The Clinicopathological and Gene Expression Profile (CP‐GEP) model was developed to accurately identify patients with T1-T3 primary cutaneous melanoma at low risk for nodal metastasis.,To validate the CP‐GEP model in an independent Dutch cohort of patients with melanoma.,Patients (aged ≥ 18 years) with primary cutaneous melanoma who underwent sentinel lymph node biopsy (SLNB) between 2007 and 2017 at the Erasmus Medical Centre Cancer Institute were eligible.,The CP‐GEP model combines clinicopathological features (age and Breslow thickness) with the expression of eight target genes involved in melanoma metastasis (ITGB3, PLAT, SERPINE2, GDF15, TGFBR1, LOXL4, CXCL8 and MLANA).,Using the pathology result of SLNB as the gold standard, performance measures of the CP‐GEP model were calculated, resulting in CP‐GEP high risk or low risk for nodal metastasis.,In total, 210 patients were included in the study.,Most patients presented with T2 (n = 94, 45%) or T3 (n = 70, 33%) melanoma.,Of all patients, 27% (n = 56) had a positive SLNB, with nodal metastasis in 0%, 30%, 54% and 16% of patients with T1, T2, T3 and T4 melanoma, respectively.,Overall, the CP‐GEP model had a negative predictive value (NPV) of 90·5% [95% confidence interval (CI) 77·9-96.2], with an NPV of 100% (95% CI 72·2-100) in T1, 89·3% (95% CI 72·8-96·3) in T2 and 75·0% (95% CI 30·1-95·4) in T3 melanomas.,The CP‐GEP indicated high risk in all T4 melanomas.,The CP‐GEP model is a noninvasive and validated tool that accurately identified patients with primary cutaneous melanoma at low risk for nodal metastasis.,In this validation cohort, the CP‐GEP model has shown the potential to reduce SLNB procedures in patients with melanoma.,What is already known about this topic?,The majority (70-85%) of patients with cutaneous melanoma who undergo a sentinel lymph node biopsy (SLNB) procedure have no metastasis in the SLN.To identify patients at low risk for nodal metastasis, the Clinicopathological and Gene Expression Profile (CP‐GEP) model was developed (n = 754 patients, US cohort).,The CP‐GEP model combines age, Breslow thickness and the expression of eight target genes involved in melanoma metastasis, and has the potential to reduce SLNB procedures in patients with T1-T3 cutaneous melanoma.,The majority (70-85%) of patients with cutaneous melanoma who undergo a sentinel lymph node biopsy (SLNB) procedure have no metastasis in the SLN.,To identify patients at low risk for nodal metastasis, the Clinicopathological and Gene Expression Profile (CP‐GEP) model was developed (n = 754 patients, US cohort).,The CP‐GEP model combines age, Breslow thickness and the expression of eight target genes involved in melanoma metastasis, and has the potential to reduce SLNB procedures in patients with T1-T3 cutaneous melanoma.,What does this study add?,This is the first independent validation of the CP‐GEP model in European patients with primary cutaneous melanoma.The CP‐GEP model can be applied to full‐excision tumour tissue and does not require macrodissection of tumour tissue.The CP‐GEP model has a negative predictive value of 90·5% (95% confidence interval 77·9-96·2) in T1-T3 melanomas.The CP‐GEP model is a promising tool in patient care.,In this validation cohort, the CP‐GEP model has shown the potential to reduce SLNB procedures in patients with primary cutaneous melanoma.,This is the first independent validation of the CP‐GEP model in European patients with primary cutaneous melanoma.,The CP‐GEP model can be applied to full‐excision tumour tissue and does not require macrodissection of tumour tissue.,The CP‐GEP model has a negative predictive value of 90·5% (95% confidence interval 77·9-96·2) in T1-T3 melanomas.,The CP‐GEP model is a promising tool in patient care.,In this validation cohort, the CP‐GEP model has shown the potential to reduce SLNB procedures in patients with primary cutaneous melanoma.
Cancer cells, including melanoma, often metastasize regionally through lymphatics before metastasizing systemically through the blood1-4; however, the reason for this is unclear.,Here we show that melanoma cells in lymph experience less oxidative stress and form more metastases than melanoma cells in blood.,Immunocompromised mice with patient-derived melanomas and immunocompetent mice with mouse melanomas had more melanoma cells per microliter of tumor-draining lymph than tumor-draining blood.,Cells metastasizing through blood, but not lymph, became dependent on the ferroptosis inhibitor GPX4.,Cells pre-treated with chemical ferroptosis inhibitors formed more metastases than untreated cells after intravenous, but not intralymphatic, injection.,We observed multiple differences between lymph fluid and blood plasma that may contribute to decreased oxidative stress and ferroptosis in lymph, including higher levels of glutathione and oleic acid, and less free iron, in lymph.,Oleic acid protected melanoma cells from ferroptosis in an Acsl3-dependent manner and increased their capacity to form metastatic tumors.,Melanoma cells from lymph nodes were more resistant to ferroptosis and formed more metastases after intravenous injection than melanoma cells from subcutaneous tumors.,Exposure to the lymphatic environment thus protects melanoma cells from ferroptosis and increases their ability to survive during subsequent metastasis through the blood.