Is BRAF V600E Mutation the Explanation for Age-Associated Mortality Risk in Patients With Papillary Thyroid Cancer?

It is well accepted that patient age at time of diagnosis is a key prognostic factor for differentiated thyroid cancer. Multiple thyroid cancer staging systems incorporate age, with younger age at diagnosis associated with better prognosis, even with similar disease burden. Although the seventh edition of the American Joint Committee on Cancer (AJCC) staging system dichotomizes the prognostic factor of age at 45 years and the eighth edition at 55 years, several studies have found that these categories may be overly simplified because there is a clear linear relationship between age and survival.1-4 Age is on a continuum, with younger patients with differentiated thyroid cancer often having more well-differentiated disease, more iodine-avid tumors, and better treatment response.

Searching for an explanation for the effect of patient age on papillary thyroid cancer–specific mortality, Shen et al5 evaluate the role of BRAF V600E mutation, a common mutation in papillary thyroid cancers. On average, 45% of all papillary thyroid cancers have the BRAF V600E mutation, but the prevalence varies by population. Although it is widely accepted that BRAF V600E mutation correlates with moderately worse prognosis, the presence of BRAF V600E mutation in isolation is not an independent predictor of prognosis after accounting for tumor characteristics such as lymph node metastasis, extrathyroidal extension, and distant metastasis.6 However, in the article that accompanies this editorial, Shen et al5 specifically evaluate whether presence of BRAF V600E affects age-related prognostication. In a multicenter study with median follow-up of 58 months, the authors evaluated 1,094 patients who were BRAF V600E positive and 1,524 patients who were BRAF wild type. The authors found a positive linear relationship between older patient age and increasing mortality in patients with BRAF V600E mutation. In contrast, in patients with wild-type BRAF, the mortality across age groups was low and relatively flat. After adjusting for patient sex, tumor size, extrathyroidal extension, lymph node metastasis, distant metastasis, and administered activities of radioactive iodine, the linear relationship with BRAF V600E mutation and papillary thyroid cancer–specific mortality persisted, whereas this pattern was not seen in patients with wild-type BRAF.

Because prior studies found that BRAF V600E is not an independent prognostic indicator in papillary thyroid cancer after accounting for tumor characteristics, in recent years, the clinical utility of routine BRAF V600E testing has been questioned. From a diagnostic perspective, the benefit of BRAF V600E testing at time of fine-needle aspiration is low. Cytopathology report of papillary thyroid cancer is already accurate, and an indeterminate cytopathology report is infrequently secondary to a BRAF V600E–positive papillary thyroid cancer.7 The benefit of BRAF V600E mutation testing in surgical planning is also unclear because mutation status may not add additional insight compared with routine preoperative neck ultrasound.8 In addition, there are currently insufficient data to support the use of BRAF V600E mutation testing to guide postoperative radioactive iodine use.9 However, although routine BRAF V600E mutation testing has not been shown to improve diagnostic or treatment decisions, this study by Shen et al5 suggests that it could play a role in prognostication. If the authors’ data are accurate, with the current staging systems, some patients with wild-type BRAF may be upstaged secondary to an incorrect assumption that their advanced age indicates poorer prognosis. The authors suggest that future staging systems may be improved by incorporating BRAF V600E mutation status.(...)

Journal of Clinical Oncology , éditorial en libre accès, 2016

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