BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer

Context How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. Objective To study whether BRAF V600E affected LNM-associated mortality in PTC. Design, Setting, Participants We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 (IQR 35–58) years and median follow-up time of 58 (IQR 26–107) months. Results Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAFV600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAFV600E patients; mortality rates were 2/659 (0.3%) versus 4/321 (1.2%) in non-LNM versus LNM patients (P=0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAFV600E CPTC, morality rates were 7/515 (1.4%) versus 28/363 (7.7%) in non-LNM versus LNM patients (P<0.001), corresponding to HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAFV600E versus absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. Conclusions LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.