Genotyping of cerebrospinal fluid in lung cancer patients with leptomeningeal metastasis

Abstract

Background: The prognosis of non-small-cell lung cancer (NSCLC) with leptomeningeal metastasis (LM) is poor. Detection of cell-free DNA (cfDNA) by next generation sequencing (NGS) in cerebrospinal fluid (CSF) may facilitate diagnosis of LM and identification of drug resistance mechanisms, yet its clinical use needs to be further verified. Methods: We performed a retrospective cohort study to assess the genetic profiles of paired CSF and plasma samples in lung cancer patients with LM. Of 17 patients screened, a total of 14 patients with LM and paired NGS tests were enrolled. Results: All patients harbor driver gene mutations, including 12 epidermal growth factor receptor (EGFR) activating mutations, 1 anaplastic lymphoma kinase (ALK) rearrangement, and 1 ROS-1 fusion. Genetic mutations were detected in CSF cfDNA from 92.9% patients (13/14), which was significantly higher than that from the plasma (9/14, 64.2%). The mutations were highly divergent between CSF and plasma cfDNA, with a concordance rate of 24.38% and 10 mutations shared by the two media. CSF cfDNA could also benefit the analysis of resistance mechanisms to targeted therapies. In five patients who experienced progression on 1st or 2nd generation EGFR-tyrosine kinase inhibitors (TKIs), RB1 mutation, and amplification of MET and EGFR were detected in CSF cfDNA only. In eight patients with LM progression on osimertinib resistance, EGFR amplification was detected in CSF cfDNA from four patients, whereas no CNVs were detected in the matched plasma samples. Conclusions: In conclusion, CSF could be superior to plasma in providing a more comprehensive genetic landscape of LM to find out drug resistance mechanisms and guide subsequent treatments.

Cerebrospinal Fluid Circulating Tumor DNA Genotyping and Survival Analysis in Lung Adenocarcinoma With Leptomeningeal Metastases

“…What's more, we demonstrated that CSF ctDNA has a signifcantly higher detection rate than plasma. This result is consistent with previous study which show that CSF ctDNA exhibite a more comprehensive genetic landscape than plasma of CNS metastases [14,16,17,19]. Previous studies have compared the detection rate of EGFR and found that it is higher in CSF than plasma.…”

“…CSF ctDNA exhibit unique genetic pro es and distinct resistance mechanisms during treatment in NSCLC patients with brain metastases, so it is crucial to test for acquired resistance at CNS progression [13,14]. ctDNA is more abundantly present in the CSF than in plasma and has been shown as a biomarker of treatment effect and tumor evolution in patients with LM [15][16][17]. In order to fully explore the effectiveness of CSF ctDNA representing genetic information in LM versus that of plasma ctDNA in our study, we compared the matched CSF and plasma from the same LM patients.…”

Quantification of Cerebrospinal Fluid Tumor DNA in Lung Cancer Patients with Suspected Leptomeningeal Carcinomatosis

“…Recent cohort studies have demonstrated the feasibility of detecting CSF-tDNA in patients with EGFR-mutant and ALK-rearranged NSCLC. [27][28][29][30][31][32][33][34][35][36][37] Consistent observations across these reports are higher variant allele fractions (VAFs) in CSF compared to plasma and better concordance between the original tumor and CSF-tDNA, than between tumor and plasma ctDNA. Preliminary results suggest the sensitivity of CSF-tDNA is superior to that to CSF cytology 23 and the utility of CSF-tDNA to predict treatment response remains unknown.…”