Quantitative BRAF p.V600E mutation monitoring in cerebrospinal fluid cell-free DNA reflects therapeutic response to BRAF/MEK inhibitors in papillary craniopharyngioma: a report of two cases

Papillary craniopharyngioma (PCP), molecularly defined by the BRAF p.V600E mutation in > 90% of cases, is a highly specific target for BRAF/MEK inhibitor therapy, based on dramatic radiologic responses observed in clinical trials. However, the utility of real-time molecular monitoring remains largely unexplored. Here, we present two patients with BRAF p.V600E-mutant PCP who achieved exceptional tumor volume reductions of 95% and 98% following targeted therapy with dabrafenib and trametinib. To monitor molecular burden, cerebrospinal fluid samples collected longitudinally through preexisting access devices, including Ommaya reservoirs and shunt valves, were quantitatively analyzed for the BRAF p.V600E mutation burden in cell-free DNA (cfDNA). In both cases, the BRAF p.V600E mutation copy number in the CSF rapidly declined and became undetectable, in parallel with radiologic tumor shrinkage. Notably, Case 1 maintained the negative mutation status and did not experience recurrence during the 9-month follow-up period. These findings demonstrate that digital polymerase chain reaction-based monitoring of CSF-derived cfDNA is a sensitive and objective tool for assessing molecular response in PCP, reflecting the real-time efficacy of targeted treatment and providing a framework for individualized management and early detection of recurrence in precision neurooncology.