Frontline Approach to Metastatic BRAF-Mutant Melanoma Diagnosis, Molecular Evaluation, and Treatment Choice

An estimated 76,100 patients will be diagnosed with invasive melanoma in the United States in 2014, and 9,710 patients will die from the disease. In almost all cases, the cause of death is related to the development of widespread metastatic disease. Although death rates from most types of cancer have steadily decreased in the United States--a 20% decrease during two decades from a peak of 215.1 deaths per 100,000 population in 1991 to 171.8 in 2010--death rates from melanoma have steadily increased during the same time, especially among males. The news regarding melanoma is far from all bad. Increases in our understanding of the human immune system have led to the development of new immunotherapeutic drugs such as ipilimumab, which has been shown to improve survival in phase III trials in metastatic melanoma, and anti-programmed death 1 (anti-PD1) antibodies, recently hailed by ASCO as one of the past year's most noteworthy clinical cancer advances. However, no discovery has influenced and, indeed, transformed the management of metastatic melanoma more than the identifıcation of activating mutations in the BRAF gene in the mitogen-activated protein kinase (MAPK) pathway, which occur in about half of cutaneous melanomas and can be targeted with small molecule inhibitors of the BRAF protein, the downstream MEK protein, or both. This article will address how patients with metastatic melanoma are evaluated for their mutation status and how the presence of a targetable mutation influences therapeutic decisions regarding systemic therapy and even surgery.