Targeted treatment of brainstem neurohistiocytosis guided by urinary cell-free DNA.

OBJECTIVE: To identify a treatment-responsive BRAF(V600E) mutation in brainstem neurohistiocytosis, where no lesional tissue was readily obtainable, using a cell-free DNA approach.

METHODS: Cell-free DNA was extracted from urine and allele-specific PCR for the BRAF(V600E) mutation was performed. Response to conventional treatment (corticosteroids and interferon) and targeted treatment with a BRAF inhibitor was assessed by clinical evaluation, gadolinium-enhanced MRI brain scan, and serial testing of urinary cell-free DNA for mutant alleles.

RESULTS: BRAF(V600E) mutation could be readily identified in urinary cell-free DNA at an allele frequency of 4.2%. Treatment of Erdheim-Chester disease with corticosteroids and interferon was ineffective and associated with disease progression. Treatment with BRAF inhibitors was associated with clinical improvement and near-complete radiologic remission. Following 6 months of BRAF inhibitor therapy, no enhancing lesions could be detected in the brain and mutant alleles were cleared from the urine.

CONCLUSIONS: Analysis of urinary cell-free DNA using allele-specific PCR for BRAF(V600E) mutations allows rapid noninvasive identification of a highly treatment-responsive pathway, leading to clinical and radiologic remission of disease. Our case demonstrates that this assay may have a particular role in challenging neurohistiocytosis cases, where attempts at obtaining lesional tissue have failed or are not feasible.

CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence. This is a single observation study without controls.