Association BetweenNRASandBRAFMutational Status and Melanoma-Specific Survival Among Patients With Higher-Risk Primary Melanoma

Abstract

Melanomas frequently harbor mutually exclusive BRAF or NRAS mutations that arise early in tumor progression and persist throughout the course of the disease.^1,2 These mutations influence tumor development and maintenance through constitutive activation of the RAS–RAF–mitogen-activated protein (MAP)-kinase kinase (MEK)–extracellular signal-regulated kinases (ERK) pathway.^1,3 Their clinical relevance is underscored by improved survival of patients with stage IV disease with BRAF-mutant melanomas treated with BRAF inhibitors alone or in combination with MEK inhibition.^4-6 These targeted therapies along with new immunotherapies^7,8 are rapidly changing treatment paradigms for metastatic melanoma, and some are under investigation as adjuvant therapies.⁹ Identification of patients at high risk of death from melanoma based on their primary melanoma tumor characteristics before sign of recurrence remains important to inform evidence-based follow-up of patients and adjuvant trials. Equally important is the identification of patients who rarely die of melanoma, as they can be spared the risks of adjuvant therapy. However, it remains unknown whether the primary melanoma NRAS/BRAF mutational status influences survival from melanoma during the natural course of the disease.