Impact of BRAF mutation status in the prognosis of cutaneous melanoma: an area of ongoing research

Abstract

This review is intended to provide an updated role of molecular genetics and various targeted therapies that have been developed to treat advanced stages of melanoma. Because of the declining success in melanoma therapy, the curative treatment for advanced stage melanoma has been a challenge for clinicians. Several mutations such as N-RAS, p53, BRAF including mutant-BRAF that lead to activation of kinase pathway, are implicated in the development of malignant melanoma. However, the current literature depicts that the prognostic role of BRAF mutation in disease progression is still controversial. While its higher level in advanced stage disease is associated with decreased overall survival (OS), some studies show that it failed to confer as an independent prognostic predictor of the disease. This has also led researchers to accomplish newer therapeutic strategies that lead to improved disease-response and grant survival benefits. Vemurafenib, a BRAF inhibitor agent, is one of the few available targeted therapies that is FDA approved and provides promising results in metastatic disease. However, its resistance at an early stage is of great concern. Recent implementation of combinational therapies including "targeted therapy", immunotherapy, and biological agents has appealed many researchers to define the adjunctive role of available therapies and their limitations in advanced stage and metastatic melanoma. This commends the need for future multi-institutional studies to confirm the clinical validity of different therapeutic strategies on a large scale population.

Keywords: Malignant melanoma; disease progression; immunotherapy; mutations; vemurafenib.

Figure 1

Image displaying signaling pathways triggered by binding of growth factors to tyrosine kinase receptor that triggers RAS, RAF, MAPK and ERK pathways leading to cell growth and proliferation. Mutations in BRAF (V600E) which can lead to accelerated cell growth and cancer formation of melanoma cells. Inhibition of mutant BRAF by Vemurafenib (red cross) in the melanoma cells shuts down the signaling pathway causing tumor regression following cell apoptosis, tumor antigen expression and decreased release of cytokines and VEGF. MAPK, mitogen-activated protein kinase; ERK, extracellular-signal regulated kinase; EGF, vascular endothelial growth factor.

Figure 2

Image displaying multiple hypotheses for acquired BRAF inhibition resistance to chemotherapeutic agents (BRAF inhibitors) and mechanisms causing MAPK pathway reactivation. This process further leads to tumor relapse thus suggesting trials of combinational therapy (BRAF inhibitors, MEK inhibitors and/or Immunotherapy) at different levels of the pathway to prevent tumor progression. MAPK, mitogen-activated protein kinase.