We searched PubMed for early (phase 1 and 2) and randomised controlled (phase 3) clinical trials in advanced melanoma, published in English after 2000, with the terms “melanoma” and “treatment”. These studies were reviewed for therapeutic approach, novelty, and clinical outcomes. We also searched PubMed with the terms “melanoma”, “melanoma subtypes”, “melanoma and BRAF V600E”, “melanoma and KIT”, “melanoma and bio-chemotherapy”, “melanoma and CTLA-4”, and “melanoma and survival”. Relevant
ReviewTreatment implications of the emerging molecular classification system for melanoma
Introduction
Malignant melanoma is an aggressive form of skin cancer with an incidence that is rising worldwide. Patients with advanced disease have universally poor prognosis, with median survival of 3–11 months depending on various prognostic factors. In the USA, about 8600 deaths per year are attributed to melanoma.1
Despite years of assessment of conventional chemotherapeutics and so-called targeted agents as treatment for melanoma, only ipilimumab—a T-cell potentiator—has shown an improvement in overall survival for patients with metastatic disease in a randomised phase 3 trial.2 Difficulties in identification of effective treatments could have, in part, been due to an inability to account for the genetic heterogeneity of melanoma. Such a heterogeneous disease is unlikely to be treated successfully with a uniform approach. A few cutaneous melanomas are responsive to dacarbazine (response rate 15%), highlighting the need for definition of subtype-specific predictors of response.3, 4 Understanding the underlying molecular aberrations driving tumour progression in melanoma should improve our ability to develop rational and more effective treatments, and could finally allow us to improve outcomes for patients with advanced disease.
Herein, we present our interpretation of the emerging molecular subclassification of melanoma, focusing particularly on three subsets that have current relevant treatment implications: melanoma characterised by BRAF mutations; melanoma characterised by alterations of KIT; and melanoma characterised by mutations in GNAQ and GNA11. We anticipate that this proposed classification system will continue to evolve as we further our understanding of these molecular pathways and their cross-talk. Although the treatments we discuss remain investigational, results available thus far are promising and definitive clinical trials are ongoing.
Section snippets
Emergence of a molecular classification system for melanoma
Melanoma is widely known to be a molecularly heterogeneous disease; however, only recently have we been able to identify patients with clinically relevant molecular signatures and assess response to treatment in these subgroups. A molecular classification system will replace conventional histological criteria, which divide melanoma into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. No evidence shows conclusively that this histological classification
Therapeutic implications for melanoma characterised by BRAF mutations
The enzyme BRAF is a member of the RAF (rapidly accelerated fibrosarcoma) family of serine/threonine kinases that also includes ARAF and RAF1 (also known as CRAF). It is an intermediary component of the MAPK pathway, which incorporates the enzymes RAS (rat sarcoma; encoded by HRAS, NRAS, and KRAS), RAF, MEK (MAPK/ERK kinase; encoded by MAP2K1 and MAP2K2), and ERK (extracellular-signal-regulated kinase; encoded by MAPK1 and MAPK3). The MAPK pathway is downstream of receptor tyrosine kinases,
Therapeutic implications for melanoma characterised by KIT mutations
KIT is a type III transmembrane receptor tyrosine kinase composed of five extracellular immunoglobulin domains, one transmembrane region, an inhibitory cytoplasmic juxtamembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment.43 Binding of its ligand—stem-cell factor—results in receptor dimerisation, autophosphorylation, and downstream activation of the MAPK, PI3K-AKT1, and JAK (Janus kinase)-STAT (signal transducer and activator of transcription) signalling
Therapeutic implications for melanoma characterised by GNAQ and GNA11 mutations
Unlike cutaneous melanoma, uveal melanoma is not characterised by the presence of activating mutations in BRAF or NRAS.70 However, activation of the MAPK pathway in uveal melanoma remains important for disease development and progression. An activating mutation has been reported in codon 209 (Gln209Leu) of guanine nucleotide-binding protein Q polypeptide (GNAQ; mutation designated herein as GNAQQ209L), a heterotrimeric protein that couples transmembrane domain receptors to intracellular
Considerations and future perspectives
Although long recognised as a clinically heterogeneous disease, advanced melanoma has historically been treated uniformly. This therapeutic strategy has proven unsuccessful for control of disease progression and extension of survival. We are becoming increasingly aware that effective treatment for advanced melanoma needs a thorough understanding of the disease's biology and genetics, because one treatment will not benefit all molecular subtypes. Development of effective treatments will require
Search strategy and selection criteria
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