PURPOSE: Monitoring disease progression in patients with high-grade gliomas (HGGs) is challenging due to treatment-related changes on imaging and the requirement for neurosurgical intervention to obtain diagnostic tissue. DNA junctions in HGGs often amplify oncogenes, making these DNA fragments potentially more abundant in blood than monoallelic mutations. Herein, we piloted a cell-free DNA approach for disease detection in plasma of patients with HGGs by leveraging patient-specific DNA junctions associated with oncogene amplifications. EXPERIMENTAL DESIGN: Whole genome sequencing of grade 3 or 4 IDH-mutant or wild-type astrocytomas was utilized to identify amplified junctions. Individualized qPCR assays were developed using patient-specific primers designed for the amplified junction. ctDNA levels containing these junctions were measured in patient plasma samples. RESULTS: Unique amplified junctions were evaluated by individualized semi-quantitative PCR assays in presurgical plasma of 18 patients, 15 with tumor-associated focal amplifications and three without. High-copy number junctions were robustly detected in plasma of 14/15 patients (93.3%) with amplified junctions and none of the controls. Changes in junction abundance correlated with disease trajectory in serial plasma samples from five patients, including increased abundance of amplified junctions preceding radiographic disease progression. CONCLUSION: In patients with grade 3 or 4 astrocytomas who had tumor-associated amplifications, patient-specific amplified junctions were successfully detected in assayed plasma from most patients. Longitudinal analysis of plasma samples correlated with disease trajectory, including cytoreduction and progression.