Testing patterns, patient and tumour characteristics and survival by NRAS and KIT genotype in melanoma

Background: NRAS and KIT mutations in melanoma bring implications for prognosis, follow-up, selection into trials and potential future treatment with targeted therapies. The frequency of NRAS/KIT mutations and their association with patient/tumour characteristics and survival is poorly documented.

Objectives:To report national data from England on, (1) the frequency of NRAS and KIT mutations, (2) the association of patient/tumour characteristics with NRAS and KIT mutations, and (3) survival of patients with NRAS and KIT mutations.

Methods: This retrospective cohort study identified all new melanomas diagnosed in England from 2016-2021 and molecular NRAS/KIT testing using data from the National Disease Registration Service. Multivariate logistic regression determined the association between a) NRAS and KIT testing with patient/tumour characteristics, b) NRAS genotype with patient/tumour characteristics. Age-standardised net survival (NS) analysed melanoma-specific mortality by NRAS and KIT genotype.

Results: Of new melanomas diagnosed, 6.6% (6045/91415) and 3.0% (2705/91415) had a NRAS and KIT test registered. The proportion of successfully tested tumours NRAS and KIT mutated were 30.8% (1811/5887) and 5.8% (148/2560). East of England NRAS tested the highest proportion of cutaneous tumours (11.2% (1114/9950)) compared to the lowest in the North West (1.4% (172/12296)). Elderly patients were more likely to have NRAS mutations (OR 1.01, 95%CI 1.01-1.02). Females (OR 0.81, 95%CI 0.71-0.91) and head/neck melanomas (OR 0.37, 95%CI 0.31-0.44) were less likely to have NRAS mutations. There was no significant difference in 5-year NS between all-stage NRAS WT and mutated tumours (WT NS 62.3%, 95%CI 58.9-65.9 vs mutated NS 58.5%, 95%CI 54.0-63.4). Similarly, there was no significant difference in 5-year NS between KIT WT and mutated tumours (WT NS 50.4%, 95% CI 44.7-57.3 vs mutated NS 52.1%, 95% CI 37.1-73.2).

Conclusions: This is the largest national dataset on melanoma NRAS and KIT status published to date. Variations in NRAS/KIT testing by geographic/demographic factors drives initiatives to ensure consistent care. NRAS mutated melanoma had high incidence which emphasises the unmet need to develop therapies and trials for NRAS mutated melanoma. This study increases our understanding of biomarkers NRAS and KIT and provides a foundation for optimising melanoma care, contributing to advancements in precision oncology.