Liquid Biopsy Diagnosis of CNS Metastases

  • Mafalda Antunes Ferreira
  • Silvia D’Ambrosi
  • Thomas Würdinger
  • Pieter Wesseling
  • Danijela Koppers-LalicEmail author


The application of liquid biopsy approaches to diagnose cancer and to monitor treatment response has rapidly grown in the last 5 years. The liquid biopsy analysis provides an opportunity to obtain complementary molecular information from different bodily fluids (e.g., blood, urine, cerebrospinal fluid) that may allow for improved management of cancer patients. Apart from cytological and biochemical analysis of cerebrospinal fluid (CSF), the use of liquid biopsy as a diagnostic tool for central nervous system (CNS) metastases is still in its early stage. Identification and more extensive characterization of tumor cells and proteins, but also of circulating tumor DNA (ctDNA) and different forms of RNA in CSF, is increasingly pursued in order to improve the diagnosis and management of patients with CNS metastases. Furthermore, the utility of liquid biopsies for monitoring treatment responses of patients with CNS metastases is beginning to be explored. Although several challenges remain, current technological progress in assay development will allow to tackle limitations imposed by lack of standardized and validated methods for liquid biopsy-based diagnostics of CNS metastases. Inclusion of liquid biopsies in the design of longitudinal cohort studies with combined analysis of various liquid biopsy biosources is expected to advance the discovery of reliable molecular biomarkers for prediction and early detection of CNS metastases. As the result, novel treatment modalities may become available for patients at high risk of CNS metastases, preventing their future occurrence and thereby improving patient outcomes.


Liquid biopsy CNS metastases CSF Blood Biosources DNA RNA 



Branched-chain amino acids


Cell-free DNA


Cell-free RNA


Circular RNA


Circulating nucleic acids


Central nervous system


Copy number variation


Circulating proteins


Cerebrospinal fluid


Circulating tumor cell


Circulating tumor-derived DNA


Carcinoma of unknown primary


Digital droplet PCR


Double-stranded DNA


Epidermal growth factor receptor


European Medicines Agency


Epithelial to mesenchymal transition


Epithelial cell adhesion molecule


European Society of Medical Oncology


Extracellular vesicles


Flow cytometry


US Food and Drug Administration


Formalin-fixed paraffin-embedded


Human epidermal growth factor receptor


Diagnostic medical device


Lactate dehydrogenases


Leptomeningeal metastases


Long non-coding RNA


Loss of heterozygosity




Messenger RNA


Next-generation sequencing


Non-small cell lung cancer


Polymerase chain reaction


Positive predictive value


Particle swarm optimization


Single-stranded DNA


Tumor-educated platelets


Tumor microenvironment


Whole-exome sequencing


Whole-genome sequencing



The authors apologize for not citing all the studies, technologies, and clinical trials on the topic of liquid biopsies and CNS metastases in this chapter. The authors thank L. Salvador for his assistance in drafting the figure included in this chapter. The work of authors M.A.F., S.D., D.K.L., and T.W. is supported by H2020 MSCA ITN ELBA GA#765492, and D.K.L. is a recipient of the Dutch Cancer Foundation grant (KWF2017-10476) and the Cancer Center Amsterdam foundation grant (CCA2017-2-16).


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Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Mafalda Antunes Ferreira
    • 1
  • Silvia D’Ambrosi
    • 1
  • Thomas Würdinger
    • 1
  • Pieter Wesseling
    • 2
    • 3
  • Danijela Koppers-Lalic
    • 1
    Email author
  1. 1.Department of NeurosurgeryCancer Center Amsterdam, Amsterdam Universities Medical Centers/VU University Medical CenterAmsterdamThe Netherlands
  2. 2.Department of PathologyBrain Tumor Center Amsterdam, Amsterdam Universities Medical Centers/VU University Medical CenterAmsterdamThe Netherlands
  3. 3.Princess Maxima Center for Pediatric OncologyUtrechtThe Netherlands

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