisconsin.

The V600E mutation in BRAF, which involves substitution of glutamate (E) for valine (V) at codon 600, is found in 30% to 80% of PTC cases. The mutation is rarely found in benign thyroid nodules and has high positive predictive value for PTC.

"There are 1 or 2 other very rare BRAF mutations that have been identified[, but] they are too uncommon to correlate to any specific clinical characteristics," said Dr. Yip in her email to Medscape Oncology. "The V600E mutation is by far the most common. It is actually an activating mutation and causes overexpression of BRAF."

Previous studies in the literature had established that BRAF-positive PTC tumors were more often found at advanced stages (stages III or IV), more likely to recur, and associated with decreased survival. The present study investigated whether identifying BRAF status by preoperative fine needle aspiration (FNA) cytology could guide surgical treatment of PTC.

Prospective BRAF testing was carried out on specimens obtained by FNA and surgical specimens with nodules 3 mm or greater in size. PTC patients were grouped by BRAF status into 2 cohorts: 106 BRAF-positive patients and 226 BRAF-negative patients (100 of whom made up the control group). PTC was diagnosed by FNA cytology in 76 (37%) of the 206 patients and by postoperative histology in the remaining 130 patients.

The occurrence of BRAF-positive and BRAF-negative tumors differed significantly among PTC variants. Among the 199 patients evaluated, 59% of the BRAF-negative tumors compared with 9% of BRAF-positive tumors were the follicular variant type of PTC (P < .001); 5% of BRAF-negative tumors compared with 30% of BRAF-positive tumors were tall cell variant (P = .03).

However, this distribution may be slightly skewed. "Our series has a higher than normal proportion of tall cell variant in both BRAF-negative and BRAF-positive groups," said Dr. Yip. "We are not sure why but speculate perhaps that there is a regional variance. Tall cell variant is also known to have aggressive characteristics. In contrast, follicular variant is thought to be much more of an indolent tumor."

Because 25% to 30% of the specimens were not classified by subtype, Dr. Yip suggested that more interesting variants such as tall cell or follicular tumors may have been preferentially noted by the pathologists. Nevertheless, the correspondence between aggressive tumors (tall cell, having a significantly greater proportion of the BRAF-positive cases) and indolent tumors (follicular, involving a significantly greater proportion of the BRAF-negative cases) supports the clinical relevance of BRAF testing.

Among patients eventually identified as having BRAF-positive tumors, only 70% were detected by FNA testing (sensitivity, 70%). However, all patients initially identified as having BRAF-positive tumors by FNA cytology were confirmed as having PTC (specificity, 100%).

Most important to the purpose of this study was that, of the BRAF-positive patients initially designated (incorrectly) as BRAF-negative or of unknown BRAF status, 24% required further surgery to complete the thyroidectomy or for "persistent PTC." Thus, the study concludes that "optimizing initial surgery may be the best therapeutic option for BRAF-positive PTC."

Dr. Yip explained further: "We feel strongly that molecular testing of cytology specimens offers improved diagnostic sensitivity and, for that reason, should be considered routine. Instead of potentially undergoing repeated invasive procedures, molecular testing can provide valuable additional information, streamlining patient care."

The study demonstrated that molecular testing for BRAF status can direct surgical management and avoid the necessity of repeated surgeries that add to patient risk. "Only a cost-benefit analysis will really tell us if the additional expense justifies the improvement in patient care, which we are in the process of evaluating," Dr. Yip observed.

Although the increased expense of more tests might be an initial concern in the routine use of molecular testing to inform surgical procedures, pathologic examination of tumors is moving in the direction of routine genetic analyses.

"This, to me, is the future. We'll just have to figure ways to bring the cost down," commented David L. Bartlett, MD, associate professor of surgery and chief of the Division of Surgical Oncology, University of Pittsburgh Medical Center, in a telephone interview with Medscape Oncology.

"Once this kind of testing becomes routine for all cancers, to do this mutational analysis should not be a significant burden on the healthcare dollars overall. The big key here would be if you avoid a second operation," Dr. Bartlett pointed out. "You're avoiding a lot of costs inherent in putting a patient through another operation, as well as just assuming it's a lot easier on the patients."