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

Abstract

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.KEY POINTSDramatic recent advances in the management of metastatic BRAF-mutant melanoma have significantly improved outcomes for patients with the disease.For now, the best approach begins with a thorough evaluation the extent and resectability of the patient's metastatic disease and involves a multidisciplinary decision-making process that takes into account the disease burden and symptomatology, the kinetics of tumor progression, and, above all, patient preferences.Not every patient with unresectable metastatic BRAF-mutant melanoma will initially receive kinase inhibitor therapy when that approach is used in today's environment.During the next few years we are likely to see changes in how frequently surgery and immunologic therapies are used in front-line management of metastatic BRAF-mutant melanoma.