Poorer Melanoma-Specific Survival With Stage ≥ T2b Tumors With NRAS or BRAF Mutation


Key Points

  • NRAS and BRAF mutations were associated with approximately threefold greater risk of death from melanoma in patients with tumor stage ≥ T2b.
  • The presence of the mutations was not associated with an increased risk of melanoma mortality in patients with lower tumor stage.

In a population-based study reported in JAMA Oncology, Thomas and colleagues found significantly poorer disease-specific survival among melanoma patients with stage ≥ T2b tumors with NRAS or BRAF mutation.

Study Details

The study included data from 912 U.S. or Australian patients in the Genes, Environment, and Melanoma study. Patients were diagnosed with first primary cutaneous melanoma in 2000 and had a median follow-up of 7.6 years, through 2007.

Tumor Characteristics

Among all tumors, 13% were positive for NRAS mutation, 30% were positive for BRAF mutation, and 57% were NRAS and BRAF wild-type. In a multivariate model including clinicopathologic characteristics, NRAS-mutant melanoma was associated (P < .05 for all) with the presence of mitoses (odds ratio [OR] = 1.8), lower tumor-infiltrating lymphocyte grade (OR = 0.5 for nonbrisk and OR = 0.3 for brisk vs absent tumor-infiltrating lymphocytes), and anatomic site other than scalp/neck (OR = 0.1 for scalp/neck vs trunk/pelvis). BRAF-mutant melanoma was associated (P < .05 for all) with younger age (OR = 0.7 for age 50–69 and OR = 0.5 for age ≥ 70 vs age < 50 years), superficial spreading subtype (OR = 0.5 for nodular, OR = 0.4 for lentigo maligna, and OR = 0.2 for unclassified/other vs superficial spreading), and the presence of mitoses (OR = 1.7).


In analysis adjusting for age, sex, site, American Joint Committee on Cancer (AJCC) tumor stage, tumor-infiltrating lymphocyte grade, and study center, melanoma-specific survival was nonsignificantly reduced with NRAS-mutant (hazard ratio [HR] = 1.7, 95% confidence interval [CI] = 0.8–3.4) and BRAF-mutant (HR = 1.5, 95% CI = 0.8–2.9) vs wild-type melanoma among all patients. In patients with higher-risk (stage ≥ T2b) tumors, melanoma-specific survival was significantly poorer in those with NRAS mutation (HR = 2.9, 95% CI = 1.1–7.7) and BRAF mutation (HR = 3.1, 95% CI = 1.2–8.5). Among patients with lower-risk (stage T2a or lower) tumors, HRs were 0.9 (95% CI = 0.3–3.0) in those with NRAS mutation and 0.6 (95% CI = 0.2–1.7) in those with BRAF mutation.

The investigators concluded: “Lower [tumor-infiltrating lymphocyte] grade for [NRAS mutation–positive] melanoma suggests it has a more immunosuppressed microenvironment, which may affect its response to immunotherapies.

“The approximate threefold increased risk of death for higher-risk tumors harboring NRAS or BRAF mutations after adjusting for other prognostic factors compared with [wild-type] melanomas indicates that the prognostic implication of these mutations deserves further investigation, particularly in higher-AJCC stage primary melanomas.”

Nancy E. Thomas, MD, PhD, of University of North Carolina, Chapel Hill, is the corresponding author of the JAMA Oncology article.

The study was supported by the National Cancer Institute, National Institute of Environmental Health Sciences, and University of Sydney Medical Foundation Program.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.