Mark T J van Bussel1, Dick Pluim1, Bojana Milojkovic Kerklaan1, Mijke Bol1, Karolina Sikorska1, Dorothé T C Linders1, Daan van den Broek1, Jos H Beijnen1, Jan H M Schellens1, Dieta Brandsma2. 1. From the Division of Pharmacology (M.T.J.v.B., D.P., B.M.K., J.H.B., J.H.M.S.), Clinical Pharmacology (M.T.J.v.B., B.M.K., J.H.B., J.H.M.S), Division of Pathology (M.B.), Department of Biometrics (K.S.), Department of Laboratory Medicine (D.T.C.L., D.v.d.B.), and Department of Neuro-oncology (D.B.), Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; and Science Faculty (J.H.B., J.H.M.S), Pharmaceutical Sciences, Division of Pharmaco-epidemiology and Clinical Pharmacology, Utrecht University, the Netherlands. 2. From the Division of Pharmacology (M.T.J.v.B., D.P., B.M.K., J.H.B., J.H.M.S.), Clinical Pharmacology (M.T.J.v.B., B.M.K., J.H.B., J.H.M.S), Division of Pathology (M.B.), Department of Biometrics (K.S.), Department of Laboratory Medicine (D.T.C.L., D.v.d.B.), and Department of Neuro-oncology (D.B.), Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam; and Science Faculty (J.H.B., J.H.M.S), Pharmaceutical Sciences, Division of Pharmaco-epidemiology and Clinical Pharmacology, Utrecht University, the Netherlands. d.brandsma@nki.nl.
Abstract
OBJECTIVE: The primary objective was to determine the sensitivity and specificity of epithelial cell adhesion molecule (EpCAM) immunoflow cytometry circulating tumor cells (CTC) analysis in CSF in patients with suspected leptomeningeal metastases (LM). The secondary objective was to explore the distribution of driver mutations in the primary tumor, plasma, cell free CSF (cfCSF), and isolated CTC from CSF in non-small cell lung cancer (NSCLC). METHODS: We tested the performance of the CTC assay vs CSF cytology in a prospective study in 81 patients with a clinical suspicion of LM but a nonconfirmatory MRI. In an NSCLC subcohort, we analyzed circulating tumor (ct)DNA of the selected driver mutations by digital droplet PCR (ddPCR). RESULTS: The sensitivity of the CTC assay was 94% (95% confidence interval [CI] 80-99) and the specificity was 100% (95% CI 91-100) at the optimal cutoff of 0.9 CTC/mL. The sensitivity of cytology was 76% (95% CI 58-89). Twelve of the 23 patients with NSCLC had mutated epidermal growth factor receptor (EGFR). All 5 tested patients with LM demonstrated the primary EGFR driver mutation in cfCSF. The driver mutation could also be detected in CTC isolated from CSF. CONCLUSION: CTC in CSF are detected with a high sensitivity for the diagnosis of LM. ddPCR can determine EGFR mutations in both cfCSF and isolated CTC from CSF of patients with EGFR-mutated NSCLC and LM. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EpCAM-based immunoflow cytometry analysis of CSF accurately identifies patients with LM.
OBJECTIVE: The primary objective was to determine the sensitivity and specificity of epithelial cell adhesion molecule (EpCAM) immunoflow cytometry circulating tumor cells (CTC) analysis in CSF in patients with suspected leptomeningeal metastases (LM). The secondary objective was to explore the distribution of driver mutations in the primary tumor, plasma, cell free CSF (cfCSF), and isolated CTC from CSF in non-small cell lung cancer (NSCLC). METHODS: We tested the performance of the CTC assay vs CSF cytology in a prospective study in 81 patients with a clinical suspicion of LM but a nonconfirmatory MRI. In an NSCLC subcohort, we analyzed circulating tumor (ct)DNA of the selected driver mutations by digital droplet PCR (ddPCR). RESULTS: The sensitivity of the CTC assay was 94% (95% confidence interval [CI] 80-99) and the specificity was 100% (95% CI 91-100) at the optimal cutoff of 0.9 CTC/mL. The sensitivity of cytology was 76% (95% CI 58-89). Twelve of the 23 patients with NSCLC had mutated epidermal growth factor receptor (EGFR). All 5 tested patients with LM demonstrated the primary EGFR driver mutation in cfCSF. The driver mutation could also be detected in CTC isolated from CSF. CONCLUSION: CTC in CSF are detected with a high sensitivity for the diagnosis of LM. ddPCR can determine EGFR mutations in both cfCSF and isolated CTC from CSF of patients with EGFR-mutated NSCLC and LM. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that EpCAM-based immunoflow cytometry analysis of CSF accurately identifies patients with LM.
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