Mutation Hikes Death Risk in Thyroid Cancer

Patients with papillary thyroid cancer (PTC) who are carriers of the BRAF V600E mutation may have worse mortality, researchers found.

In a retrospective study, overall mortality was significantly higher in mutation carriers than in those who were negative for BRAF V600E (5.3% versus 1.1%, P<0.001), Michael Mingzhao Xing, MD, of Johns Hopkins University, and colleagues reported in the April 10 issue of the Journal of the American Medical Association.

But the overall mortality in PTC is low, they warned, which rendered some associations insignificant in controlled analyses.

“Therefore, how to use BRAF V600E for the management of mortality risk among patients with PTC is not clear,” they wrote. “These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC.”

Their retrospective study assessed the records of 1,849 patients with PTC who were evaluated and treated at 13 centers around the world between 1978 and 2011. The median age was 46 and they had a median follow-up of 33 months.

Overall, the mutation was present in a large proportion (45.7%) of PTC patients. Of those who died, 80.4% had a BRAF V600E mutation.

Xing and colleagues found significantly higher mortality in mutation-positive patients. In multivariate analyses, mutation carriers had a significantly greater risk of death after adjusting for diagnosis, sex, and medical center (HR 2.66, 95% CI 1.3 to 5.43).

But the relationship lost significance after adjustment for lymph node metastasis, extrathyroidal invasion, and distant metastasis, they noted.

The researchers also found higher mutation-associated mortality in two clinicopathological subcategories:

  Lymph node metastasis: 26.26 deaths per 1,000 person-years versus 5.93 deaths (HR 4.43, 95% CI 2.06 to 9.51)
  Distant tumor metastasis: 87.72 deaths per 1,000 person-years versus 32.28 (HR 2.63, 95% CI 1.21 to 5.72)

However, the significance of those factors was lost after adjusting for patient age, sex, and medical center, they noted, adding that the attenuation of significance in multivariate analyses may have something to do with the low number of PTC-specific deaths in the study.

In an accompanying editorial, Anne Cappola, MD, and Susan Mandel, MD, MPH, of the University of Pennsylvania in Philadelphia, said the findings provide two important insights.

First, they suggest that this mutation “mediates features of the clinically aggressive tumors that account for the vast majority of PTC mortality,” and provides a “strong biological rationale for current trials of targeted tyrosine kinase inhibitor therapy” for patients with the mutation who have advanced disease.

On the other hand, the results suggest that screening for the mutation “doesn’t add predictive value for PTC-related mortality beyond the information collected in process of PTC tumor staging.”

“This is particularly relevant when considering that 45% of all PTC tumors are BRAF V600E-positive, and implies that additional tumor or host genomic factors may influence tumor aggressiveness,” they wrote.

“Although these findings do not support widespread BRAF V600E testing,” they concluded, “they do support the need for additional study of how BRAF testing can be used to improve the already excellent prognosis of patients with PTC.”

The study was supported by the National Institutes of Health, the Ministry of Science and Higher Education, the Byrne Foundation, the Fondazione Cassa di Risparmio di Perugia, the Associazione Italiana per la Ricerca sul Cancro, the Beadle Family Foundation, and the New South Wales Cancer Institute.

Two of the researchers are co-holders of a patent related to a BRAF V600E mutation in thyroid cancer.

The researchers reported relationships with AstraZeneca, Bayer, Exelixis, Genzyme, Roche, Euro7000, Novartis, Pfizer, Eisai, OxiGene, Ipsen, Sanofi, Ethicon Endosurgery, Medtronic, Amgen, Mech Sharpe & Dohme, and Genzyme.

An editorialist reported relationships with Asuragen.

Primary source: Journal of the American Medical Association
Source reference: Xing M, et al “Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer” JAMA 2013; 309(14): 1493-1501.

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