The clinical significance ofBRAFandNRASmutations in a clinic-based metastatic melanoma cohort

Abstract

SummaryBackground BRAF 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 = 0Á02). 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) 2Á35, 95% confidence interval (CI) 1Á10-5Á01, P = 0Á03]. We also observed a trend towards better prognosis for patients with wild-type and NRASmutant tumours compared with BRAF V600E-mutant tumours (HR 0Á64, 95% CI 0Á39-1Á04, P = 0Á07; and HR 0Á76, 95% CI 0Á48-1Á21, P = 0Á25, 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.

Time and tumor type (primary or metastatic) do not influence the detection of BRAF/NRAS mutations in formalin fixed paraffin embedded samples from melanomas

“…This evidence has already been reported [16]. As previously observed [15,[17][18][19], in some samples we have detected co-occurrence of BRAF and NRAS mutations. At the single cell level, mutations in BRAF or NRAS are mutually exclusive [17].…”

NF1‐mutated melanoma tumors harbor distinct clinical and biological characteristics

“…Although the division of melanoma by MAPK mutation status is biologically relevant and predictive in MAPK inhibitor therapy, controversy exists regarding the prognostic significance of such classification (Carlino et al ., 2014; Ekedahl et al ., 2013). …”

Nras in melanoma: Targeting the undruggable target

“…The effect of these mutations on clinical outcome remains uncertain [59,61,73,74]. Table 1 summarizes most important studies on the prognostic role of NRAS in melanoma [63,68,[74][75][76][77][78][79]61,[80][81][82][83]. The majority of these studies have been retrospective in nature, and most of them included patients with recurrent or metastatic disease.…”