NRAS mutation status is an independent prognostic factor in metastatic melanoma

Abstract

Background: There is a need for improved prognostic markers in melanoma. In this study, the authors tested the prognostic significance and clinicopathologic correlations of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) mutations in patients with metastatic melanoma.

Methods: Clinical and pathologic data were collected retrospectively on melanoma patients who were clinically tested for BRAF (exon 15) and NRAS (exons 1 and 2) mutations at The University of Texas M. D. Anderson Cancer Center. Analyses were performed to identify significant associations of mutations with tumor and patient characteristics and with survival from the diagnosis of stage IV disease.

Results: The genotypes of the full cohort (n = 677) were 47% BRAF mutation, 20% NRAS mutation, and 32% wild-type for BRAF and NRAS ("WT"). Tumor mutation status was associated (P = .008) with the risk of central nervous system involvement at the diagnosis of stage IV disease, with a higher prevalence observed in BRAF-mutant (24%) and NRAS-mutant (23%) patients than in WT patients (12%). Among patients with nonuveal melanoma who underwent mutation testing within 6 months of stage IV diagnosis (n = 313), patients with NRAS mutations had a median survival of 8.2 months from stage IV diagnosis, which was shorter than the median survival of WT patients (15.1 months; P = .004). Multivariate analysis of this population incorporating age, sex, metastases (M1) category, serum lactate dehydrogenase level, and mutation status confirmed that NRAS mutations are associated independently with decreased overall survival (vs WT; P = .005; hazard ratio, 2.05).

Conclusions: Patients with BRAF or NRAS mutations were more likely than WT patients to have central nervous system involvement at the time they were diagnosed with distant metastatic disease. NRAS mutation status was identified as an independent predictor of shorter survival after a diagnosis of stage IV melanoma.

Figure 1. Overall survival from the diagnosis of stage IV by BRAF and NRAS mutation status

Kaplan Meier analysis of survival from stage IV diagnosis for (A) all stage IV patients (n=519) and (B) non-uveal stage IV melanoma patients with molecular testing within 6 months of stage IV diagnosis (n=313). Green, WT patients; Red, NRAS patients; Blue, BRAF patients [in Panel (B), dashed line indicates outcomes in BRAF patients treated with a BRAF or MEK inhibitor (abbreviated BRAF w/i, BRAF w/inhibitor in figure); solid blue line, BRAF patients not treated with a BRAF or MEK inhibitor (abbreviated BRAF w/o i, BRAF w/o inhibitor in figure)].

Figure 1. Overall survival from the diagnosis of stage IV by BRAF and NRAS mutation status

Kaplan Meier analysis of survival from stage IV diagnosis for (A) all stage IV patients (n=519) and (B) non-uveal stage IV melanoma patients with molecular testing within 6 months of stage IV diagnosis (n=313). Green, WT patients; Red, NRAS patients; Blue, BRAF patients [in Panel (B), dashed line indicates outcomes in BRAF patients treated with a BRAF or MEK inhibitor (abbreviated BRAF w/i, BRAF w/inhibitor in figure); solid blue line, BRAF patients not treated with a BRAF or MEK inhibitor (abbreviated BRAF w/o i, BRAF w/o inhibitor in figure)].

Figure 2. Overall survival from the diagnosis of stage IV by BRAF and NRAS mutation status in patients without CNS involvement at the diagnosis of stage IV disease

Kaplan-Meier analysis of survival from stage IV among non-uveal metastatic melanoma patients with molecular testing within 6 months of stage IV diagnosis who did not have CNS involvement at stage IV presentation (n=240). Green, WT patients; Red, NRAS patients; Blue, BRAF patients [dashed line indicates outcomes in BRAF patients treated with a BRAF or MEK inhibitor (abbreviated BRAF w/i, BRAF w/inhibitor in figure); solid blue line, BRAF patients not treated with a BRAF or MEK inhibitor (abbreviated BRAF w/o i, BRAF w/o inhibitor in figure)].