TERT, BRAF Mutations Mean Poor Papillary Thyroid Cancer Outcomes

Nancy A Melville

October 27, 2017

VICTORIA, British Columbia — The presence of a telomerase reverse transcriptase (TERT) promotor mutation, combined with the more common BRAF mutation, is associated with an increased risk of poorer outcomes in papillary thyroid cancer (PTC), particularly in older patients, according to new research.

"We confirmed that TERT promoter mutations are found in about 15% of BRAF-mutated PTC," said senior author Barbara Jarząb, PhD, MD, of the department of nuclear medicine and endocrine oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice Branch, Gliwice, Poland, in presenting the findings here at the 2017 Annual Meeting of the American Thyroid Association.

"In older patients, over the age of 45, the coexistence of BRAF/TERT promoter mutations better separates patients with worse outcome than BRAF mutation alone," Dr Jarząb explained.

While PTC is typically associated with excellent prognosis in the majority of patients, approximately 15% to 20% have recurrence or persistent disease.

Among those patients, the BRAFV600E mutation has been identified as a predictor of poorer outcomes; however, the clinical utility of the mutation is limited because it is highly common.

Meanwhile, recent research has shown the TERT promoter mutation to be present in approximately 10% of differentiated thyroid cancers (Endocr Relat Cancer. 2014;21:825-830).

And another study published earlier this year further showed that among six poor prognostic markers for PTC, the combination of BRAF and TERT was seen as likely the most aggressive (Endocr Relat Cancer. 2017;24:41-52).

Asked to comment on the new findings from Poland, Angela M Leung, MD, an assistant professor of medicine with the division of endocrinology, diabetes, and metabolism at the University of California, Los Angeles David Geffen School of Medicine, who comoderated the session at the ATA meeting, said these results are an important addition to the advancement of research of molecular markers in helping with the treatment of thyroid cancer.

"Molecular markers, such as BRAF and TERT mutations, have substantially changed how we manage patients with thyroid nodules and thyroid cancer in the past several years," Dr Leung told Medscape Medical News.

TERT Promoter Mutations Detected Only in Those > 45 Years

To better understand the prevalence of TERT promoter mutations in BRAF-mutated PTC and their prognostic significance, Dr Jarząb and her colleagues are conducting a DNA analysis on 200 BRAF-mutation confirmed tissue samples from PTC tumors.

Of 88 samples that have been evaluated for TERT mutation to date, 84% were from female patients, with a median age of 50 and a median follow-up of 31 months.

Most individuals (86; 97%) were treated with a total thyroidectomy, including 54 (61%) with central lymph-node dissection, 15 (17%) with lateral neck dissection, and 69 (78%) also received radioiodine treatment.

Of the samples, the TERT promoter mutation was found in 14 (16%), with the most frequent mutation, found in 13 patients, identified as C228T, and one patient harboring mutation C250T.

Interestingly, the TERT promoter mutations were detected only in patients over 45 years of age, and older age at the time of diagnosis was a key characteristic associated with this (mean of 69 years for TERT-positive patients vs 54 years forTERT negative; < .0003).

Factors associated with poorer prognosis among those with TERT promoter mutations and BRAFV600E mutations, compared with those with only the BRAF mutation, included larger tumor diameter (31.6 vs 15.8; < .002) and lymph-node metastases (P < .02)

At a median follow-up of 31 months, 5% of TERT-negative patients had a recurrence of disease, compared with 36% of TERT-positive patients (P = .02), and there was a trend for a higher rate of persistent disease in TERT-positive patients (21% vs 4% in TERT-negative patients; = .08).

"When we looked at patients over the age of 45, the majority of treatment failures, 72%…occurred in patients with the BRAF and TERT mutations, while only 28% involved patients without TERT promoter mutation," Dr Jarząb said.

Important Treatment Implications

In response to a question from the audience on the clinical significance of the findings, Dr Jarząb said that with more replication, they could have important treatment implications.

"I think first we need more cases before we can draw a conclusion about age; however, these preliminary results suggest that probably for patients with a coexistence of TERT with a BRAF mutation, there should be more aggressive treatment," she said.

Dr Leung said the utility suggested by this discovery — of being able to further substratify which patients with papillary thyroid cancer will have worse outcomes — "is in line with the more customized care that healthcare in general is moving toward."

She noted that the finding of the risk in older age was not necessarily surprising.

"This finding is reasonable, as older age is generally considered an independent risk factor for disease recurrence," she said.

The authors and Dr Leung had no relevant financial relationships.

2017 Annual Meeting of the American Thyroid Association. October 19, 2017; Vancouver, British Columbia. Abstract 3.

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