Circulating cell-free BRAFV600E as a biomarker in children with Langerhans cell histiocytosis

The BRAF(V600E) mutation is reported in half of patients with Langerhans cell histiocytosis (LCH). This study investigated the detection of the BRAF(V600E) allele in circulating cell-free (ccf) DNA in a paediatric LCH cohort. Children with BRAF(V600E)-mutated LCH were investigated to detect ccf BRAF(V600E) at diagnosis (n = 48) and during follow-up (n = 17) using a picolitre-droplet digital PCR assay. At diagnosis, ccf BRAF(V600E) was positive in 15/15 (100%) patients with risk-organ positive multisystem (RO+ MS) LCH, 5/12 (42%) of patients with RO- MS LCH and 3/21 (14%) patients with single-system (SS) LCH (P < 0.001, Fisher's exact test). The positive BRAF(V600E) load was higher for RO+ patients (mean, 2.90%; range, 0.04-11.4%) than for RO- patients (mean, 0.16%; range, 0.01-0.39) (P = 0.003, Mann-Whitney U test). After first-line vinblastine-steroid induction therapy, 7/7 (100%) of the non-responders remained positive for ccf BRAF(V600E) compared to 2/4 (50%) of the partial-responders and 0/4 of the complete responders (P = 0.002, Fisher's exact test). Six children treated with vemurafenib showed a clinical response that was associated with a decrease in the ccf BRAF(V600E) load at day 15. Thus, ccf BRAF(V600E) is a promising biomarker for monitoring the response to therapy for children with RO+ MS LCH or RO- LCH resistant to first-line chemotherapy.