Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases

Seoane, Joan; Mattos-Arruda, Leticia De; Rhun, Émilie Le; Bardelli, Alberto; Weller, Michael

doi:10.1093/annonc/mdy544

Cited by 114 publications

(85 citation statements)

References 82 publications

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“…In contrast, CSF is more difficult to extract, and the volumes obtained are frequently limited. However, CSF is in direct contact with the brain and constitutes a valuable material for genetic testing in patients with SNC metastases or brain tumors (De Mattos‐Arruda et al , ; Mouliere et al , ; Nevel et al , ; Panditharatna et al , ; Pentsova et al , ; Seoane et al , ; Zhao et al , ). Despite the potential of CSF, PE, or ASC as liquid biopsies, attention at the clinical level has been focused on blood and the performance and clinical utility of prospective molecular profiling in those fluids has not been adequately investigated.…”

Section: Discussionmentioning

confidence: 99%

Prospective detection of mutations in cerebrospinal fluid, pleural effusion, and ascites of advanced cancer patients to guide treatment decisions

et al. 2019

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Many advanced cases of cancer show central nervous system, pleural, or peritoneal involvement. In this study, we prospectively analyzed if cerebrospinal fluid (CSF), pleural effusion (PE), and/or ascites (ASC) can be used to detect driver mutations and guide treatment decisions. We collected 42 CSF, PE, and ASC samples from advanced non‐small‐cell lung cancer and melanoma patients. Cell‐free DNA (cfDNA) was purified and driver mutations analyzed and quantified by PNA‐Q‐PCR or next‐generation sequencing. All 42 fluid samples were evaluable; clinically relevant mutations were detected in 41 (97.6%). Twenty‐three fluids had paired blood samples, 22 were mutation positive in fluid but only 14 in blood, and the abundance of the mutant alleles was significantly higher in fluids. Of the 34 fluids obtained at progression to different therapies, EGFR resistance mutations were detected in nine and ALK acquired mutations in two. The results of testing of CSF, PE, and ASC were used to guide treatment decisions, such as initiation of osimertinib treatment or selection of specific ALK tyrosine–kinase inhibitors. In conclusion, fluids close to metastatic sites are superior to blood for the detection of relevant mutations and can offer valuable clinical information, particularly in patients progressing to targeted therapies.

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Section: Discussionmentioning

confidence: 99%

Prospective detection of mutations in cerebrospinal fluid, pleural effusion, and ascites of advanced cancer patients to guide treatment decisions

et al. 2019

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“…Therefore, in this study, we aimed to compare the results from CSF ctDNA with plasma ctDNA, plasma CTCs, and brain tissue specimens in patients with brain metastasis from NSCLC. The assessment of CSF ctDNA could provide a snapshot of what actually occurs in brain metastases, to more precisely guide therapy . Sequencing of CSF ctDNA revealed specific mutation patterns in driver genes among patients with NSCLC and brain metastases.…”

Section: Discussionmentioning

confidence: 99%

“…The assessment of CSF ctDNA could provide a snapshot of what actually occurs in brain metastases, 11,15 to more precisely guide therapy. [16][17][18] Sequencing of CSF ctDNA revealed specific mutation patterns in driver genes among patients with NSCLC and brain metastases. This is the first study comparing CSF ctDNA, blood ctDNA, CTCs, and brain tissue in patients with NSCLC and brain metastases.…”

Section: Discussionmentioning

confidence: 99%

Detection of circulating tumor DNA from non‐small cell lung cancer brain metastasis in cerebrospinal fluid samples

