Real-World Evidence Confirms Risk Stratification of the 31-GEP and i31-GEP in Prospectively Tested Patients with Stage I-III Cutaneous Melanoma

Abstract

Introduction: Current American Joint Committee on Cancer (AJCC 8th edition) guidelines in patients with cutaneous melanoma (CM) separate them into risk categories based on the pathological tumor data of Breslow thickness, ulceration status, and sentinel lymph node status. The 31-gene expression profile was developed and prospectively validated to identify patients considered high or low risk by AJCC with low or high-risk tumor biology who may be over- or under-treated by current guidelines. To further advance personalized patient care, the 31-GEP result was integrated with clinical and pathological factors (i31-GEP for risk of recurrence, ROR) to provide a personalized, precise risk of tumor recurrence. 
 
 Methods: Patients with stage I-III CM enrolled in the CONNECTION study were prospectively tested with the 31-GEP between 2013 and 2017 (n=1,831). Kaplan-Meier analysis with the log-rank test was used to estimate survival differences between low (Class 1A), intermediate (Class 1B/2A), and high (Class 2) risk groups and the i31-GEP risk groups. The i31-GEP ROR combines Breslow thickness, ulceration, SLN status, mitotic rate, tumor location, age, and the 31-GEP result to provide a personalized estimate of recurrence-free survival (RFS). While guidelines have not established a ROR threshold for determining when to escalate or de-escalate care, the NCCN uses stage IIA versus IIB as the cut-point. This cut-point translates to a 5-year RFS rate of 69.8% and was used for the present analysis. Cox multivariable regression analysis was used to identify predictors of recurrence. 
 
 Results: Patients with a Class 1A result had higher 5-year RFS than those with a Class 1B/2A or Class 2B result (94.4% vs. 78.6% vs. 65.5%, p<0.001). The following were significant predictors of recurrence in multivariable analysis: Class 1B/2A (HR=2.07, p<0.001), Class 2B (HR=2.40, p<0.001), positive SLN (HR=4.54, p<0.001), Breslow thickness (HR=1.09, p=0.028), presence of ulceration (HR=1.57, p=0.005), mitotic rate >2/mm2 (HR=1.47, p=0.016), and age (HR=1.02, p<0.001). Patients with a low-risk i31-GEP result had significantly higher 5-year RFS than those considered high risk by the i31-GEP (92.4% vs. 49.7%, p<0.001). 
 
 Conclusions: The i31-GEP is validated in a real-world group of prospectively tested patients. The independent i31-GEP ROR test result improves identification of patients whose management should be escalated or de-escalated within current guidelines.