PURPOSE More than 80% of patients who undergo sentinel lymph node (SLN) biopsy have no nodal metastasis. Here, we describe a model that combines clinicopathologic and molecular variables to identify patients with thin- and intermediate-thickness melanomas who may forgo the SLN biopsy procedure because of their low risk of nodal metastasis. PATIENTS AND METHODS Genes with functional roles in melanoma metastasis were discovered by analysis of next-generation sequencing data and case-control studies. We then used polymerase chain reaction to quantify gene expression in diagnostic biopsy tissue across a prospectively designed archival cohort of 754 consecutive thin- and intermediate-thickness primary cutaneous melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. A penalized maximum likelihood estimation algorithm was used to train logistic regression models in a repeated cross-validation scheme to predict the presence of SLN metastasis from molecular, clinical, and histologic variables. RESULTS Expression of genes with roles in epithelial-to-mesenchymal transition (glia-derived nexin, growth differentiation factor 15, integrin-β3, interleukin 8, lysyl oxidase homolog 4, transforming growth factor-β receptor type 1, and tissue-type plasminogen activator) and melanosome function (melanoma antigen recognized by T cells 1) were associated with SLN metastasis. The predictive ability of a model that only considered clinicopathologic or gene expression variables was outperformed by a model that included molecular variables in combination with the clinicopathologic predictors Breslow thickness and patient age (area under the receiver operating characteristic curve, 0.82; 95% CI, 0.78 to 0.86; SLN biopsy reduction rate, 42%; negative predictive value, 96%). CONCLUSION A combined model that included clinicopathologic and gene expression variables improved the identification of patients with melanoma who may forgo the SLN biopsy procedure because of their low risk of nodal metastasis.

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Patients with stage I/IIA cutaneous melanoma (CM) are currently not eligible for adjuvant therapies despite uncertainty in relapse risk. Here, we studied the ability of a recently developed model which combines clinicopathologic and gene expression variables (CP-GEP) to identify stage I/IIA melanoma patients who have a high risk for disease relapse. Patients and methods: Archival specimens from a cohort of 837 consecutive primary CMs were used for assessing the prognostic performance of CP-GEP. The CP-GEP model combines Breslow thickness and patient age, with the expression of eight genes in the primary tumour. Our specific patient group, represented by 580 stage I/IIA patients, was stratified based on their risk of relapse: CP-GEP High Risk and CP-GEP Low Risk. The main clinical end-point of this study was five-year relapse-free survival (RFS).

Background Approximately 85% of melanoma patients who undergo a sentinel lymph node biopsy (SLNB) are node-negative. Melanoma incidence is highest in patients ≥65 years, but their SLNB positivity rate is lower than in younger patients. CP-GEP, a model combining clinicopathologic and gene expression variables, identifies primary cutaneous melanoma (CM) patients who may safely forgo SLNB due to their low risk for nodal metastasis. Here, we validate CP-GEP in a U.S. melanoma patient cohort.Methods A cohort of 208 adult patients with primary CM from the Mayo Clinic and West Virginia University was used. Patients were stratified according to their risk for nodal metastasis: CP-GEP High Risk and CP-GEP Low Risk. The main performance measures were SLNB reduction rate (RR) and negative predictive value (NPV).Results SLNB positivity rate for the entire cohort was 21%. Most patients had a T1b (34%) or T2a (31%) melanoma. In the T1-T2 group (153 patients), CP-GEP achieved an SLNB RR of 41.8% (95% CI: 33.9-50.1) at an NPV of 93.8% (95% CI: 84.8-98.3). Subgroup analysis showed similar performance in T1-T2 patients ≥65 years of age (51 patients; SLNB positivity rate, 9.8%): SLNB RR of 43.1% (95% CI: 29.3-57.8) at an NPV of 95.5% (95% CI: 77.2-99.9). ConclusionWe confirmed the potential of CP-GEP to reduce negative SLNB in all relevant age groups. Our findings are especially relevant to patients ≥65 years, where surgery is often elective. CP-GEP may guide SLNB decision-making in clinical practice.The CP-GEP model was previously developed on a large prospectively collected cohort of 754 archived U.S. patients who underwent an SLNB within 90 days of primary melanoma

Integrins are the major family of cell adhesion receptors in humans and essential for a wide range of normal physiology, including formation and maintenance of tissue structure integrity, cell migration, proliferation, and differentiation. Integrins also play a prominent role in tumor growth and metastasis. Translational research has tried to define the contribution of integrins to the phenotypic aggressiveness of melanoma because such knowledge is clinically useful. For example, differential expression of integrins in primary cutaneous melanoma can be used to distinguish indolent from aggressive, prometastatic melanoma.Recent studies have shown that gene expression-based testing of patient-derived melanoma tissue is feasible, and molecular tests may fully replace interventional surgical methods such as sentinel lymph node biopsies in the future. Because of their central role in mediating invasion and metastasis, integrins are likely to be useful biomarkers. Integrins are also attractive candidate targets for interventional therapy. This article focuses on the role of integrins in melanoma and highlights recent advances in the field of translational research.

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Dr. Meves reports a financial interest in a molecular test being developed by SkylineDx in the area of melanoma. Mayo Clinic has reviewed this relationship and taken appropriate steps to protect the scientific integrity of the research.