Combining the 31-gene expression profile test for cutaneous melanoma with the American Joint Committee on Cancer staging identifies the highest-risk patients with stage I-II disease

Introduction: Management guidelines for cutaneous melanoma (CM) are based on patients’ recurrence risk by stage. Most newly diagnosed patients (88%) will be categorized as node-negative (stage I-II) and will be considered low-risk. However, because of the size of this group, the small percentage of stage I-II individuals who do die of melanoma account for the majority of melanoma-associated deaths. In collaboration with the Surveillance, Epidemiology, and End Results (SEER) program, we demonstrated, in a large, unselected cohort of clinically tested patients, that the 31-GEP test identifies those individuals with stage I-II disease, who have higher risk of melanoma-specific death and who may benefit from more aggressive management.  Methods: SEER registries linked individuals diagnosed with CM between 2013-2018 were linked to data for 31-GEP-tested patients (N=9,207 after exclusions). For this study, analysis focused on the subset reported as node-negative (N=6,301). Patient 5-year melanoma-specific survival (MSS) was estimated using Kaplan-Meier analysis and the log-rank test for patients considered by the 31-GEP to be low-risk (Class 1A), intermediate-risk (Class 1B/2A), or high-risk (Class 2B). Multivariable Cox regression analysis was used to evaluate significant predictors of melanoma-specific death. Notably, at the time of diagnosis, none of the immune checkpoint inhibitor or targeted signal transduction therapies were approved for use in node-negative patients, providing a largely contemporary therapy naïve cohort.   Results: Patients with a Class 2B 31-GEP result had significantly lower 5-year MSS than patients with Class 1B/2A or Class 1A results (85.0% vs. 95.6% vs. 97.9%, p<0.001). The 31-GEP Class 2B result (HR=4.08, p<0.001) was the strongest predictor of melanoma-specific death. Breslow thickness (HR=1.16, p=0.002), presence of ulceration (HR=2.10, p=0.006), and age (HR=1.05, p<0.001) were also significant predictors of melanoma-specific death. The 31-GEP had a sensitivity of 78.4% and a negative predictive value (NPV) of 99.4%. Combining the 31-GEP Class result with AJCC staging could increase the sensitivity to 82.0% while maintaining a high NPV (99.4%).  Conclusion: In a large, unselected cohort of patients with stage I-II CM, the 31-GEP Class 2B identified patients with a high risk of progression and death from melanoma who should be considered for more aggressive management. Conversely, the high NPV suggests that the 31-GEP reliably identifies patients at low risk of tumor progression who could safely avoid intensive surveillance and intervention.