Genomic Profiling of Circulating Tumor DNA From Cerebrospinal Fluid to Guide Clinical Decision Making for Patients With Primary and Metastatic Brain Tumors (original) (raw)
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Cells, 2019
One of the greatest challenges in neuro-oncology is diagnosis and therapy (theranostics) of leptomeningeal metastasis (LM), brain metastasis (BM) and brain tumors (BT), which are associated with poor prognosis in patients. Retrospective analyses suggest that cerebrospinal fluid (CSF) is one of the promising diagnostic targets because CSF passes through central nervous system, harvests tumor-related markers from brain tissue and, then, delivers them into peripheral parts of the human body where CSF can be sampled using minimally invasive and routine clinical procedure. However, limited sensitivity of the established clinical diagnostic cytology in vitro and MRI in vivo together with minimal therapeutic options do not provide patient care at early, potentially treatable, stages of LM, BM and BT. Novel technologies are in demand. This review outlines the advantages, limitations and clinical utility of emerging liquid biopsy in vitro and photoacoustic flow cytometry (PAFC) in vivo for a...
Nature Communications, 2015
Cell-free circulating tumour DNA (ctDNA) in plasma has been shown to be informative of the genomic alterations present in tumours and has been used to monitor tumour progression and response to treatments. However, patients with brain tumours do not present with or present with low amounts of ctDNA in plasma precluding the genomic characterization of brain cancer through plasma ctDNA. Here we show that ctDNA derived from central nervous system tumours is more abundantly present in the cerebrospinal fluid (CSF) than in plasma. Massively parallel sequencing of CSF ctDNA more comprehensively characterizes the genomic alterations of brain tumours than plasma, allowing the identification of actionable brain tumour somatic mutations. We show that CSF ctDNA levels longitudinally fluctuate in time and follow the changes in brain tumour burden providing biomarkers to monitor brain malignancies. Moreover, CSF ctDNA is shown to facilitate and complement the diagnosis of leptomeningeal carcinomatosis.
Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2016
Cancer spread to the central nervous system (CNS) often is diagnosed late and is unresponsive to therapy. Mechanisms of tumor dissemination and evolution within the CNS are largely unknown because of limited access to tumor tissue. We sequenced 341 cancer-associated genes in cell-free DNA from cerebrospinal fluid (CSF) obtained through routine lumbar puncture in 53 patients with suspected or known CNS involvement by cancer. We detected high-confidence somatic alterations in 63% (20 of 32) of patients with CNS metastases of solid tumors, 50% (six of 12) of patients with primary brain tumors, and 0% (zero of nine) of patients without CNS involvement by cancer. Several patients with tumor progression in the CNS during therapy with inhibitors of oncogenic kinases harbored mutations in the kinase target or kinase bypass pathways. In patients with glioma, the most common malignant primary brain tumor in adults, examination of cell-free DNA uncovered patterns of tumor evolution, including ...
Frontiers in Neurology, 2015
Detection of circulating tumor cells (CTCs) in the blood via so-called "liquid biopsies" carries enormous clinical potential in malignancies of the central nervous system (CNS) because of the potential to follow disease evolution with a blood test, without the need for repeat neurosurgical procedures with their inherent risk of patient morbidity. To date, studies in non-CNS malignancies, particularly in breast cancer, show increasing reproducibility of detection methods for these rare tumor cells in the circulation. However, no method has yet received full recommendation to use in clinical practice, in part because of lack of a sufficient evidence base regarding clinical utility. In CNS malignancies, one of the main challenges is finding a suitable biomarker for identification of these cells, because automated systems, such as the widely used Cell Search system, are reliant on markers, such as the epithelial cell adhesion molecule, which are not present in CNS tumors. This review examines methods for CTC enrichment and detection, and reviews the progress in non-CNS tumors and the potential for using this technique in human brain tumors.
Neuro-Oncology, 2018
BACKGROUND: Brain tumors are the second most common malignancy in children, and are the leading cause of death from childhood cancer. Although significant strides have been achieved in improving survival of most childhood malignancies, the outcome for children with brain tumors has remained poor. Advanced imaging techniques can reduce diagnostic uncertainty, but the need to identify better disease markers is immense and remains unmet. In that regard, analysis of circulating biomarkers is a novel and promising avenue for monitoring disease status. Despite increasing use in tumor research, circulating tumor cells (CTCs) have not been studied in pediatric brain tumor and only scarcely investigated in adult brain tumors. METHOD: Based on previous research showing cell surface vimentin (CSV) as a key surface marker for CTC detection, we developed an automated CSV-based CTC capture method for pediatric brain tumor using the Abnova CytoQuest CR CTC isolation platform. With this platform, we processed PBMCs isolated from whole blood samples through the automated system to trap CSV-positive CTCs on to a chip. Captured cells are then stained for CSV and CD45 before automated scanning and detection to determine CTC yield per sample. RESULT: Ten patients were consented on the study, nine patients (3 high grade glioma, 3 brain stem glioma, 1 pineoblastoma, 1 medulloblastoma, 1 atypical teratoid rhabdoid tumor) had an adequate samples for testing, of those 7 had CTC detected from PBMCs. Our results show that brain tumors patients can and do exhibit CSV+ CTCs. These findings do not distinguish between various types of brain malignancies as evidenced by positive CTC isolation in multiple types of gliomas and embryonal tumors. CONCLUSION: Overall, we present the first study of CTCs in pediatric tumors using an automated approach. This is a promising methodology for future tumor risk stratification and treatment response monitoring.
