Clinical outcome and pathologic features associated with NRAS mutation in cutaneous melanoma.

Abstract

8500 Background: Mutations in NRAS and BRAF are common in cutaneous melanoma leading to constitutive activation of the MAPK pathway controlling cell proliferation. We examined the effect of NRAS mutations on the pathologic features and clinical outcomes in patients with cutaneous melanoma when compared to tumors containing BRAF mutations and those wild-type (WT) for both. Methods: Clinical outcome data was obtained from a prospective cohort study of 251 patients with cutaneous melanoma from Australian melanoma centers. Mutations in exon 2 of NRAS (N61R) and exon 15 of BRAF were detected by high resolution melting and sequence verified. Cox proportional hazards regression was performed to examine the significance of NRAS and BRAF mutations on pathologic features, overall survival (OS), melanoma specific survival (MSS) and disease free survival. Results: 249 patients with a median follow-up of 47 months were available. NRAS mutations were found in 36 (14%) patients, BRAF mutations in 112 (45%) and 101 (41%) were WT. 39 deaths occurred, 28 due to melanoma. Overall survival was similar in the three groups. Compared to WT in univariate analysis, there was shorter MSS in patients with NRAS mutations (HR 2.51; p = 0.05) but no difference in those with mutations in BRAF (HR 0.98; p = 0.96). NRAS mutations were associated with thicker tumors with 75% of tumors > 1 mm thick having mutations in NRAS compared to 40% for BRAF and 34% for WT. NRAS mutations were also associated with increased proliferation rates with 75% of tumors having > 1 mitosis/mm2 containing mutations in NRAS (BRAF 40% WT 55%). Multivariate analysis of MSS identified NRAS mutations as an independent adverse prognostic factor (HR 3.22; p = 0.03) along with site, Breslow thickness and presence of mitosis (p < 0.03). BRAF mutations had no effect on MSS (HR 1.68; p = 0.26). Conclusions: NRAS mutation in cutaneous melanoma is associated with higher rates of tumour proliferation when compared to BRAF and WT melanoma and independently of this, associated with shorter melanoma specific survival. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Novartis, Pfizer