Circulating epithelial tumor cell analysis in CSF in patients with leptomeningeal metastases

Abstract

ObjectiveThe 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).MethodsWe 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).ResultsThe 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.ConclusionCTC 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 evidenceThis study provides Class III evidence that EpCAM-based immunoflow cytometry analysis of CSF accurately identifies patients with LM.

Diagnosis of leptomeningeal metastasis through identification of circulating tumor cells in cerebrospinal fluid using the TargetSelector™ assay

“…Our ndings are in agreement with recent data that an EpCAM-based assay had a sensitivity of 94% and speci city of 100% for LM among patients with metastatic epithelial malignancies, compared with a sensitivity of 76% for standard cytopathologic analysis [24]. Epithelial cell adhesion molecule (EpCAM) is a surface antigen on epithelial malignancies,…”

“…Given that the identi cation of variants in PIK3CA and other genes can have treatment implications in MBC [27], TS could have clinical utility among patients with CNS metastatic disease. Similarly, previous studies using EpCAM-based assays and NGS have identi ed actionable mutations in the CSF of patients with metastatic malignancies, including EGFR mutations in non-small cell lung cancer [14,24]. Further studies using TS should evaluate its ability to detect genomic variants in the CSF of patients with non-breast malignancies.…”

Endocrine therapy for the treatment of leptomeningeal carcinomatosis in luminal breast cancer: a comprehensive review

“…Adding complexity to SACT options for these patients is the not rare event of discordance in hormone receptor status between primary tumor and CNS metastasis, with an HR+ primary switching to negative in one-fifth to one-third of cases [ 72 , 73 , 82 ]. New diagnostic techniques, such as analysis of circulating epithelial tumor cell DNA in CSF, could help increase diagnostic sensitivity and specificity and establish ABC subgroups as well as driver and resistance mutations, which could help dictate therapeutic choices [ 83 ].…”

The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers

“…Several groups have developed flow cytometry-based approaches for the detection of breast cancer LM, capturing cells positive for tumor cell specific markers from CSF [53][54][55]. Others have applied rare cell capture technologies to standard CSF cytology approaches to improve the detection sensitivity of tumor cells [56][57][58][59]. Approaches examining the genome, transcriptome, proteome, or miRNAs found in CSF may also hold future promise in diagnosing LM [37,[60][61][62].…”