Yang

Xing

et al. 2020

Thoracic Cancer

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Background Evaluating the molecular characteristics of brain metastases is limited by difficult access and by the blood–brain barrier, which prevents circulating tumor DNA (ctDNA) from entering the blood. In this study, we aimed to compare the sequencing results from cerebrospinal fluid (CSF) ctDNA versus plasma ctDNA, plasma circulating tumor cells (CTCs), and brain tissue specimens from patients with brain metastasis from non‐small cell lung cancer (NSCLC). Methods This was a prospective study of 21 consecutive patients with NSCLC and brain metastasis diagnosed between April 2018 and January 2019. Samples of CSF and peripheral blood were obtained from all 21 patients. Brain tissues were obtained from five patients after surgical resection. Next‐generation sequencing was performed using the Ion system. Single nucleotide variants (SNVs) and small insertions or deletions (indels) were searched. Results Mutations were detected in the CSF ctDNA of 20 (95.2%) patients. The detection rate of epidermal growth factor receptor (EGFR) mutations in CSF ctDNA was 57.1% (12/21) whereas this rate was only 23.8% (5/21) in peripheral blood ctDNA and in CTCs. EGFR mutations were found in the CSF of 9 of 11 (81.8%) patients with leptomeningeal metastases, as compared with three of 10 (30%) patients with brain parenchymal metastases. Mutations were also detected in KIT, PIK3CA, TP53, SMAD4, ATM, SMARCB1, PTEN, FLT3, GNAS, STK11, MET, CTNNB1, APC, FBXW7, ERBB4, and KDR (all >10%). The status of EGFR and TP53 mutations was consistent between CSF ctDNA and brain lesion tissue in all five patients. Conclusion Sequencing of CSF ctDNA revealed specific mutation patterns in driver genes among patients with NSCLC and brain metastasis. Key points In some small‐sample studies, the importance of cerebrospinal fluid in guiding the treatment of cancerous brain lesions has been verified in that it may reflect genomic mutations of brain tumors relatively accurately. Cerebrospinal fluid is a new form of liquid biopsy that can be helpful in improving the management of patients with brain metastasis from non‐small cell lung cancer by detecting genetic abnormalities specific to brain metastases.

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“…It is also of note that the choice of biofluids may affect the performance of liquid biopsy assays. For example, while in glioblastoma the detection of tumor-specific mutations is possible in both peripheral blood and cerebrospinal fluid (Al-Nedawi et al, 2008;Skog et al, 2008;Graner et al, 2009;Figueroa et al, 2017), the latter represents the liquid space more proximal to cancer cells, rendering signal detection more robust (Zachariah et al, 2018;Seoane et al, 2019). Thus, a better understanding of biological processes and regulatory mechanisms that control the release of liquid biopsy analytes may hold the key to a more rational use of biofluid sources, molecular signal recovery methods and detection techniques for specific cancers and medical purposes.…”

Section: Biological Regulators Of Liquid Biopsy Signalsmentioning

confidence: 99%

Leukobiopsy – A Possible New Liquid Biopsy Platform for Detecting Oncogenic Mutations

et al. 2020

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Detection of unique oncogenic alterations encoded by the sequence or biochemical modification in cancer-associated transforming macromolecules has revolutionized diagnosis, classification and management of human cancers. While these signatures were traditionally regarded as largely intracellular and confined to the tumor mass, oncogenic mutations and actionable cancer-related molecular alterations can also be accessed remotely through their recovery from biofluids of either rare circulating tumor cells (CTCs), or of more abundant non-cellular carriers, such as extracellular vesicles (EVs), protein complexes, or cell-free tumor DNA (ctDNA). Tumor-related macromolecules may also accumulate in circulating platelets. Collectively, these approaches are known as liquid biopsy and hold promise as non-invasive, real-time opportunities to access to the evolving molecular landscape of human malignancies. More recently, a possibility of recovering cancer-specific DNA sequences from circulating leukocytes has also been postulated using experimental models. While it is often assumed that these and other liquid biopsy approaches rely on material passively shed from the tumor mass or its debris, recent evidence suggests that several regulated processes contribute to the abundance, nature, half-life, and turnover of different circulating cancer-related molecular signals. Moreover, many of these signals possess biological activity and may elicit local and systemic regulatory responses. Thus, a better understanding of the biology of liquid biopsy platforms and analytes may enable achieving improved performance of this promising and emerging diagnostic strategy in cancer.

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Cerebrospinal fluid cell-free tumour DNA as a liquid biopsy for primary brain tumours and central nervous system metastases

Cited by 114 publications

References 82 publications

Prospective detection of mutations in cerebrospinal fluid, pleural effusion, and ascites of advanced cancer patients to guide treatment decisions

Prospective detection of mutations in cerebrospinal fluid, pleural effusion, and ascites of advanced cancer patients to guide treatment decisions

Detection of circulating tumor DNA from non‐small cell lung cancer brain metastasis in cerebrospinal fluid samples

Leukobiopsy – A Possible New Liquid Biopsy Platform for Detecting Oncogenic Mutations

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