Advances in molecular profiling of malignant melanoma: ready for clinical practice?

Abstract

Cutaneous malignant melanoma (CMM) is one of the most common cancers in the western world, with a rapidly increasing incidence. Clinically, CMM is a highly heterogeneous disease that is currently divided according to the American Joint Committee on Cancer (AJCC) staging system [1]. Several tumor-intrinsic features such as Breslow thickness, ulceration and mitotic rate are incorporated in the AJCC staging system, representing well-established prognostic markers. CMM patients with T1 tumors ( 4 mm in thickness) have a survival rate of approximately 40% [1]. Despite the excellent prognosis within the T1 group, there have been efforts to further stratify these tumors using tumor infiltrating lymphocytes (TILs), mitogenicity and the AJCC variables [2]. Overall, this study shows that these features may add independent prognostic information in thin melanomas. However, a major challenge lies within stage II CMM, that is, lymph node negative patients with tumors having a Breslow thickness ranging from at least 1 mm to very large lesions (>4 mm), with or without ulceration. Survival for these patients varies considerably and refinement with additional prognostic biomarkers is needed. Based on the discovery in 2002 of frequent BRAF mutations in CMM [3], and their virtually mutually exclusive occurrence with NRAS mutations, tumors are today molecularly divided by BRAF and NRAS mutation status. Research in CMM was then focused on determining the therapeutic relevance of this oncogene. Previously, in 2010 the efficacy of selective BRAF kinase inhibitors was demonstrated and subsequently reinforced by Phase II studies [4–6]. In all, BRAF mutation (most commonly Val600Glu) is now established as a strong predictor for BRAF inhibition treatment. BRAF mutation status is also one of the cornerstones in the CMM classification proposed by the group of Boris Bastian in 2005 [7]. They describe that BRAF mutation is frequently found in CMMs that are intermittently sun-induced (e.g., melanomas located on the trunk), while tumors located on non-sun-induced sites (acral and mucosal melanomas) usually are BRAF wild-type. Furthermore, BRAF mutation has been proposed as a marker of poor prognosis in the distant “A combination of mutation and gene expression molecular profiling has great potential for future individualized care of patients with melanoma.”