Depending on the tumour type and stage, considerable fractions of patients with cancer will have metastatic disease relapse within 5 years of primary tumour resec-tion despite initially being free of detectable meta stases. Hormone receptor-positive breast cancer is the pro-totypical cancer that is associated with late relapses, which can occur over a period of 20 years (and probably more): among the patients with stage T1 disease, the 20-year risk of distant recurrence is 13% in those with no nodal involvement (T1N0), 20% in those with 1-3 involved nodes (T1N1-3) and 34% in those with 4-9 involved nodes (T1N4-9); among patients with stage T2 disease, the risks are 19%, 26% and 41%, respectively 1. Thus, a considerable fraction of patients with seemingly successful treatment of early stage cancer have occult micrometastases or minimal residual disease (MRD) that persists after initial therapy as a potential source of subsequent metastatic relapse at distant sites. MRD detection and monitoring are established and widely used in patients with haematological malignancies but remain challenging in patients with solid tumours owing to difficulty in sampling the low concentrations of circulating tumour cells (CTCs) or factors shed from the cancer cells into the bloodstream. Over the past few years, considerable advances have been made in the development of technologies to detect blood-based, tumour-specific biomarkers, such as CTCs and circulating cell-free tumour DNA (ctDNA). The advent of real-time, high-sensitivity liquid biopsy assays has enabled the identification of MRD in individual patients with cancer. Herein, we outline the current CTC-based and ctDNA-based approaches for the detection and characterization MRD in patients with solid tumours and discuss the associated challenges. We also highlight the advances that might facilitate implementation of these technologies in future clinical trials designed to test the efficacy of anticancer agents in the neoadjuvant or adjuvant settings. In this context, liquid biopsy assays can be used to monitor MRD, thereby aiding the discovery of new drugs that effectively eliminate or control residual tumour cells in patients who have a high risk of disease relapse after primary therapy. Technologies for the assessment of MRD In the following sections, we provide a brief update focused on current technologies used for the enrichment , detection and characterization of CTCs in blood. Technologies for the analysis of ctDNA present in blood samples have been reviewed in detail elsewhere 2-4. Abstract | Liquid biopsy has been introduced as a new diagnostic concept predicated on the analysis of circulating tumour cells (CTCs) or circulating tumour-derived factors, in particular, cell-free tumour DNA (ctDNA). Highly sensitive liquid biopsy assays have been developed that can now be applied to detect and characterize minimal residual disease (MRD), which reflects the presence of tumour cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumour cells left behind after local therapy that eventually lead to local recurrence. This application is the new frontier of liquid biopsy analyses, which are challenged by the very low concentrations of CTCs and ctDNA in blood samples. In this Review , we discuss the key technologies that can be used to detect and characterize CTCs in surveillance of MRD and provide a brief overview of similar roles of ctDNA analyses. We then focus on the current clinical data on the use of CTCs and ctDNA in the detection and monitoring of MRD and in obtaining information on therapeutic targets and resistance mechanisms relevant to the management of individual patients with cancer.
Liquid biopsy in gliomas: A RANO review and proposals for clinical applications
Neuro-oncology, 2022
Background. There is an extensive literature highlighting the utility of blood-based liquid biopsies in several extracranial tumors for diagnosis and monitoring. Methods. The RANO (Response Assessment in Neuro-Oncology) group developed a multidisciplinary international Task Force to review the English literature on liquid biopsy in gliomas focusing on the most frequently used techniques, that is circulating tumor DNA, circulating tumor cells, and extracellular vesicles in blood and CSF. Results. ctDNA has a higher sensitivity and capacity to represent the spatial and temporal heterogeneity in comparison to circulating tumor cells. Exosomes have the advantages to cross an intact blood-brain barrier and carry also RNA, miRNA, and proteins. Several clinical applications of liquid biopsies are suggested: to establish a diagnosis when tissue is not available, monitor the residual disease after surgery, distinguish progression from pseudoprogression, and predict the outcome. Conclusions. There is a need for standardization of biofluid collection, choice of an analyte, and detection strategies along with rigorous testing in future clinical trials to validate findings and enable entry into clinical practice.
Advanced Biosystems, 2020
Liquid biopsy for the detection and monitoring of central nervous system (CNS) tumors is of significant clinical interest. At initial diagnosis, the majority of patients with central nervous system tumors undergo magnetic resonance imaging (MRI), followed by invasive brain biopsy to determine the molecular diagnosis of the WHO 2016 classification paradigm. Despite the importance of MRI for long-term treatment monitoring, in the majority of patients who receive chemoradiation therapy for glioblastoma (GBM), it can be challenging to distinguish between radiation treatment effects including pseudoprogression, radiation necrosis (RN) and recurrent/ progressive disease (PD) based on imaging alone. Tissue biopsy-based monitoring is high risk and not always feasible. However, distinguishing these entities is of critical importance for management of patients and can significantly affect survival. Liquid biopsy strategies including circulating tumor cells (CTCs), circulating free DNA (CfDNA) and extracellular vesicles (EVs) have the potential to afford significant useful molecular information at both the stage of diagnosis and monitoring for these tumors. We review current liquid biopsy-based approaches in the context of tumor monitoring to differentiate PD from pseudoprogression and RN.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2018
Diffuse gliomas are the most common primary tumor of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies. We performed an analysis of , ATRX, , and gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors. Analysis of the mutational status of the , and genes allowed the classification of 79% of the 64...