Correlation of BRAF and NRAS mutation status with tumor characteristics and treatment outcomes in melanoma patients with brain metastasis.

Abstract

8584 Background: The management of melanoma has evolved rapidly with the identification of activating mutations in the majority of patients (pts). We reviewed characteristics and outcomes of molecularly characterized melanoma pts with brain metastasis (BM) to help design and interpret future clinical trials. Methods: We reviewed clinical and pathologic features of melanoma pts with known BRAF and NRAS mutation status and BM. Pt demographics, intra- (IC) and extra-cranial (EC) tumor characteristics, and IC/EC disease treatments were correlated to BM treatment outcomes (local and distant brain control [LC, DC]) and overall survival (OS). Univariate and multivariate analyses were performed to identify significant associations between mutation status and outcome. Results: We identified 296 pts with melanoma BM and known BRAF/NRAS mutation status diagnosed from 2005 to 2011. Mutation prevalence was BRAF 57%, NRAS 17%, and wild-type for both genes (WT) 26%. The initial treatments given for BM were surgery/radiosurgery (SRS) 60%, surgery/SRS + whole brain radiation (WBRT) 7%, WBRT alone 19%, systemic therapy alone 9%, and no treatment 5%. Mutation status was not significantly associated with sex, performance status, EC disease status, number of brain lesions, or BM treatment. Pts with mutations were younger (p<0.0001) and more likely to have symptomatic BM (p=0.0003) than WT pts. In univariate analysis, BM treatment strategy (p<0.001) and mutation status predicted for poor LC, with 6 month LC rates of 70% for any mutation and 88% for WT (HR=1.86, p=0.048). Compared to systemic agents alone, use of radiation (SRS or WBRT) improved LC for pts with a mutation (HR 0.23, p=0.0006). Subsequent multivariate analysis identified mutation status and radiation treatment as independent predictors of LC (HR 2.5 and 0.25, respectively). Mutation status did not predict for DC or OS. Conclusions: The presence of BRAF and NRAS mutations predicts worse LC following conventional treatments for melanoma BM. Radiation may improve LC in pts with a mutation. This data suggest a role for combining radiation with targeted therapies in melanoma pts with activating BRAF or NRAS mutations in the treatment of BM.