Patient Age–Associated Mortality Risk Is Differentiated by BRAF V600E Status in Papillary Thyroid Cancer

Abstract

For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and MethodsWe conducted a comparative study of the relationship between patient age at diagnosis and PTCspecific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. ResultsThere was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. ConclusionThe long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.

A molecular approach combined with American Thyroid Association classification better stratifies recurrence risk of classic histology papillary thyroid cancer

“…These data corroborate findings in a large 459 patient study from the University of California, San Francisco, in which BRAF V600E mutation was also not associated with negative clinicopathologic factors . In a recent publication, BRAF V600E mutation did not worsen cancer‐specific mortality in patients <45 years old . Thus, the association of BRAF V600E mutation with aggressive PTC pathology and clinical recurrence remains unclear.…”

“…19 In a recent publication, BRAF V600E mutation did not worsen cancer-specific mortality in patients <45 years old. 20 Thus, the association of BRAF V600E mutation with aggressive PTC pathology and clinical recurrence remains unclear. The lack of association between BRAF mutation and MAPK (dpERK) activation at the protein level in PTCs could partially explain this discrepancy.…”

The BRAF V600E mutation is a predictor of the effect of radioiodine therapy in papillary thyroid cancer

“…In the current prognosis evaluation system of thyroid cancer, the patient's age is a recognized risk factor for death; various clinical guidelines and risk assessment models include the patient's age as the primary risk factor in the management and prognostic evaluation of thyroid cancer. The presence of the BRAF mutation is closely related to the patient's age; thus, there may be synergistic effects leading to a poor prognosis [33]. Therefore, in the risk assessment of PTC patients, the BRAF gene mutation and the patient age should be considered as factors associated with a poor prognosis.…”

Fasting serum glucose, thyroid‐stimulating hormone, and thyroid hormones and risk of papillary thyroid cancer: A case‐control study

“…The etiology of thyroid cancer remains unclear to date. Numerous studies have identified a number of risk factors for PTC, such as old age, female sex, radiation exposure, high body surface area and weight changes, and gene BRAF V600E mutation . These factors are all reportedly associated with poor clinical outcomes of PTC, including extrathyroidal extension, lymph node metastasis, and distant metastasis.…”