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Cell-Free DNA Analysis Outperforms Cytology for Leptomeningeal Disease Detection

NEW YORK – Cell-free DNA analysis appears to be more sensitive and accurate than a cytological approach for diagnosing leptomeningeal disease (LMD) in most cases, a new study has found.

Leptomeningeal disease, in which cancer metastasizes to the cerebrospinal fluid, occurs in 4 to 15 percent of cancer patients and is associated with poor survival, with untreated patients dying within four to six weeks. While cytological analysis of cerebrospinal fluid is the current diagnostic approach, it has low sensitivity, leading researchers from Harvard Medical School to examine whether cell-free DNA analysis from CSF may diagnose LMD more accurately.

"If we are able to confidently diagnose LMD using cell-free DNA earlier and with fewer invasive procedures, then we can institute treatment sooner and enroll [patients in] clinical trials for new LMD treatments," co-senior author Brastianos from Harvard and her colleagues Scott Carter at the Broad Institute and Michael White from the University of Rochester Medical Center said in an email. "The ultimate hope is that we can improve patient survival with earlier diagnosis and treatment for this deadly disease."

In a study appearing Monday in JAMA Network Open, they researchers compared CSF samples from more than two dozen patients that were analyzed by both cytology and genomic sequencing. They found that in most cases, cfDNA analysis had both higher sensitivity and accuracy than cytological analysis, suggesting this approach might be better suited at diagnosing LMD.

For their analysis, the researchers obtained CSF samples by lumbar puncture or shunt from 30 patients. Most patients in the cohort — 17 individuals — had breast cancer as their primary cancer type and all but one had a solid tumor as their primary tumor type. Also, 23 patients had parenchymal brain metastases.

Of these patients, 22 had previously been diagnosed with LMD by cytological analysis and eight had no evidence of LMD. However, three patients without evidence of LMD had parenchymal tumors that abutted the CSF and had to be removed from the analysis as their CSF showed false-positive cfDNA results.

For the remainder of the cohort, cfDNA analysis accurately detected LMD in 94 percent of cases, as compared to 74 percent for cytological analysis. Additionally, cfDNA analysis had a sensitivity of 93 percent, while cytological analysis had a sensitivity of 72 percent. Both approaches had similar specificities.

Some patients with LMD are frequently or persistently negative for the disease via cytological analysis despite a diagnosis by MRI and clinical assessment, a situation that affects about 10 percent of patients. Within this cohort, cfDNA could diagnose such persistently negative patients, according to the researchers.

The findings suggest that cfDNA analysis of CSF could be a viable approach for diagnosing LMD. The researchers cautioned, though, that the approach should not be used for patients with parenchymal tumors that abut the CSF, as cfDNA was found in their CSF despite the absence of LMD. Instead, cytological and MRI methods might be preferred in these patients, they noted.

"In the future, we hope to incorporate cell-free DNA in addition to cytology-proven disease to guide enrollment to prospective clinical trials in LMD," the researchers said in their email. "As our study was done retrospectively, prospective data will help solidify our hypothesis that cell-free DNA is more sensitive and specific to LMD than cytology and MRI, as well as give preliminary insight into whether earlier detection and clinical trial enrollment leads to better outcomes."