Serum markers improve current prediction of metastasis development in early‐stage melanoma patients: a machine learning‐based study

• Published in: Molecular oncology 2020-08, Vol.14 (8), p.1705-1718
• Main Authors: Mancuso, Filippo, Lage, Sergio, Rasero, Javier, Díaz‐Ramón, José Luis, Apraiz, Aintzane, Pérez‐Yarza, Gorka, Ezkurra, Pilar Ariadna, Penas, Cristina, Sánchez‐Diez, Ana, García‐Vazquez, María Dolores, Gardeazabal, Jesús, Izu, Rosa, Mujika, Karmele, Cortés, Jesús, Asumendi, Aintzane, Boyano, María Dolores
• Format: Article
• Language: English
• Subjects: Algorithms; Antimicrobial agents; Biobanks; Biomarkers; Calibration; Cytokines; Dermatology; dermcidin; Developmental stages; Disease; Granulocytes; Growth factors; Immune response; Immunoassay; Interleukin 4; interleukins; Kinases; Learning algorithms; Leukocytes (granulocytic); Machine learning; Macrophages; Medical prognosis; Melanoma; Metastases; Metastasis; Patients; Precision medicine; prognosis; Proteins; serum biomarkers; Serum levels; Skin cancer; Transforming growth factor-b; γ-Interferon
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12732

Metastasis development represents an important threat for melanoma patients, even when diagnosed at early stages and upon removal of the primary tumor. In this scenario, determination of prognostic biomarkers would be of great interest. Serum contains information about the general status of the organism and therefore represents a valuable source for biomarkers. Thus, we aimed to define serological biomarkers that could be used along with clinical and histopathological features of the disease to predict metastatic events on the early‐stage population of patients. We previously demonstrated that in stage II melanoma patients, serum levels of dermcidin (DCD) were associated with metastatic progression. Based on the relevance of the immune response on the cancer progression and the recent association of DCD with local and systemic immune response against cancer cells, serum DCD was analyzed in a new cohort of patients along with interleukin 4 (IL‐4), IL‐6, IL‐10, IL‐17A, interferon γ (IFN‐γ), transforming growth factor‐β (TGF‐ β), and granulocyte–macrophage colony‐stimulating factor (GM‐CSF). We initially recruited 448 melanoma patients, 323 of whom were diagnosed as stages I‐II according to AJCC. Levels of selected cytokines were determined by ELISA and Luminex, and obtained data were analyzed employing machine learning and Kaplan–Meier techniques to define an algorithm capable of accurately classifying early‐stage melanoma patients with a high and low risk of developing metastasis. The results show that in early‐stage melanoma patients, serum levels of the cytokines IL‐4, GM‐CSF, and DCD together with the Breslow thickness are those that best predict melanoma metastasis. Moreover, resulting algorithm represents a new tool to discriminate subjects with good prognosis from those with high risk for a future metastasis. Melanoma displays a remarkable capacity for dissemination even when detected at early stages. We developed a decision rule that considers Breslow thickness of the removed malignant lesion and IL‐4, GM‐CSF, and DCD serum levels in order to foresee the risk for future metastasis development of those stage I‐II patients. This algorithm may represent a tool to design more personalized follow‐up strategies.