Evaluating the diagnostic performance of leptomeningeal diagnosis with CNSide compared to standard cytology.

Abstract

2028 Background: Prior reports cited detection rates of leptomeningeal metastases (LM) using CNSide vs standard CSF cytology of 78% vs 55% in NSCLC and 84% vs 52% in various solid tumor cohorts. The objective of this study was to compare the real-world performance of the CNSide assay in diagnosing LM versus CSF cytology from lumbar puncture (LP) and established EANO-ESMD LM diagnostic criteria (EANO). Methods: We retrospectively analyzed all neuro-oncology patients from January, 2020 to December, 2022 with suspected LM who underwent LP with CSF cytology and CNSide. The CNSide assay included tumor cells (CSF-TCs) and cell-free DNA (cfDNA). LM diagnostic probability was defined by EANO criteria. Descriptive statistics and confusion matrix were calculated. Results: 87 patients (66 [76%] women) met eligibility criteria for inclusion with median age of 63 (23-87) years; 35 (40%) had uncontrolled systemic disease. The most common primary histologies were breast (45%) and lung (41%); 33% of primary lung cancers harbored molecular alterations, while primary breast cancers expressed hormone receptors in 69% and HER2 alterations in 10%. Across all primary histologies, 53 (61%) cases harbored molecular alterations, of which 27 (31%) had molecular alterations also detected by CNSide. For 7 (8%) cases with negative cytology and CNSide, CNSide detected alterations by cfDNA assays. LM was diagnosed by CSF cytology in 23 (27%) cases, consistent with confirmed LM by EANO. 36 (41%) cases had confirmed LM by CSF cytology or CNSide; all cytology positive and equivocal cases were detected by CNSide. Patients with negative CSF cytology were further defined as probable (19, 23%), possible (35, 42%), or (7, 8%) lack of evidence by EANO. Modifying EANO criteria to include both standard CSF cytology and CNSide led to 36 (41%) confirmed LM cases, an increase of 13 cases in addition to the 23 cytology positive cases (+56.5%). Compared to CNSide, standard CSF cytology had a sensitivity of 70%, but an expected 100% specificity. Compared to the established higher specificity of CNSide, EANO had 100% sensitivity, but only 18% specificity for diagnosing LM, assuming all EANO possible, probable, or confirmed cases were positive, while specificity improved to 74% with slight decrease sensitivity to 94% if only probable or confirmed cases were considered positive. Conclusions: In the largest, retrospective, single institution, real-world study, implementation of CNSide showed increased sensitivity relative to standard cytology and increased specificity relative to EANO criteria, and provided clinically relevant, cell-based molecular and cell-free DNA analyses. CNSide increased the diagnostic yield by 56.5%.