The Integrated 31-Gene Expression Profile Test (i31-GEP) for Cutaneous Melanoma Outperforms the CP-GEP at Identifying Patients who can Forego Sentinel Lymph Node Biopsy when Applying NCCN Guidelines

Abstract

Introduction: Eighty-eight percent of patients who receive a sentinel lymph node biopsy (SLNB) receive a negative result. Current guidelines suggest avoiding SLNB if the risk of positivity is <5%. A low threshold for performing SLNB indicates worry about missing positive nodes but results in many unnecessary biopsies. The integrated 31-gene expression profile (i31-GEP) test combines the 31-GEP with Breslow thickness, age, ulceration, and mitotic rate using a validated neural network algorithm to identify patients with <5% risk by reporting a precise, individualized likelihood score. Using logistic regression, a separate GEP (8 genes plus Breslow thickness and age; CP-GEP) also aims to identify patients who can forego SLNB by binning patients into low- and high-risk categories. This study compared the i31-GEP for SLNB with the CP-GEP to identify patients who can safely forego SLNB. Methods: This study evaluated the genes, gene pathways, and relative contribution of the two gene signatures relative to clinical and pathologic factors and further analyzed patients with T1b-T2 tumors from previously published studies in U.S. cohorts for the i31-GEP (n=763) and CP-GEP (n=153). A ratio of true-to-false-negative i31-GEP for SLNB and CP-GEP test results was compared to the guideline-established ratio of 19 negatives to one missed positive (19:1) if foregoing SLNB using a 5% risk threshold. Results: The i31-GEP had a 30:1 true-to-false-negative ratio, compared to 15:1 using CP-GEP. In T1b tumors, the i31-GEP ratio increased to 35:1 compared to 14:1 using CP-GEP. Limitations: Retrospective design, which could lead to bias. Patients included in both analyses were primarily from institutional surgical centers, and referral bias may not make the result generalizable. Conclusion: Only the i31-GEP provided benefit over guideline-established care for identifying patients with low risk of SLN positivity.

Incorporating Prognostic Gene Expression Profile Assays into the Management of Cutaneous Melanoma: An Expert Consensus Panel

“…After screening the articles, 32 met inclusion criteria and were distributed to the panelists for review prior to the roundtable discussion. Of these articles, the number of papers that specifically studied the validity, accuracy, or clinical utility of each test was: 22 for the 31-GEP test 4,[19][20][21][22][23][24][26][27][28][29][30][31][34][35][36][37][38][39][40][41][42] , 2 for the 11-GEP test 11,34 , and 7 for the 8-GEP + CP test. 5,13,23,[43][44][45][46]…”

“…For the 8-GEP + CEP test, a validation study analyzing the test's ability to predict SLNB positivity found that this model has a NPV of 90.5% (95% Confidence Interval [CI]: 77.9-96.2%) in T1-4 CMs. 44 In comparing the three GEP tests, the panel consensus was that there were significantly more studies supporting the validity, accuracy, and clinical utility of the 31-GEP test compared to the 11-GEP and 8-GEP + CP tests (22 studies validating the 31-GEP test 4,[19][20][21][22][23][24][26][27][28][29][30][31][34][35][36][37][38][39][40][41][42] , compared to just 2 studies validating the 11-GEP test 11,34 and 7 studies validating the 8-GEP + CP test 5,13,23,[43][44][45][46] ). Based on the limited studies for the 8-GEP + CP and the 11-GEP test, the panel concluded that there was insufficient data to assess their validity and utility or currently recommend usage in the clinical setting until further studies are performed.…”

“…A retrospective comparison of the i31-GEP test and the 8-GEP + CP test showed that the i-31GEP had a 30:1 true-to-false-negative SLNB ratio compared to a 15:1 ratio for the 8-GEP + CP test. 23 Another study found that the i31-GEP test was able to outperform an online nomogram from the Melanoma Institute of Australia (MIA) 51 given the wide variance of that model's prediction, 4 which may not be actionable within NCCN guideline parameters. In comparing this nomogram with the i31-GEP in a retrospective cohort of 582 patients, the i-31GEP was able to identify 28.5% of patients as having a <5% risk of SLNB positivity while also having an upper 95% CI ≤ 10% compared with only a 0.9% (p<0.001) when using the MIA nomogram.…”