Elsevier

The Lancet Oncology

Volume 12, Issue 9, September 2011, Pages 913-922
The Lancet Oncology

Review
Treatment implications of the emerging molecular classification system for melanoma

https://doi.org/10.1016/S1470-2045(10)70274-6Get rights and content

Summary

Melanoma is an aggressive disease with few standard treatment options. The conventional classification system for this disease is based on histological growth patterns, with division into four subtypes: superficial spreading, lentigo maligna, nodular, and acral lentiginous. Major limitations of this classification system are absence of prognostic importance and little correlation with treatment outcomes. Recent preclinical and clinical findings support the notion that melanoma is not one malignant disorder but rather a family of distinct molecular diseases. Incorporation of genetic signatures into the conventional histopathological classification of melanoma has great implications for development of new and effective treatments. Genes of the mitogen-associated protein kinase (MAPK) pathway harbour alterations sometimes identified in people with melanoma. The mutation Val600Glu in the BRAF oncogene (designated BRAFV600E) has been associated with sensitivity in vitro and in vivo to agents that inhibit BRAFV600E or MEK (a kinase in the MAPK pathway). Melanomas arising from mucosal, acral, chronically sun-damaged surfaces sometimes have oncogenic mutations in KIT, against which several inhibitors have shown clinical efficacy. Some uveal melanomas have activating mutations in GNAQ and GNA11, rendering them potentially susceptible to MEK inhibition. These findings suggest that prospective genotyping of patients with melanoma should be used increasingly as we work to develop new and effective treatments for this disease.

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

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

References (78)

  • FS Hodi et al.

    Improved survival with ipilimumab in patients with metastatic melanoma

    N Engl J Med

    (2010)
  • MR Middleton et al.

    Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma

    J Clin Oncol

    (2000)
  • PB Chapman et al.

    Phase III multicenter randomized trial of the Dartmouth regimen versus dacarbazine in patients with metastatic melanoma

    J Clin Oncol

    (1999)
  • RL Barnhill et al.

    Predicting five-year outcome for patients with cutaneous melanoma in a population-based study

    Cancer

    (1996)
  • VJ McGovern et al.

    The classification of malignant melanoma and its histologic reporting

    Cancer

    (1973)
  • WH Clark et al.

    The histogenesis and biologic behavior of primary human malignant melanomas of the skin

    Cancer Res

    (1969)
  • H Davies et al.

    Mutations of the BRAF gene in human cancer

    Nature

    (2002)
  • DC Whiteman et al.

    p53 expression and risk factors for cutaneous melanoma: a case-control study

    Int J Cancer

    (1998)
  • DC Whiteman et al.

    Melanocytic nevi, solar keratoses, and divergent pathways to cutaneous melanoma

    J Natl Cancer Inst

    (2003)
  • JA Curtin et al.

    Distinct sets of genetic alterations in melanoma

    N Engl J Med

    (2005)
  • H Davies et al.

    Mutations of the BRAF gene in human cancer

    Nature

    (2002)
  • JL Maldonado et al.

    Determinants of BRAF mutations in primary melanomas

    J Natl Cancer Inst

    (2003)
  • M Bohm et al.

    Identification of p90RSK as the probable CREB-Ser133 kinase in human melanocytes

    Cell Growth Differ

    (1995)
  • J Ackermann et al.

    Metastasizing melanoma formation caused by expression of activated N-RasQ61K on an INK4a-deficient background

    Cancer Res

    (2005)
  • L Chin et al.

    Essential role for oncogenic Ras in tumour maintenance

    Nature

    (1999)
  • DB Solit et al.

    BRAF mutation predicts sensitivity to MEK inhibition

    Nature

    (2006)
  • L Liu et al.

    Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5

    Cancer Res

    (2006)
  • A Hauschild et al.

    Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma

    J Clin Oncol

    (2009)
  • KT Flaherty et al.

    Final results of E2603: a double-blind, randomized phase III trial comparing carboplatin (C)/paclitaxel (P) with or without sorafenib (S) in metastatic melanoma

    Proc Am Soc Clin Oncol

    (2010)
  • GK Schwartz et al.

    A phase I study of XL281, a selective oral RAF kinase inhibitor, in patients (Pts) with advanced solid tumors

    Proc Am Soc Clin Oncol

    (2009)
  • R Kefford et al.

    Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors

    Proc Am Soc Clin Oncol

    (2010)
  • J Tsai et al.

    Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity

    Proc Natl Acad Sci USA

    (2008)
  • KT Flaherty et al.

    Inhibition of mutated, activated BRAF in metastatic melanoma

    N Engl J Med

    (2010)
  • Melanoma 2010 Congress

    Pigment Cell Melanoma Res

    (2010)
  • E Hatzivassiliou et al.

    A fusion of the EBV latent membrane protein-1 (LMP1) transmembrane domains to the CD40 cytoplasmic domain is similar to LMP1 in constitutive activation of epidermal growth factor receptor expression, nuclear factor-kB, and stress-activated protein kinase

    J Immunol

    (1998)
  • PI Poulikakos et al.

    RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

    Nature

    (2010)
  • KS Smalley et al.

    CRAF inhibition induces apoptosis in melanoma cells with non-V600E BRAF mutations

    Oncogene

    (2009)
  • TC Yeh et al.

    Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor

    Clin Cancer Res

    (2007)
  • BB Friday et al.

    A potential role for modulation of a negative feedback loop between Erk and Raf in mediating sensitivity to the MEK inhibitor AZD6244 (ARRY-142886) in human lung cancer cell lines

  • Cited by (0)

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