Clinical utility of plasma cell-free DNA in gliomas

Noninvasive molecular profiling of tumors using plasma-based next-generation sequencing (NGS) is increasingly used to aid in diagnosis, treatment selection, and disease monitoring in oncology. In patients with glioma, however, the plasma cell-free DNA (cfDNA) tumor fraction, defined as the fractional proportion of circulating tumor-derived DNA (ctDNA) relative to total cfDNA, is especially low, in large part due to the blood-brain barrier. As a result, commercial plasma-based NGS assays, designed to screen for a small number of actionable genomic alterations, are not sensitive enough to guide the management of patients with glioma. As this has been long recognized in neuro-oncology, significant research efforts have been undertaken to improve the sensitivity of plasma ctDNA detection in patients with glioma and to understand the biology and clinical relevance of non-tumor-derived cfDNA, which makes up most of the total cfDNA pool. Here, we review key recent advances in the field of plasma cfDNA analysis in patients with glioma, including (1) the prognostic impact of pre-treatment and on-treatment total plasma cfDNA concentrations, (2) use of tumor-guided sequencing approaches to improve the sensitivity of ctDNA detection in the plasma, and (3) the emergence of plasma cfDNA methylomics for detection and discrimination of glioma from other primary intracranial tumors.