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Abstract and Introduction
Abstract
BackgroundBRAF and NRAS mutations are frequently found in melanoma tumours, and recently developed BRAF-targeted therapies demonstrate significant clinical benefit.
Objectives We sought to investigate the clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort.
Methods In total, 237 tumours, mostly metastatic lesions, from 203 patients were screened for mutations in exon 15 of BRAF and exon 2 of NRAS using Sanger sequencing. BRAF and NRAS mutation status was analysed in relation to clinical and histopathological characteristics, and outcome.
Results Mutation in BRAF and NRAS was present in 43% (88% V600E, 10% V600K) and 30% (48% Q61K, 40% Q61R) of metastatic melanomas, respectively. We found consistent BRAF and NRAS mutation status in all but one of 27 patients with multiple metastases. BRAF mutation was associated with younger age at primary diagnosis (P = 0·02). Among patients with distant metastatic melanoma, patients with BRAF-mutant tumours without BRAF inhibitor treatment had inferior survival compared with patients with BRAF inhibitor treatment [hazard ratio (HR) 2·35, 95% confidence interval (CI) 1·10–5·01, P = 0·03]. We also observed a trend towards better prognosis for patients with wild-type and NRAS-mutant tumours compared with BRAF V600E-mutant tumours (HR 0·64, 95% CI 0·39–1·04, P = 0·07; and HR 0·76, 95% CI 0·48–1·21, P = 0·25, respectively).
Conclusions We were able to confirm the effect of BRAF inhibitor treatment in a single clinical institution. The results suggest further that BRAF mutation is a weak prognostic factor but a strong predictive factor and that BRAF-mutant melanoma might constitute one or more distinct subtypes of the disease with certain aetiology and clinical outcome.
Introduction
Constitutively activating BRAF mutations occur in approximately 40% of primary cutaneous melanomas. The most prevalent mutation is a T1799A transversion in exon 15 of the gene, which causes a V600E (Val600Glu) amino acid substitution in the protein. Mutation in BRAF leads to hyperactivity of the mitogen-activated protein kinase (MAPK)–extracellular signal-related kinase signalling pathway. Targeted therapy directed specifically towards BRAF V600E-mutated melanoma has demonstrated dramatic, although predominantly transient, clinical response. This highlights BRAF as an important clinical marker in the management of patients with melanoma. The second most commonly mutated oncogene in melanoma, NRAS, is mutated in 15–20% of cases and has been implicated as a prognostic factor in metastatic melanoma. Importantly, BRAF and NRAS mutations are mutually exclusive, and targeted therapeutic options for NRAS-mutant melanomas are under intense investigation.
Early studies have indicated that mutation in BRAF is an early event in melanoma development, and it has been hypothesized that BRAF mutation represents a separate pathway in the pathogenesis, reflecting a particular subtype of melanoma with a distinct phenotype and clinical outcome. In primary melanoma, BRAF mutation has been associated with younger age at diagnosis, localization to the trunk, absence of chronic sun damage, occult or one primary melanoma, and certain histopathological characteristics [presence of mitosis, superficial spreading melanoma (SSM) and low Breslow thickness], while NRAS mutation has been associated with thicker tumours and occurrence on the extremities.BRAF or NRAS status does not seem to predict overall survival or recurrence-free survival, but some studies point towards shorter survival for patients with BRAF-mutant metastatic disease.
In the current study, we aimed to determine the clinical significance of BRAF and NRAS mutations in a large cohort of surgically treated patients with metastatic melanoma. We sought to investigate the correlation to both clinical and histopathological characteristics, and outcome. Furthermore, we set out to determine the role of BRAF as a treatment-predictive factor.
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