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

Abstract

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.

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]…”

“…48 While sentinel lymph node positivity is a key prognostic marker, studies have shown that < 20% of patients who undergo the biopsy are found to have nodal metastasis. 50 Given that the procedure has a > 10% risk of complications such as bleeding, infection, pain, neuropathy, lymphocele, lymphatic fistula, and lymphedema 4 , identifying patients that can safely forego the biopsy can significantly reduce morbidity. A multi-center validation study of the i-31 GEP test (a test that integrates the 31-GEP with clinicopathological features including Breslow thickness, mitotic rate, ulceration status, and patient age) showed that the test increased the proportion of patients with T1-T4 tumors predicted to have <5% risk of SLNB positivity from 8.5% to 27.7% with a negative predictive value (NPV) of 98%.…”

“…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.…”

“…2 The development and validation of gene expression profile (GEP) assays that use a quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) to identify the level of expression of certain groups of signature genes has significantly advanced cancer prognostic assessment. [3][4][5][6][7][8] Because the level of expression of these signature genes varies between benign and malignant lesions as well as lesions that have a lower or higher likelihood for metastasis, these tests can provide important prognostic information. In addition, studies have demonstrated that genomics can identify a high-risk subset of CM patients with stage I and II disease that are at greater risk for recurrence, metastasis, and increased mortality based on their lesions' genetic profile.…”

“…In addition, studies have demonstrated that genomics can identify a high-risk subset of CM patients with stage I and II disease that are at greater risk for recurrence, metastasis, and increased mortality based on their lesions' genetic profile. [3][4][5] Tens of thousands of CM GEP tests are currently being ordered annually in the US to aid clinicians in their prognostic assessment of patients with CM. 9 However, current CM staging according to AJCC8 as well as guidelines put forth by the National Comprehensive Cancer Network (NCCN) do not formally incorporate GEP test data to further stratify patients.…”