Detection of cell‐free circulating BRAFV600E by droplet digital polymerase chain reaction in patients with and without melanoma under dermatological surveillance

Summary Background The p.V600E mutation in the BRAF protein is the most frequent mutation in cutaneous melanoma and is a recurrent alteration found in common benign naevi. Analysis of the cell‐free BRAF c.1799T>A, p.V600E mutation (cfBRAFV600E) in plasma has emerged as a biomarker for monitoring prognosis and treatment response in patients with melanoma. Objectives To quantify cfBRAFV600E levels in plasma from patients with melanoma and from patients without melanoma undergoing regular follow‐up of their melanocytic lesions, in order to assess the clinical significance of the test. Methods We quantified cfBRAFV600E by droplet digital polymerase chain reaction in plasma from 146 patients without melanoma undergoing continuous dermatological screening, from 26 stage III and seven stage IV patients with BRAF‐mutant melanoma, and from 32 patients with melanoma who were free of disease for 3 or more years. Results Among disease‐free patients and individuals without melanoma, 52% presented a high naevus count (> 50) and 49% had clinically atypical naevi. cfBRAFV600E was detected in 71% of patients with stage IV melanoma and 15% with stage III, and in 1·4% of individuals without melanoma. No cfBRAFV600E mutation was detected in disease‐free patients with melanoma. Individuals without melanoma had lower cfBRAFV600E levels than patients with melanoma. We established a variant allelic frequency of 0·26% or 5 copies mL−1 of cfBRAFV600E as the optimal cutoff value for identifying patients with melanoma with > 99% specificity. Conclusions This study suggests that naevus‐related factors do not influence the detection of cfBRAFV600E in individuals without melanoma, and supports the clinical diagnostic value of plasma cfBRAFV600E quantification in patients with melanoma. What's already known about this topic? The analysis of the BRAF c.1799T>A (p.V600E) mutation in cell‐free (cf)DNA has emerged as a potential biomarker for monitoring prognosis and treatment response in patients with metastatic BRAFV600E melanoma. The BRAFV600E alteration is a common genetic alteration found in benign proliferations such as melanocytic naevi. No information exists about the impact of the number of common acquired naevi or the presence of clinically atypical naevi in cfBRAFV600E detection in an individual. What does this study add? The cfBRAFV600E mutation is detected in plasma from a reduced number of individuals without melanoma undergoing continuous dermatological follow‐up. A high numbe