Cerebrospinal fluid-derived circulating tumor DNA is more comprehensive than plasma in NSCLC patients with leptomeningeal metastases regardless of extracranial evolution

Yang, Hainan; Wen, Lu; Zhao, Chao; Chen, Jianing; Zhou, Zhaoming; Zhou, Cheng; Cai, Linbo; Zhou, Cai-cun

doi:10.1016/j.heliyon.2022.e12374

Cited by 8 publications

(7 citation statements)

References 16 publications

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“…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.…”

Section: Introductionmentioning

confidence: 61%

“…46,47 In the selection of patients most likely to benefit from TKI re-challenge, plasma ctDNA and CSF-tDNA could allow personalized surveillance of resistance mechanisms within and outside of the CNS. 27,[31][32][33]48 Early changes in clonal composition, particularly those conferring therapeutic resistance, could aid clinical decision-making in identifying drugs most likely to be effective. Additionally, beyond the dynamic heterogeneity in tumor genotype over time, spatial heterogeneity may also help direct therapy.…”

Section: Discussionmentioning

confidence: 99%

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

Azad,

Nanjo,

Jin

et al. 2024

Preprint

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IntroductionCerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring neoplastic processes of the central nervous system. We hypothesize that analysis of CSF-tDNA in patients with advanced lung cancer improves the sensitivity of leptomeningeal disease (LMD) diagnosis and enables central nervous system response monitoring.MethodsWe applied CAPP-Seq using a lung cancer-specific sequencing panel to 81 CSF, blood, and tissue samples from 24 patients with advanced lung cancer who underwent lumbar puncture (LP) for suspected LMD. A subset of the cohort (N = 12) participated in a prospective clinical trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment with.ResultsCSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%;P< 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman’s ρ, 0.45;P= 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1;P= 0.02). Among patients with progression on targeted therapy, resistance mutations, such asEGFRT790M andMETamplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2,P= 0.009).ConclusionsDetection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA may improve the sensitivity of LMD diagnosis, enable improved prognostication, and drive therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

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Section: Introductionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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

Azad,

Nanjo,

Jin

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…EGFR-TKI re-challenge remains promising, with multiple studies evaluating re-administration of EGFR-targeted therapy after salvage cytotoxic chemotherapy 46 , 47 . In the selection of patients most likely to benefit from TKI re-challenge, plasma ctDNA, and CSF-tDNA could allow personalized surveillance of resistance mechanisms within and outside of the CNS 27 , 31 – 33 , 48 . Early changes in clonal composition, particularly those conferring therapeutic resistance, could aid clinical decision-making in identifying drugs most likely to be effective.…”

Section: Discussionmentioning

confidence: 99%

Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis

Azad,

Nanjo,

Jin

et al. 2024

npj Precis. Onc.

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Cerebrospinal fluid tumor-derived DNA (CSF-tDNA) analysis is a promising approach for monitoring the neoplastic processes of the central nervous system. We applied a lung cancer-specific sequencing panel (CAPP-Seq) to 81 CSF, blood, and tissue samples from 24 lung cancer patients who underwent lumbar puncture (LP) for suspected leptomeningeal disease (LMD). A subset of the cohort (N = 12) participated in a prospective trial of osimertinib for refractory LMD in which serial LPs were performed before and during treatment. CSF-tDNA variant allele fractions (VAFs) were significantly higher than plasma circulating tumor DNA (ctDNA) VAFs (median CSF-tDNA, 32.7%; median plasma ctDNA, 1.8%; P < 0.0001). Concentrations of tumor DNA in CSF and plasma were positively correlated (Spearman’s ρ, 0.45; P = 0.03). For LMD diagnosis, cytology was 81.8% sensitive and CSF-tDNA was 91.7% sensitive. CSF-tDNA was also strongly prognostic for overall survival (HR = 7.1; P = 0.02). Among patients with progression on targeted therapy, resistance mutations, such as EGFR T790M and MET amplification, were common in peripheral blood but were rare in time-matched CSF, indicating differences in resistance mechanisms based on the anatomic compartment. In the osimertinib cohort, patients with CNS progression had increased CSF-tDNA VAFs at follow-up LP. Post-osimertinib CSF-tDNA VAF was strongly prognostic for CNS progression (HR = 6.2, P = 0.009). Detection of CSF-tDNA in lung cancer patients with suspected LMD is feasible and may have clinical utility. CSF-tDNA improves the sensitivity of LMD diagnosis, enables improved prognostication, and drives therapeutic strategies that account for spatial heterogeneity in resistance mechanisms.

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“…In general, liquid biopsies are divided into three major categories based on the tumor-derived materials namely circulating tumor DNA (ctDNA), circulating tumor cells (CTCs) and exos/extracellular vesicles. ctDNA [ 22 , 23 ] and exosomal microRNAs [ 24 ] have shown aspects in the diagnosing and monitoring of LC. Further more, CSF seems more comprehensive than plasma in liquid biopsy of patients with LC because it carries more driver genomic mutations and potential prognostic markers [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

Cerebrospinal fluid exosomal protein alterations via proteomic analysis of NSCLC with leptomeningeal carcinomatosis

Hou,

Chen,

Qiu

et al. 2023

J Neurooncol

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Purpose Leptomeningeal carcinomatosis (LC) is a rare complication of non-small cell lung cancer (NSCLC) with highly mortality. Cerebrospinal fluid (CSF) as a special kind of tumor microenvironment (TME) better represents alterations than plasma. However, the clinical value of protein profiles of exosome in CSF as liquid biopsy remains unclear. Methods In this study, CSF samples of NSCLC patients with (LC group) or without (NSCLC group) LC were collected and compared to patients without tumors (normal group). CSF exosomes were isolated by ultracentrifugation and protein profiles were performed by label-free proteomics. Differentially expressed proteins (DEPs) were detected by bioinformatics tools and verified by parallel reaction monitoring (PRM). Results A total of 814 proteins were detected. Bioinformatics analysis revealed their shared function in the complement activation, extracellular region, and complement and coagulation cascades. Between LC and NSCLC group, 72 DEPs were found among which FN1 demonstrated the highest betweenness centrality (BC) after protein-protein interaction network analysis. Conclusion We investigated the application of label free and PRM based proteomics to detect key proteins related to LC. FN1 may serve as potential indicator to classify LC and NSCLC. Extracellular matrix (ECM) and epithelial-mesenchymal transition (EMT) are important in the process of LC. These data is promising for early prediction and diagnosis of LC.

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Cerebrospinal fluid-derived circulating tumor DNA is more comprehensive than plasma in NSCLC patients with leptomeningeal metastases regardless of extracranial evolution

Cited by 8 publications

References 16 publications

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

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

Quantification of cerebrospinal fluid tumor DNA in lung cancer patients with suspected leptomeningeal carcinomatosis

Cerebrospinal fluid exosomal protein alterations via proteomic analysis of NSCLC with leptomeningeal carcinomatosis

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