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

## TL;DR

This study analyzes the frequency and impact of NRAS and KIT mutations in melanoma patients in England, highlighting geographic and demographic variations in testing and the need for targeted therapies.

## Contribution

The study presents the largest national dataset on melanoma NRAS and KIT status, revealing regional and demographic testing disparities and emphasizing the need for NRAS-targeted treatments.

## Key findings

- NRAS and KIT mutations were tested in 6.6% and 3.0% of melanomas, respectively, with significant regional and demographic variations in testing rates.
- NRAS mutations were more common in older patients and less common in women and those with head/neck melanomas.
- No significant difference in 5-year survival was found between NRAS/KIT wildtype and mutated tumors.

## Abstract

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.

To report national data from England on (i) the frequency of NRAS and KIT mutations, (ii) the association of patient/tumour characteristics with NRAS and KIT mutations, and (iii) the survival of patients with NRAS and KIT mutations.

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

Of new melanomas diagnosed, 6.6% (6045/91 415) and 3.0% (2705/91 415) had an NRAS and KIT test registered. The proportion of successfully tested tumours that were 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 with the lowest in the North West (1.4%, 172/12 296). Older patients were more likely to have NRAS mutations [odds ratio (OR) 1.01, 95% confidence interval (CI) 1.01–1.02]. Women (OR 0.81, 95% CI 0.71–0.91) and those with 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 wildtype (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).

This is the largest national dataset on melanoma NRAS and KIT status published to date to the best of our knowledge. Variations in NRAS/KIT testing by geographic/demographic factors drive initiatives to ensure consistent care. NRAS-mutated melanoma had a high incidence, which emphasizes 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 optimizing melanoma care, contributing to advancements in precision oncology.

This retrospective cohort study is the largest national dataset on melanoma NRAS and KIT status ever published, to the best of our knowledge, with 6045 and 2705 tumours with an NRAS and KIT test registered in England. Regional and demographic variations in NRAS and KIT testing were identified, which drives initiatives to achieve optimal and consistent care. NRAS-mutated melanoma has a high incidence, underscoring the importance of future research to develop therapies for NRAS-mutated melanomas.