title: 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.
authors.affiliation: Section of Oncology, Institute of Medicine, University of Bergen, Bergen, Norway.
authors.forename: Einar
authors.initials: E
authors.lastname: Birkeland
authors.forename: Christian
authors.initials: C
authors.lastname: Busch
authors.forename: Elisabet Ognedal
authors.initials: EO
authors.lastname: Berge
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisler
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.forename: Johan Richard
authors.initials: JR
authors.lastname: Lillehaug
authors.forename: Stian
authors.initials: S
authors.lastname: Knappskog
authors.forename: Per Eystein
authors.initials: PE
authors.lastname: Lønning
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D003606:Dacarbazine / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D018906:Antineoplastic Agents, Alkylating; D008565:Membrane Proteins; D012333:RNA, Messenger; D003606:Dacarbazine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human