The Integrated 31-Gene Expression Profile (i31-GEP) Test for Cutaneous Melanoma Outperforms a Clinicopathologic-Only Nomogram at Identifying Patients who can Forego Sentinel Lymph Node Biopsy

Introduction: National guidelines for cutaneous melanoma suggest avoiding sentinel lymph node biopsy (SLNB) if the risk of SLN positivity is <5% (T1a with no high-risk features), considering SLNB if the risk is 5-10% (T1a with additional high-risk features (T1aHR) and T1b), and offering SLNB if the risk is >10% (T2-T4). Because most patients (88%) who undergo an SLNB have a negative result, novel tools to identify patients who can safely forgo SLNB are critical. The integrated 31-gene expression profile (i31-GEP for SLNB) test for cutaneous melanoma combines tumor molecular biology with clinicopathologic features to provide a precise risk of SLN positivity. The Melanoma Institute of Australia (MIA) developed a nomogram that uses only clinicopathologic features to predict SLN positivity. Methods: We compared the i31-GEP for SLNB to the MIA nomogram in patients with T1-T2 tumors with complete data (n=582). The precision of each tool to identify patients with <5% SLN positivity risk was analyzed using 95% confidence intervals. To be considered low risk, the predicted risk must be <5% and the upper 95% confidence interval must be ≤10%, and to be considered high-risk, the predicted risk must be >10% and the lower 95% CI ≥5%. Results: The i31-GEP for SLNB identified 28.5% (166/582) of patients as having a <5% risk of SLN positivity while also having an upper 95% CI ≤10% compared with 0.9% (5/582, p<0.001) using the MIA nomogram. In patients with a pre-test likelihood of SLN positivity of 5-10% (T1aHR-T1b), the i31-GEP reclassified risk in 60.2% (171/284) of patients as being <5% or >10% compared to 13.7% (39/284, p<0.001) using the MIA nomogram. In patients with a known SLN status (n=466), the i31-GEP for SLNB identified 22.1% (103/466) of patients as having <5% risk, with a 3.9% (4/103) SLN positivity rate compared to 0.6% (3/466, p<0.001) identified by the MIA as having a <5% risk with a 33.3% (1/3) SLN positivity rate. Conclusions: The i31-GEP test outperformed the MIA nomogram in identifying patients who could safely forego SLNB. Integrating the 31-GEP molecular risk stratification tool with clinicopathologic features provides precise SLN positivity risk to better guide patient management in patients with T1-T2 tumors, for whom SLNB guidance could be most impactful.