Coexisting BRAF, TERT mutations predict poorer survival in papillary thyroid cancer

LAKE BUENA VISTA, Fla. — Coexisting BRAF V600E and TERT promoter mutations significantly increased the risk for disease-specific mortality in patients with papillary thyroid cancer, according to study results presented at the International Thyroid Congress.

Although certain patients with papillary thyroid cancer appear to be highly susceptible to disease-specific mortality, the influence of genetic factors had been unclear. In a previous study, Xing and colleagues suggested that coexisting BRAF V600E and TERT promoter mutations played a unique role in disease-specific mortality.

Thus, they sought to validate their initial findings in an extended cohort study of 1,051 patients (median age, 46 years; women, n = 764) with papillary thyroid cancer.

“There was a lot that remained unknown in our first study,” Michael Mingzhao Xing, MD, PhD, professor of medicine and oncology at The Johns Hopkins University School of Medicine, said during a presentation. “In this larger and longer study, we were able to analyze the relationship of these disease-specific patient mutations and their influence on disease-specific mortality and all-cause mortality.”

The researchers tested patients for the presence of both mutations. The median follow-up was 89 months (interquartile range, 48-142).

In the entire cohort, 629 patients had neither mutation, 292 patients harbored BRAF V600E alone, 64 patients harbored TERT mutations alone, and 66 patients harbored both mutations.

The concurrent presence of BRAF V600E and TERT promoter mutations remained significantly associated with a high risk for disease-specific mortality in the larger patient cohort. The researchers observed mortality rates of 0.6% (n = 4) for patients with neither mutation, 2.4% (n = 7) for patients with BRAF V600E alone, 6.3% (n = 4) for patients with TERT mutations alone, and 22.7% (n = 15) for patients with both mutations.

These percentages correlated with deaths per 1,000-person years of 0.8 (95% CI, 0.3-2.13) for neither mutation, 3.08 (95% CI, 1.47-6.46) for the BRAF V600E mutation, 6.62 (95% CI, 2.48-17.64) for the TERT mutation and 29.86 (95% CI, 18-49.52) for both mutations.

When compared with patients with wild-type BRAF V600E and TERT, HRs for mortality were 3.08 (95% CI, 0.87-10.84) for BRAF V600E alone, 8.18 (95% CI, 2.04-32.75) for TERT alone and 37.77 (95% CI, 12.5-114.09) for both.

After adjusting for age, sex, tumor size, tumor multifocality, extrathyroidal invasion, vascular invasion and cervical lymph node metastases, the risk for mortality among patients harboring both mutations remained significant (HR = 9.34; 95% CI, 2.53-34.48).

Results of Kaplan-Meier analyses showed modest declines in disease-specific survival for patients harboring one mutation but a sharp decline for patients who harbored both.

The researchers did not observe an effect of mutation status on non–disease-specific mortality.

“The reported effect of BRAF mutation or TERT promoter mutation in the literature likely contains a major component of the effect from the coexisting other,” Xing said. “I think, truly, that TERT and BRAF team up for trouble in thyroid cancer.” – by Cameron Kelsall

Reference:
Xing M, et al. Short Call Oral Abstract 3. Presented at: International Thyroid Congress; Oct. 18-23, 2015; Lake Buena Vista, Fla.

Disclosure: HemOnc Today was unable to obtain a list of the researchers’ relevant financial disclosures at time of reporting.