Circulating tumor DNA predicts tumor progression and poor survival in patients with stage III melanoma.

Data regarding circulating tumor DNA (ctDNA) in stage III melanoma are scarce. The main objective was to analyze the usefulness of ctDNA determination in predicting tumor progression in patients with stage III melanoma. A prospective multicenter study was designed based on patients with stage III cutaneous melanoma. We studied BRAF, NRAS, and TERT promoter mutations in primary or metastatic tumors. Blood samples were collected after detecting a positive lymph node by sentinel lymph node biopsy; preoperative in patients with lymph node metastasis; or before any treatment in patients with confirmed unresectable lymph node metastasis or in-transit metastasis; 4 weeks after lymph node surgery (postoperative); and every 3 or 6 months after the baseline sample. From each sample, we isolated cell-free DNA, and previously identified mutations were searched for to identify ctDNA. ctDNA was detected in 21 (21/48, 43.8%) patients. Recurrence at a distant site and recurrence in two or more locations were associated with ctDNA detection at the time of recurrence (P < 0.05). Plasma ctDNA detection at any time during follow-up was significantly associated with progression (P = 0.011), overall mortality (P < 0.001), and melanoma-specific death (P < 0.001). We did not find an association between detectable ctDNA before surgery and disease progression; however, patients with detectable postsurgical ctDNA exhibited a lower recurrence-free survival, overall survival, and melanoma-specific survival. Prospective longitudinal blood sampling for the identification of ctDNA provides information regarding recurrence and survival.