Measuring variant allele frequency in cerebrospinal fluid provides quantitative signals for cancer diagnosis and treatment monitoring.
A new study suggests that liquid biopsy of cerebrospinal fluid (CSF) can help diagnose leptomeningeal disease (LMD), a condition in which magnetic resonance imaging (MRI) and traditional cytology often yield inconclusive results.
LMD is a difficult diagnosis in neuro-oncology. MRI returns normal or inconclusive results in 20% to 30% of confirmed cases, and CSF cytology can miss approximately one in three patients during initial testing, according to a press release from Belay Diagnostics.
The peer-reviewed study, published in Diagnostics, evaluated the Summit liquid biopsy assay. By measuring variant allele frequency (VAF) in tumor-derived DNA from CSF, the assay provides quantitative signals to support diagnosis and monitor treatment response over time.
Study Findings and VAF Thresholds
Researchers analyzed 118 CSF specimens from patients with a provisional diagnosis of metastatic central nervous system (CNS) cancer, including primary malignancies of the breast and lung. The assay identified clinically significant variants in all 118 specimens across 22 genes, including TP53, EGFR, KRAS, and PIK3CA.
The study identified a VAF threshold of 5% as a potentially meaningful marker for LMD. Specifically, 69% of patients with confirmed LMD had VAFs above 5%, while most patients with parenchymal metastases or unconfirmed LMD remained below that threshold.
In cases where imaging and cytology were inconclusive, an elevated VAF prompted further investigation that ultimately led to confirmed LMD diagnoses. In 10 additional cases initially categorized as parenchymal metastases or suspected LMD, VAFs above 5% were later associated with confirmed LMD on clinical or pathological follow-up.
Monitoring Treatment Response
For patients undergoing treatment, serial CSF testing showed that VAF changes tracked clinical outcomes. In a group of 14 patients with repeat testing, 50% showed decreasing or absent VAF following treatment, which correlated with clinical improvement.
In other instances, a rising VAF corresponded with disease progression. In three cases, new variants appeared on repeat testing, suggesting clonal evolution or spatial heterogeneity within the leptomeningeal space. These findings indicate that serial CSF liquid biopsy may capture how tumor genomics evolve over time.
“This study illustrates how liquid biopsy with the Belay assay represents a paradigm shift in neuro-oncology. This technology allows for the continuous monitoring of a tumor’s molecular evolution, enabling physicians to detect clonal evolution and possibly treatment resistance ahead of radiographic progression, closing the gap between biological change and clinical intervention,” says Nancy Ann O Bush, MD, PhD, clinical director of the division of neuro-oncology in the department of neurological surgery and neurology at the University of California, San Francisco, in a release.
The researchers note that this work provides the foundation for prospective validation in larger, tumor-specific cohorts.
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