Influence of BRAF and NRAS Mutations on Distant Intracranial Recurrence and Survival in Metastatic Melanoma Following Radiosurgery

Abstract

The clinical course of patients with metastatic melanoma with brain metastases can be quite varied. This study aims to compare outcomes based on mutational status of BRAF and NRAS following stereotactic radiosurgery (SRS). A prospectively maintained database of patients receiving SRS between November 2002 and December 2012 was queried to determine the rate of new brain metastasis development in patients with metastatic melanoma following SRS. Patients receiving whole brain radiation therapy as first line treatment were excluded. BRAF and NRAS mutational status was determined by Sanger sequencing. The impact of mutation status on risk of distant intracranial recurrence and overall survival (OS) from brain metastasis diagnosis was determined using Poisson regression with robust estimation of errors and Cox proportional hazards analyses, respectively. Other factors including systemic disease control and intracranial disease burden were explored as potential predictors of recurrence and OS in a similar fashion. One hundred eight patients were identified with a mean age of 63 years (range, 24-90 years), of which 68% were male and 94.4% were white. A NRAS mutation was found in 9 patients (8.3%) and BRAF mutation in 24 (22.2%). Median OS from brain metastasis diagnosis was 312 days (range, 228-471 days). A larger number of brain metastases at diagnosis and uncontrolled systemic disease were found to be univariate predictors of worsened OS (HR 1.04, p = 0.012; HR 2.52, p = 0.001, resp). Only uncontrolled systemic disease was a significant predictor of OS on multivariate analysis (HR 10.63, p = 0.022). Mutation status for BRAF and NRAS did not appear to influence survival in our cohort. NRAS-mutated patients were found to be at significantly higher risk of distant intracranial recurrence as compared to wild type patients (IRR for wild type compared to NRAS-mutated, 0.27, p = 0.011). No other variables were found to be significant predictors of recurrence. Although metastatic melanoma follows a highly variable clinical course, NRAS mutations appear to influence the number of intracranial recurrences experienced by patients. Other disease factors including systemic disease control and number of brain metastases at diagnosis seem to influence OS.