Low BRAF and NRAS expression levels are associated with clinical benefit from DTIC therapy and prognosis in metastatic melanoma

Abstract

Metastatic melanoma is characterized by a poor response to chemotherapy. Furthermore, there is a lack of established predictive and prognostic markers. In this single institution study, we correlated mutation status and expression levels of BRAF and NRAS to dacarbazine (DTIC) treatment response as well as progression-free and overall survival in a cohort of 85 patients diagnosed with advanced melanoma. Neither BRAF nor NRAS mutation status correlated to treatment response. However, patients with tumors harboring NRAS mutations had a shorter overall survival (p < 0.001) compared to patients with tumors wild-type for NRAS. Patients having a clinical benefit (objective response or stable disease at 3 months) on DTIC therapy had lower BRAF and NRAS expression levels compared to patients progressing on therapy (p = 0.037 and 0.003, respectively). For BRAF expression, this association was stronger among patients with tumors wild-type for BRAF (p = 0.005). Further, low BRAF as well as NRAS expression levels were associated with a longer progression-free survival in the total population (p = 0.004 and <0.001, respectively). Contrasting low NRAS expression levels, which were associated with improved overall survival in the total population (p = 0.01), low BRAF levels were associated with improved overall survival only among patients with tumors wild-type for BRAF (p = 0.013). These findings indicate that BRAF and NRAS expression levels may influence responses to DTIC as well as prognosis in patients with advanced melanoma.

Fig. 1

Expression characteristics of BRAF mRNA. Expression levels of BRAF mRNA in: a benign melanocytic nevi and in metastatic melanoma biopsies, b tumors with wild-type or mutated BRAF, and c tumors with or without BRAF copy-number gains. Asterisks denote significance levels: *p ≤ 0.05, **p ≤ 0.005, ***p ≤ 0.001

Fig. 2

BRAF mRNA expression and response to DTIC treatment. BRAF mRNA expression among patients experiencing a clinical benefit or progressive disease (PD) 3 months after commencement of DTIC chemotherapy. a BRAF expression in the total patient group, b data as presented in a, but limited to patients with tumors harboring wild-type BRAF, c similar analysis performed for tumors harboring BRAF V600 mutations. Asterisks denote significance levels: *p ≤ 0.05, **p ≤ 0.005

Fig. 3

NRAS mRNA expression. a Expression levels of NRAS mRNA in benign melanocytic nevi (n = 8) and metastatic melanoma (n = 82). b Correlation plot showing the expression of NRAS in each tumor in relation to BRAF expression. c Expression levels of NRAS mRNA in patients experiencing a clinical benefit or progressive disease (PD) 3 months after commencement of chemotherapy. Asterisks denote significance levels: *p ≤ 0.05, **p ≤ 0.005

Fig. 4

Progression-free and overall survival with respect to BRAF/NRAS status. Kaplan–Meier curves showing overall and progression-free survival: a, b patients with tumors harboring BRAF mutations or NRAS mutations, c, d effect of BRAF expression levels above or below the median value among patients evaluable for treatment response (median value determined among all patients). Solid curves represent all patients; dashed curves represent only patients with tumors harboring wild-type BRAF; e, f effect of NRAS expression levels above or below the median value among patients evaluable for treatment response (median value determined among all patients), g, h effect of combined BRAF/NRAS expression levels: one or both above compared to both below the median values. *All three groups included in the analysis