BRAF Mutation and Thyroid Cancer Recurrence

Thyroid cancer is the most common endocrine malignancy, with an incidence that has been increasing rapidly since the mid-1990s. Papillary thyroid cancer (PTC) accounts for more than 85% to 90% of all thyroid malignancies. In general, PTC has an excellent prognosis, with a 5-year survival rate of approximately 98%. However, although most PTC can be treated successfully with surgery, radioiodine ablation, and thyroid suppression therapy, tumor recurrence occurs in 5% to 20% of patients. If distant tumor recurrences occur, the 10-year survival rate of PTC is reduced to approximately 40%. The development of molecular determinants of disease recurrence has the potential to improve the clinical management of patients with PTC by assisting in risk stratification and pairing the use of more aggressive treatments with patients who are at higher risk of recurrence. The BRAF V600E mutation is the most common genetic mutation detected in patients with PTC and occurs in approximately 45% of patients. However, thus far, its usefulness as a prognostic marker in PTC has been controversial. Previous work has shown that patients with a BRAF mutation may be more likely to have clinicopathologic characteristics of more aggressive disease, such as extrathyroidal invasion, lymph node metastasis, and advanced tumor stage at initial surgery. Furthermore, a recent large multicenter retrospective study by Xing et al found that in an unadjusted analysis, the presence of the BRAF V600E mutation was significantly associated with PTC-related mortality. However, this association lost statistical significance after adjusting for clinical and clinicopathologic risk factors such as patient age, lymph node metastasis, extrathyroidal invasion, and distant metastasis. The prognostic value of the BRAF V600E mutation in PTC was subsequently questioned in an accompanying editorial. Therefore, until now, it has been debated whether the BRAF mutation status provides any useful prognostic value beyond that obtained from traditional pathologist and radiologic evaluation. In the article that accompanies this editorial, Xing et al report the largest study to date to suggest that the BRAF V600E mutation has prognostic value for recurrence in PTC. In a collaborative effort involving data from 2,099 patients from 16 medical centers in eight countries, the authors showed that the presence of a BRAF V600E mutation is significantly associated with an increased risk of PTC recurrence, even after adjusting for several traditional clinicopathologic risk factors including tumor size, extrathyroidal extension, lymph node metastases, and multifocality. Within the subtypes of classic papillary thyroid carcinoma and follicular-variant papillary thyroid carcinoma, recurrence rates were statistically higher in BRAF mutation–positive PTC compared with BRAF mutation–negative PTC. These differences remained statistically significant after adjusting for the traditional clinicopathologic risk factors listed. Notably absent from the pathologic risk factors accounted for in this analysis are lymphatic or vascular invasion or the presence of foci with adverse histology (ie, tall-cell features); it would be worthwhile to know whether BRAF mutation is independent of these known risk factors. Despite the worse outcome in recurrence-free survival (shown in Figs 2A and 2B of the article by Xing et al), the effect of the BRAF mutation seems to be small when a direct comparison is made with the corresponding subset that lacks the mutation, and may be further diminished if additional clinicopathologic factors are taken into account. The vast majority of patients who were included in this study seem to have also been evaluated in this group’s previous study that examined the relationship between BRAF mutation status and PTCrelated mortality. Therefore, it is noteworthy that BRAF mutation status has emerged as a more robust prognostic factor for PTC recurrence than for PTC-related mortality. Should the relationship hold up after additional known clinicopathologic factors are included, it will raise the question of where in clinical practice BRAF mutation testing should be applied. Although the clinical role of testing for the BRAF mutation continues to intrigue, prospective data will be required to support that BRAF mutation testing can improve outcomes when incorporated into clinical decision making. Until the completion of a study that provides such data, it is unknown whether BRAF mutation testing can improve the management of patients with PTC. Given the costs and the potential for significant psychological and emotional harm related to the anxiety that may accompany BRAF mutation testing, we believe that there is insufficient evidence to support widespread use of BRAF mutation testing for patients with PTC at this time. However, ultimately, there may be a few subgroups of patients for whom BRAF mutation testing is eventually shown to improve management of PTC when used in combination with traditional clinical and pathologic risk factors to most accurately risk stratify patients. One such subgroup may be patients with conventionally low-risk PTC. In this study by Xing et al, recurrence rates were 12.1% in patients with BRAF mutation–positive and 7.3% in patients with BRAF mutation–negative low-risk PTC. In a separate, previous cohort of 319 patients with low-risk intrathyroidal PTC, BRAF-mutated tumors had a recurrence rate of 7.5% compared with a rate of 1% for BRAF mutation–negative tumors after 5 years of follow-up. Therefore, BRAF mutation testing may eventually be shown to be helpful in identifying patients with conventionally low-risk disease who are at JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 1 JANUARY 1 2015