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Background Most patients diagnosed with cutaneous melanoma (CM) are clinically or pathologically node-negative (stage I-II). 1 Although thin tumors have better prognosis, the high number of T1 diagnoses can lead to more deaths overall.2 Thus, it is critical to identify patients with the highest risk of poor outcomes to make risk-appropriate treatment and management plans. In collaboration with the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) program, we analyzed whether the 31-GEP test identifies patients with node-negative disease who have higher risk of melanoma-specific mortality (MSM) or all-cause mortality (ACM) that may benefit from more aggressive management.Methods SEER registry data (2013-2019) were linked to patients with CM who had 31-GEP test results; node-negative patients (N0, M0) were included in this analysis (n=8,737). Five-year melanoma-specific survival (MSS) and overall survival (OS) were estimated using Kaplan-Meier analysis and compared between groups using the log-rank test. Multivariable Cox regression analysis was used to evaluate significant predictors of MSM and ACM (*p<0.05, **p<0.001).Results Patients with a Class 2B 31-GEP had significantly lower 5-year MSS (85.4%) than patients with Class 1B/2A (93.1%) or Class 1A results (98.5%, p<0.001). The 31-GEP also significantly stratified OS (72.2%, 85.6%, vs.93.8%, p<0.001). Class 2B (HR=3.88**, 2.47**) and Class 1B/2A (HR=2.65**, 1.70**) 31-GEP results were significant predictors of MSM and ACM, respectively. Breslow thickness (HR=1.21**, 1.15**) and age (HR=1.04**, 1.08**) were significant predictors of MSM and ACM, respectively. Ulceration was a significant predictor of MSM (HR=1.64*) only; mitotic rate was not a significant predictor of either.Conclusions In a large, real-world cohort of patients with clinical or pathologic node-negative CM, the 31-GEP identified those at the highest risk of death. Patients with node-negative CM and a high-risk 31-GEP result may benefit from more intensive surveillance and follow-up schedules, and eligible high-risk patients may consider adjuvant treatment options.References Helvind NM, Weitemeyer MB, Chakera AH, Hendel HW, Elleaek E, Svane IM, et al. Stage-specific risk of recurrence and death from melanoma in Denmark, 2008-2021: a national observational cohort study of 25 720 patients with stage IA to IV melanoma. JAMA Dermatology. 2023.Whiteman DC, Baade PD, Olsen CM. More people die from thin melanomas (1 mm) than from thick melanomas (>4 mm) in Queensland, Australia. J Invest Dermatol. 2015 Apr;135(4):1190–3.Ethics Approval IRB approval not applicable for NCI SEER data analysis.