Circulating Tumor DNA in Adults With Glioma: A Systematic Review and Meta-Analysis of Biomarker Performance

Abstract

BACKGROUND: Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker to capture tumor genetics in patients with brain tumors. Research into its clinical utility, however, has not been standardized because the sensitivity and specificity of ctDNA remain undefined. OBJECTIVE: To (1) review the primary literature about ctDNA in adults with glioma to compare the sensitivity and specificity of ctDNA in the cerebrospinal fluid vs the plasma and (2) to evaluate the effect of tumor grade on detection of ctDNA. METHODS: PRISMA-guided systematic review and meta-analysis was performed using published studies that assessed ctDNA in either plasma or cerebrospinal fluid among adult patients with confirmed glioma. Summary receiver operating characteristic curves were generated using the Rücker-Schumacher method, and area under the curve (AUC) was calculated. RESULTS: Meta-analysis revealed improved biomarker performance for CSF (AUC = 0.947) vs plasma (AUC = 0.741) ctDNA, although this did not reach statistical significance (P = .141). Qualitative analysis revealed greater sensitivities among single-allele PCR and small, targeted next-generation sequencing panels compared with broader panels. It additionally demonstrated higher sensitivity of ctDNA detection in high-grade vs low-grade gliomas, although these analyses were limited by a lack of specificity reporting in many studies. CONCLUSION: ctDNA seems to be a highly sensitive and specific noninvasive biomarker among adults with gliomas. To maximize its performance, CSF should be studied with targeted genetic analysis platforms, particularly in high-grade gliomas. Further studies on ctDNA are needed to define its clinical utility in diagnosis, prognostication, glioblastoma pseudoprogression, and other scenarios wherein neoadjuvant therapies may be considered.

Diagnostic and Prognostic Value of Circulating DNA Fragments in Glioblastoma Multiforme Patients

“…Circulating tumour-derived DNA, the subset of cfDNA specifically shed from tumour cells, has recently become a promising biomarker in patients with advanced cancer. The meta-analysis performed by MacMahon et al [13] revealed an improved biomarker performance for cerebrospinal fluid (AUC = 0.947) vs. plasma (AUC = 0.741) ctDNA, although this did not reach statistical significance. Our meta-analysis of two studies comprising 104 patients demonstrated a worse prognosis in patients with a higher cfDNA (HR 2.35, 95%CI 1.27-4.36, p < 0.01).…”

“…Some studies have highlighted potential benefits of the measurement of cell-free DNA fragments (cfDNA), which are released from the tumour and healthy cells into the bloodstream as a result of apoptosis, necrosis, NETosis, and active secretion via extracellular vesicles [9,[12][13][14][15][16]. According to the American Society of Clinical Oncology and the College of American Pathologists, the largest fraction of cfDNA in patients with cancer is derived from the tumour tissue of origin [17].…”

“…The elevated levels of total cfDNA have been demonstrated in malignant tumours among adults, including glioblastoma patients, relative to patients with non-neoplastic diseases [12]. However, cfDNA levels in brain tumours are reduced by 60% in medulloblastoma and by 90% in low-grade glioma, as compared to systemic malignancies [12][13][14]. In addition, the length of the DNA fragments and their source in glioblastoma are unknown and the measurement of cfDNA in GBM patients for clinical applications remains a multifaceted problem.…”

“…Currently, circulating cfDNA and ctDNA fractions are analysed in the context of inflammation, as they appear to be promising potential biomarkers for the early diagnosis or prognosis in glioblastoma [22][23][24]. To date, only two meta-analyses have been reported by MacMahon et al [13] and Jarmuzek et al [25]. Both studies showed that cfDNA appeared to be a significantly sensitive and specific biomarker in adults with low-and high-grade gliomas; however, further studies should be conducted with glioblastoma as a target.…”

Prognostic Values of Systemic Inflammatory Immunological Markers in Glioblastoma: A Systematic Review and Meta-Analysis

“…Some studies have highlighted the potential benefits of the measurement of small cell-free DNA fragments (cfDNA), which are released from the tumor and healthy cells into the bloodstream as a result of secretion, apoptosis, necrosis, or NETosis [ 35 , 36 , 37 ]. A total of 85% of plasma cfDNA fragments in cancer patients are 166 base pair (bp), 10% are 332 bp, and 5% are 498 bp in length.…”