BRAF mutation increased mortality for papillary thyroid cancer

Issue: June 25, 2013

The incidence of the BRAF V600E mutation was significantly associated with elevated cancer-related mortality among patients with papillary thyroid cancer, according to recent retrospective multicenter study results.

Perspective from Ranee Mehra, MD

“The overall 5-year patient survival rate for [papillary thyroid cancer] is 95% to 97%. A major clinical challenge is how to reliably distinguish patients who need aggressive treatments to reduce mortality from those who do not,” the researchers wrote. “This represents a widely controversial issue in thyroid cancer medicine, particularly because of the low overall mortality of this cancer. The issue has become even more challenging given the high annual incidence of [papillary thyroid cancer].”

Prior studies indicate that BRAF V600E represents a prominent oncogene in papillary thyroid cancer, but its role in cancer-related patient mortality has not been determined.

Anne R. Cappola

To assess the relationship between BRAF V600E mutation and papillary thyroid cancer-related mortality, researchers from the Johns Hopkins University School of Medicine conducted a study of 1,849 patients with papillary thyroid cancer at 13 centers in seven countries between 1978 and 2011.

The study included 1,411 women and 438 men with a median age of 46 years, with an overall median follow-up time of 33 months after their initial treatment.

According to study results, 45% of the cohort tested positive for the BRAF V600E gene. There were 56 papillary thyroid cancer-related deaths, with 45 cases (80%) of this group testing positive for BRAF V600E. The mortality of the BRAF V600E-positive patient group was 5.3%, as opposed to a mortality of 1.1% in mutation-negative patients.

Data lost statistical significance when the researchers considered the tumor characteristics in the BRAF V600E-positive mortality group. Factors such as lymph node metastasis, extrathyroidal invasion and distant metastasis indicated other known features of aggressive papillary thyroid cancer tumors, rendering the association between papillary thyroid cancer and the gene statistically insignificant.

Susan J. Mandel

In an accompanying editorial, Anne R. Cappola, MD, ScM, and Susan J. Mandel, MD, MPH, of the division of endocrinology, diabetes, and metabolism at the Perelman School of Medicine at the University of Pennsylvania, wrote: “These study results suggest that BRAF V600E testing does not add predictive value for [papillary thyroid cancer]-related mortality beyond the information collected in the process of papillary thyroid tumor staging, including postoperative histopathology reporting and clinical evaluation. This is particularly relevant when considering that 45% of all [papillary thyroid cancer] tumors are BRAF V600E-positive, and implies that additional tumor or host genomic factors may influence tumor aggressiveness.”

They added: “It is notable that despite the large collaborative effort undertaken to complete this study, the only study to examine BRAF V600E status and [papillary thyroid cancer] mortality to date, there were only 56 deaths, 45 in the BRAF V600E-positive group and 11 in the BRAF V600E-negative group. This limits the ability to garner information from stratified analyses to identify the target group for future study. It also strains statistical model validity when adjusting for confounders.”

For more information:

Cappola AR. JAMA. 2013; 309:1529-1530.

Xing M. JAMA. 2013;309:1493-1501.

Perspective

Ranee Mehra, MD

Xing and colleagues have reported that patients with papillary thyroid cancers that harbor the BRAF V600E mutation had an increased risk of cancer-related mortality, although this was not independent of high-risk tumor features. This analysis was a comprehensive undertaking that determined mutation status, clinicopathological features and survival from 1,849 patients across 13 centers. It is the largest series to evaluate the prognostic effect of the BRAF V600E mutation in this population.

As the authors cited, there are several limitations to this analysis. In particular, it is a retrospective analysis with varying stages and treatments, although the authors state that all treatments followed accepted guidelines. The patients were treated from 1978 to 2011; the study of tyrosine kinase inhibitors (TKI) for the treatment of iodine refractory thyroid cancer emerged during the later years.

It is not clear if any patients in this analysis were treated with TKI and whether that impacted mortality. In addition, given the overall low mortality associated with papillary thyroid cancer, there was limited power to perform some of the stratified analyses.

This report does raise some interesting questions. Although the intent of this study was to evaluate the prognosis associated with the BRAF V600E biomarker, now that RAF inhibitors are in development and trials for thyroid cancer, it would be interesting to determine if there is a predictive role for this biomarker with this class of drugs. In addition, studying the patterns of failure — such as the rate of central nervous system metastases — associated with BRAF V600E may help guide the clinical care of these patients. In general, this is an interesting report that will serve to facilitate understanding of the molecular mechanisms that underlie aggressive differentiated thyroid malignancies.

Ranee Mehra, MD

Attending physician

Medical oncology staff

Fox Chase Cancer Center

Disclosures: Mehra reports no relevant financial disclosures.