Margaux Wooster1, Julia E McGuinness2, Kathleen M Fenn3, Veena M Singh4, Lauren E Franks5, Shing Lee6, David Cieremans7, Andrew B Lassman7, Dawn L Hershman8, Katherine D Crew8, Melissa K Accordino2, Meghna S Trivedi2, Fabio Iwamoto7, Mary R Welch7, Aya Haggiagi7, Robbie D Schultz4, Lan Huynh4, Edgar Sales4, Deanna Fisher4, Julie Ann Mayer4, Teri Kreisl7, Kevin Kalinsky9. 1. Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY. Electronic address: maw9199@nyp.org. 2. Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY. 3. Department of Medicine, Yale School of Medicine, New Haven, CT. 4. Biocept Inc., San Diego, CA. 5. Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY. 6. Department of Biostatistics, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY. 7. Department of Neurology, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY. 8. Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY; Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY. 9. Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA.
Abstract
INTRODUCTION: Diagnosis of LM is limited by low sensitivity of cerebrospinal fluid (CSF) cytopathology. Detecting tumor cells in CSF (CSF-TCs) might be more sensitive. We evaluated if CNSide (CNSide), a novel assay for tumor cell detection in CSF, can detect CSF-TCs better than conventional CSF cytology. METHODS: We enrolled adults with metastatic breast cancer and clinical suspicion for LM to undergo lumbar puncture (LP) for CSF cytopathology and CNSide. CNSide captured CSF-TCs using a primary 10-antibody mixture, streptavidin-coated microfluidic channel, and biotinylated secondary antibodies. CSF-TCs were assessed for estrogen receptor (ER) expression by fluorescent antibody and HER2 amplification by fluorescent in situ hybridization (FISH). CSF cell-free DNA (cfDNA) was extracted for next-generation sequencing (NGS). Leptomeningeal disease was defined as positive CSF cytology and/or unequivocal MRI findings. We calculated sensitivity and specificity of CSF cytology and CNSide for the diagnosis of LM. RESULTS: Ten patients, median age 51 years (range, 37-64), underwent diagnostic LP with CSF evaluation by cytology and CNSide. CNSide had sensitivity of 100% (95% Confidence Interval [CI], 40%-100%) and specificity of 83% (95% CI, 36%-100%) for LM. Among these patients, concordance of ER and HER2 status between CSF-TCs and metastatic biopsy were 60% and 75%, respectively. NGS of CSF cfDNA identified somatic mutations in three patients, including one with PIK3CA p.H1047L in blood and CSF. CONCLUSIONS: CNSide may be a viable platform to detect CSF-TCs, with potential use as a diagnostic tool for LM in patients with metastatic breast cancer. Additional, larger studies are warranted.
INTRODUCTION: Diagnosis of LM is limited by low sensitivity of cerebrospinal fluid (CSF) cytopathology. Detecting tumor cells in CSF (CSF-TCs) might be more sensitive. We evaluated if CNSide (CNSide), a novel assay for tumor cell detection in CSF, can detect CSF-TCs better than conventional CSF cytology. METHODS: We enrolled adults with metastatic breast cancer and clinical suspicion for LM to undergo lumbar puncture (LP) for CSF cytopathology and CNSide. CNSide captured CSF-TCs using a primary 10-antibody mixture, streptavidin-coated microfluidic channel, and biotinylated secondary antibodies. CSF-TCs were assessed for estrogen receptor (ER) expression by fluorescent antibody and HER2 amplification by fluorescent in situ hybridization (FISH). CSF cell-free DNA (cfDNA) was extracted for next-generation sequencing (NGS). Leptomeningeal disease was defined as positive CSF cytology and/or unequivocal MRI findings. We calculated sensitivity and specificity of CSF cytology and CNSide for the diagnosis of LM. RESULTS: Ten patients, median age 51 years (range, 37-64), underwent diagnostic LP with CSF evaluation by cytology and CNSide. CNSide had sensitivity of 100% (95% Confidence Interval [CI], 40%-100%) and specificity of 83% (95% CI, 36%-100%) for LM. Among these patients, concordance of ER and HER2 status between CSF-TCs and metastatic biopsy were 60% and 75%, respectively. NGS of CSF cfDNA identified somatic mutations in three patients, including one with PIK3CA p.H1047L in blood and CSF. CONCLUSIONS: CNSide may be a viable platform to detect CSF-TCs, with potential use as a diagnostic tool for LM in patients with metastatic breast cancer. Additional, larger studies are warranted.
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