Interview With Young Joo Park, MD, PhD
The most common form of thyroid cancer, papillary thyroid cancer, is highly curable in most patients, but 15% to 20% of cases are caused by aggressive tumors with a high risk of recurrence and an increased rate of mortality.1
Results of a new study—the first meta-analysis to investigate the prognostic effects of the two mutations together versus each mutation alone—demonstrated that the presence of genetic mutations may increase the predictive ability of standard prognostic methods to identify which patients are at increased risk for a progressive disease course.2
The retrospective analysis, led by Young Joo Park, MD, PhD, professor of endocrinology and metabolism, at Seoul National University College of Medicine and Seoul National University Hospital in Seoul, Korea, examined the coexistence of two genetic mutations, BRFV600E and a TERT promoter mutation, and their association with high-risk clinicopathologic features of papillary carcinoma.2
“The coexistence of BRAFV600E and TERT promoter mutations has a synergistic effect on the clinicopathologic characteristics of papillary thyroid cancer, including advanced tumor, node and metastasis (TNM) staging, extrathyroidal invasion, lymph node metastasis, and distant metastasis,” Dr. Park told EndocrineWeb. “Importantly, according to the available evidence, the coexistence of BRAFV600E and TERT promoter mutations is significantly associated with recurrence and papillary thyroid cancer mortality, as well.”
An association between the BRAFV600E mutation and poor prognosis of papillary thyroid cancer was demonstrated previously,3 but the high prevalence of the mutation in this form of cancer limited its use as a prognostic marker.
More recent studies of the TERT promoter mutation as a possible marker of aggressive clinicopathologic characteristics in papillary thyroid cancer led to the investigation of their prognostic role as a genetic duet.4 V600E is the most common mutation in the BRAF gene, making it the most frequently tested in clinical laboratories.
In the current study, however, the TERT promoter mutation alone did not increase the risk of recurrence or mortality, which was an expected finding given mounting evidence suggesting that this mutation held promise as a significant prognostic molecular marker in papillary thyroid cancer.2 The authors proposed that previous studies actually failed to discriminate between the TERT promoter mutation alone compared to coexistence with a BRAFV600E mutation.
While the mechanism for the synergistic effects of these 2 mutations on prognosis is undergoing study, it is known that BRAF activates the increased expression of the TERT promoter, leading to increased tumor development and malignant transformation in papillary thyroid cancer, and that that both of these markers are present when papillary thyroid cancer is both aggressive and recurrence.4
According to Dr. Park and his colleagues, the current research fully confirms the earlier findings that coexistence of the mutations was significantly associated with tumor recurrence and papillary thyroid cancer-related mortality.3,4
“Immunohistochemistry (IHC) for BRAFV600E is routinely available in pathology laboratories and is less costly than sequencing methods. However, IHC for TERT is still not available, so we reserved testing for the 2 mutations in patients at highest risk, as determined by American Thyroid Association PTC staging systems,” Dr. Park told EndocrineWeb.
These findings suggest that all high-risk patients with papillary thyroid cancers should be tested for the BRAFV600E and TERT promoter mutations, said Dr. Park, and patients with thyroid cancers that are positive may benefit from more aggressive therapy, although that still needs to be studied.2
Dr. Park concluded, “molecular testing of the BRAFV600E and TERT promoter mutations together may be useful in assisting with risk stratification of PTC in clinical settings.”
The researchers conducted a meta-analysis of 13 published studies including 4347 patients with PTC. Of those, 283 had coexistent BRAFV600E and TERT promoter mutations.2
Compared with no mutations, coexistent BRAFV600E and TERT promoter mutations were significantly associated with age at diagnosis (Mean Difference = 16.18 [CI 13.84-18.52], male sex (Odds Ratio 2.33 [CI 1.71-3.15]), advanced TNM stage (OR = 7.51 [CI 5.38-10.48]), extrathyroidal extension (OR=8.14 [CI 5.55-11.94]), lymph node metastasis (OR = 2.94 [CI 2.12-4.09]), and distant metastasis (OR = 8.36 [CI 4.13-16.95]). 2