TY - JOUR

T1 - Tumor Cell Adhesion As a Risk Factor for Sentinel Lymph Node Metastasis in Primary Cutaneous Melanoma

AU - Meves, Alexander

AU - Nikolova, Ekaterina

AU - Heim, Joel B

AU - Squirewell, Edwin J

AU - Cappel, Mark A

AU - Pittelkow, Mark R

AU - Otley, Clark C

AU - Behrendt, Nille

AU - Saunte, Ditte M

AU - Lock-Andersen, Jorgen

AU - Schenck, Louis A

AU - Weaver, Amy L

AU - Suman, Vera J

N1 - © 2015 by American Society of Clinical Oncology.

PY - 2015/8/10

Y1 - 2015/8/10

N2 - PURPOSE: Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma.PATIENTS AND METHODS: Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables.RESULTS: ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk).CONCLUSION: The addition of cell adhesion-linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.

AB - PURPOSE: Less than 20% of patients with melanoma who undergo sentinel lymph node (SLN) biopsy based on American Society of Clinical Oncology/Society of Surgical Oncology recommendations are SLN positive. We present a multi-institutional study to discover new molecular risk factors associated with SLN positivity in thin and intermediate-thickness melanoma.PATIENTS AND METHODS: Gene clusters with functional roles in melanoma metastasis were discovered by next-generation sequencing and validated by quantitative polymerase chain reaction using a discovery set of 73 benign nevi, 76 primary cutaneous melanoma, and 11 in-transit melanoma metastases. We then used polymerase chain reaction to quantify gene expression in a model development cohort of 360 consecutive thin and intermediate-thickness melanomas and a validation cohort of 146 melanomas. Outcome of interest was SLN biopsy metastasis within 90 days of melanoma diagnosis. Logic and logistic regression analyses were used to develop a model for the likelihood of SLN metastasis from molecular, clinical, and histologic variables.RESULTS: ITGB3, LAMB1, PLAT, and TP53 expression were associated with SLN metastasis. The predictive ability of a model that included these molecular variables in combination with clinicopathologic variables (patient age, Breslow depth, and tumor ulceration) was significantly greater than a model that only considered clinicopathologic variables and also performed well in the validation cohort (area under the curve, 0.93; 95% CI, 0.87 to 0.97; false-positive and false-negative rates of 22% and 0%, respectively, using a 10% cutoff for predicted SLN metastasis risk).CONCLUSION: The addition of cell adhesion-linked gene expression variables to clinicopathologic variables improves the identification of patients with SLN metastases within 90 days of melanoma diagnosis.

KW - Adult

KW - Aged

KW - Biomarkers, Tumor/analysis

KW - Cell Adhesion

KW - Female

KW - Gene Expression Regulation, Neoplastic

KW - Humans

KW - Integrin beta3/analysis

KW - Laminin/analysis

KW - Logistic Models

KW - Lymph Nodes/pathology

KW - Lymphatic Metastasis

KW - Male

KW - Melanoma/chemistry

KW - Middle Aged

KW - Predictive Value of Tests

KW - Risk Factors

KW - Sentinel Lymph Node Biopsy

KW - Skin Neoplasms/chemistry

KW - Tissue Plasminogen Activator/analysis

KW - Tumor Suppressor Protein p53/analysis

U2 - 10.1200/JCO.2014.60.7002

DO - 10.1200/JCO.2014.60.7002

M3 - Journal article

C2 - 26150443

VL - 33

SP - 2509

EP - 2515

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 23

ER -