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Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease.

ABSTRACT: Circulating tumor DNA (ctDNA) refers to tumor-derived cell-free DNA that circulates in body fluids. Fluid samples are easier to collect than tumor tissue, and are amenable to serial collection at multiple time points during the course of a patient's illness. Studies have demonstrated the feasibility of performing mutation profiling from blood samples in cancer patients. However, detection of ctDNA in the blood of patients with brain tumors is suboptimal. Cerebrospinal fluid (CSF) can be obtained via lumbar puncture or intraventricular catheter, and may be a suitable fluid to assess ctDNA in patients with brain tumors. We detected melanoma-associated mutations by droplet-digital PCR (ddPCR) and next-generation sequencing in ctDNA obtained from the CSF (CSF-ctDNA) of melanoma patients with leptomeningeal disease. There is a strong correlation between mutation detection by ddPCR, the presence of circulating tumor cells in CSF and abnormalities in the MRI. However, approximately 30% of CSF samples that were negative or indeterminate for the presence of tumor cells by microscopic examination were positive for CSF-ctDNA by ddPCR. Our results demonstrate that CSF is a suitable fluid for evaluating ctDNA and ddPCR is superior to CSF-cytology for analysis of CSF in melanoma patients with leptomeningeal disease.

SUBMITTER: Ballester LY

PROVIDER: S-EPMC6005029 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease.

Ballester Leomar Y LY Glitza Oliva Isabella C IC Douse Dzifa Y DY Chen Melissa M MM Lan Chieh C Haydu Lauren E LE Huse Jason T JT Roy-Chowdhuri Sinchita S Luthra Rajyalakshmi R Wistuba Ignacio I II Davies Michael A MA

Journal of neuropathology and experimental neurology 20180701 7

Circulating tumor DNA (ctDNA) refers to tumor-derived cell-free DNA that circulates in body fluids. Fluid samples are easier to collect than tumor tissue, and are amenable to serial collection at multiple time points during the course of a patient's illness. Studies have demonstrated the feasibility of performing mutation profiling from blood samples in cancer patients. However, detection of ctDNA in the blood of patients with brain tumors is suboptimal. Cerebrospinal fluid (CSF) can be obtained ...[more]

PMID: 29873738

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Project description:ImportanceLeptomeningeal disease (LMD) is a devastating complication of cancer that is frequently underdiagnosed owing to the low sensitivity of cerebrospinal fluid (CSF) cytologic assessment, the current benchmark diagnostic method. Improving diagnostic sensitivity may lead to improved treatment decisions.ObjectiveTo assess whether cell-free DNA (cfDNA) analysis of CSF may be used to diagnose LMD more accurately than cytologic analysis.Design, setting, and participantsThis diagnostic study conducted in a neuro-oncology clinic at 2 large, tertiary medical centers assessed the use of genomic sequencing of CSF samples obtained from 30 patients with suspected or confirmed LMD from 2015 through 2018 to identify tumor-derived cfDNA. From the same CSF samples, cytologic analyses were conducted, and the results of the 2 tests were compared. This study consisted of 2 patient populations: 22 patients with cytologically confirmed LMD without parenchymal tumors abutting their CSF and 8 patients with parenchymal brain metastases with no evidence of LMD. Patients were considered positive for the presence of LMD if previous CSF cytologic analysis was positive for malignant cells. The analysis was conducted from 2015 to 2018.Main outcomes and measuresThe primary outcome was the diagnostic accuracy of cfDNA analysis, defined as the number of tests that resulted in correct diagnoses out of the total number of tests assayed. Hypotheses were formed before data collection.ResultsIn total, 30 patients (23 women [77%]; median age, 51 years [range, 28-81 years]), primarily presenting with metastatic solid malignant neoplasms, participated in this study. For 48 follow-up samples from patients previously diagnosed via cytologic analysis as having LMD with no parenchymal tumor abutting CSF, cfDNA findings were accurate in the assessment of LMD in 45 samples (94%; 95% CI, 83%-99%), whereas cytologic analysis was accurate in 36 samples (75%; 95% CI, 60%-86%), a significant difference (P = .02). Of 43 LMD-positive samples, CSF cfDNA analysis was sensitive to LMD in 40 samples (93%; 95% CI, 81%-99%), and cytologic analysis was sensitive to LMD in 31 samples (72%; 95% CI, 56%-85%), a significant difference (P = .02). For 3 patients with parenchymal brain metastases abutting the CSF and no suspicion of LMD, cytologic findings were negative for LMD in all 3 patients, whereas cfDNA findings were positive in all 3 patients.Conclusions and relevanceThis diagnostic study found improved sensitivity and accuracy of cfDNA CSF testing vs cytologic assessment for diagnosing LMD with the exception of parenchymal tumors abutting CSF, suggesting improved ability to diagnosis LMD. Consideration of incorporating CSF cfDNA analysis into clinical care is warranted.

Dataset Information

Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease.

Publications

Evaluating Circulating Tumor DNA From the Cerebrospinal Fluid of Patients With Melanoma and Leptomeningeal Disease.

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