The Effect of Non-Overlapping Somatic Mutations in BRAF , NRAS , NF1 , or CKIT on the Incidence and Outcome of Brain Metastases during Immune Checkpoint Inhibitor Therapy of Metastatic Melanoma.

Previous studies suggested that somatic BRAF and NRAS mutations in metastatic melanoma increase the risk for brain metastases. The risk related to other non-overlapping "driver" mutations is unknown. We performed a retrospective evaluation of the incidence, timing, and outcome of brain metastases in a population of melanoma patients that underwent uniform next-gen sequencing. All patients were treated with initial checkpoint inhibitor therapy. Seventeen of 88 patients (20.0%) developed brain metastases. Eleven patients had brain metastases at diagnosis (12.9%). These were all patients with BRAF V600 or NF1 mutations. Only six patients with NRAS , NF1 , KIT , or BRAF mutations (including fusions/internal rearrangements experienced delayed CNS progression following immunotherapy (7.1%)). No "quadruple negative" patient developed brain metastases. Patients with brain metastases at diagnosis had a better outcome than those with delayed intracranial progression. Current predictive markers, (LDH, tumor mutation burden, and PDL1) were poorly correlated with the development of brain metastases. Treatment with immunotherapy appears to reduce the incidence of brain metastases. Next-gen molecular sequencing of tumors in metastatic melanoma patients was useful in identifying genetic subpopulations with an increased or reduced risk of brain metastases. This may allow eventual personalization of screening strategies.