The Clinical Utility of Cell-Free DNA in Brain Tumor Management: A Comprehensive Review.

Brain tumors present a significant diagnostic and therapeutic challenge due to their heterogeneity and the limitations of conventional monitoring tools. Liquid biopsy, particularly the analysis of cell-free DNA (cfDNA) from biofluids, has emerged as a transformative, minimally invasive approach in neuro-oncology. By analyzing tumor-derived genetic and epigenetic alterations in cfDNA, this method offers a comprehensive molecular profile of a patient’s total tumor burden. Cerebrospinal fluid (CSF) has proven to be a superior source of tumor-derived cfDNA compared to plasma, overcoming the barrier posed by the blood-brain barrier. Clinically, cfDNA analysis enables non-invasive diagnosis, real-time monitoring of treatment response, early detection of acquired resistance, and sensitive surveillance for minimal residual disease. It has demonstrated utility across various histologies, including gliomas, medulloblastoma, brain metastases, and primary central nervous system lymphoma. However, the key limitations still include the low abundance of tumor-derived cfDNA in biofluids, particularly plasma, and the invasiveness of CSF collection, which restrict broader clinical application. This review adds value by integrating the WHO 2021 molecular framework for brain tumor classification, providing histology-specific insights into cfDNA applications. It emphasizes CSF as the superior analyte for cfDNA detection, discusses the emerging roles of minimal residual disease (MRD) monitoring and adaptive therapies, and highlights advances in multi-omics and AI-driven approaches. By explicitly focusing on these novel aspects, this study strengthens the clinical positioning of cfDNA liquid biopsy in neuro-oncology and its prospective role in precision medicine.