10203-NT-4 BRAFV600E mutation in cerebrospinal fluid correlates with the therapeutic effect of BRAF/MEK inhibitor therapy for craniopharyngioma

Abstract Background Over 90% of papillary craniopharyngiomas harbor the BRAFV600E mutation. In the U. S., clinical trials (NCT03224767) have demonstrated the high efficacy of BRAF/MEK inhibition therapy. In Japan, this therapy was approved in 2023 for advanced/recurrent solid tumors with BRAFV600E mutation when standard treatments are ineffective. We report two cases treated at our hospital showing significant clinical responses to BRAF/MEK inhibitors, along with the longitudinal detection of BRAFV600E mutation from cell-free DNA in cerebrospinal fluid (CSF). Methods BRAFV600E mutations were identified using companion diagnostics. CSF samples were serially collected from Ommaya’s reservoirs or shunt valves, and cell-free DNA was extracted. BRAFV600E quantification was performed using the QuantStudio Absolute Q digital PCR system. These results were compared with tumor volumes, CSF cell counts, and CSF protein levels. Results BRAFV600E was detected in pre-treatment CSF in both cases. Following BRAF/MEK inhibitor therapy, the mutation was no longer detectable in CSF as tumors regressed. Case 1 exhibited a 98% tumor volume reduction and successfully discontinued therapy, maintaining BRAFV600E negativity and no recurrence for 4 months. Case 2 also showed a 95% tumor reduction and therapy cessation, followed by gradual shrinkage of cystic components. Conclusion Digital PCR enabled robust BRAFV600E detection in CSF-derived cell-free DNA and reflected therapeutic efficacy. Ongoing observation will determine whether mutation re-emergence correlates with recurrence or could serve as a predictive marker.