Co-existence of BRAF V600E, TERT promoter mutations predict recurrence in papillary thyroid cancer

Issue: October 2014

Patients with papillary thyroid cancer who harbor a BRAF V600E mutation and a specific telomerase reverse transcriptase promoter mutation are at significantly increased risk for recurrence than patients who have either mutation alone, according to results of a retrospective study.

“These genetic patterns, by separating patients with papillary thyroid cancer into different risk groups and particularly by defining the group with the most aggressive disease, have important prognostic and therapeutic implications,” Michael Mingzhao Xing, MD, PhD, professor in the department of endocrinology and metabolism at Johns Hopkins School of Medicine, and colleagues wrote.

Michael Mingzhao Xing

Xing and colleagues sought to assess the prognostic value of the BRAF V600E mutation and the telomerase reverse transcriptase (TERT) promoter mutation chr5:1,295,228C_T (C228T), alone and combined.

The analysis included 507 patients (mean age 46 years) with papillary thyroid cancer. The majority of patients (71.9%) were women. Median follow-up was 2 years.

Co-existence of BRAF V600E and TERT C228T mutations were more frequently associated with high-risk clinicopathologic characteristics of papillary thyroid cancer, results showed.

Researchers calculated tumor recurrence rates of 25.8% (77.60 recurrences per 1,000 person-years; 95% CI, 58.81-102.38) among patients with BRAF V600E mutations alone vs. 9.6% (22.88 recurrences per 1,000 person-years; 95% CI, 16-32.72) for those without BRAF V600E mutations (HR=3.22; 95% CI, 2.05-5.07).

Xing and colleagues calculated a tumor recurrence rate of 47.5% (108.55 recurrences per 1,000 person-years; 95% CI, 75.43-156.2) among those with TERT C228T mutations vs. 11.4% (30.21 recurrences per 1,000 person-years; 95% CI, 22.96-39.74) among those without TERT C228T mutations (HR=3.46; 95% CI, 2.19-5.45).

Researchers calculated a tumor recurrence rate of 68.6% (211.76 recurrences per 1,000 person-years; 95% CI, 141.94-315.94) among patients with both mutations vs. 8.7% (21.6 recurrences per 1,000 person-years; 95% CI, 14.59-31.97) among patients with neither mutation (HR=8.51; 95% CI, 4.84-14.97). This association remained significant after adjustments for clinicopathologic cofactors.

Xing and colleagues observed a sharp decline in DFS curves among patients with both mutations and a moderate decline in DFS curves among patients with either mutation alone.

Patients with characterized BRAF and TERT mutation status should be enrolled onto large randomized studies to help determine the effectiveness of targeted treatments, Joanne Ngeow, MD, and Charis Eng, MD, PhD, both of the Genomic Medicine Institute at Cleveland Clinic, wrote in an accompanying editorial.

“To advance developmental therapeutics targeting TERT transcription, including signaling inhibitors, a better understanding of system behavior would be advantageous,” Ngeow and Eng wrote. “BRAF V600E not only plays a dominant role in uncontrolled cellular proliferation through spontaneous extracellular regulated kinase signaling, [it] also teams up with TERT promoter mutations in a synergistic manner. To fully realize the translational potential from a decade of insights gained from sequencing, we will need to invest resources for the deep dives necessary to understand how, mechanistically, such partnerships are forged, and in both the coding and non-coding regions.”

For more information:

Ngeow J. J Clin Oncol. 2014;doi:10.1200/JCO.2014.56.5614.
Xing M. J Clin Oncol. 2014;doi:10.1200/JCO.2014.55.5094.

Disclosure: The researchers report no relevant financial disclosures.