Liquid biopsy for pediatric diffuse midline glioma: a review of circulating tumor DNA and cerebrospinal fluid tumor DNA

Azad, Tej D.; Jin, Michael C.; Bernhardt, Lydia J.; Bettegowda, Chetan

doi:10.3171/2019.9.focus19699

Cited by 52 publications

(41 citation statements)

References 57 publications

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“…[87] However, emerging studies have reported the detection of tumor specific mutations in the cfDNA of patients with glioma ( Table 2). [87,[98][99][100][101][102][103][104][105][106][107][108][109][110] Detection of glioma specific alterations such as telomerase reverse transcriptase (TERT), [105,111] EGFRvIII, [102] IDH1, [108] and histone mutations [112] has shown promise in minimally invasive diagnosis, molecular profiling, and classification of tumors. Epidermal growth factor receptor (EGFR) gene is amplified in 30-40% of GBMs and nearly 50% of them express the in-frame deleted variant of EGFR receptor, EGFRvIII, and represents an aggressive subtype of GBM.…”

Section: Circulating Tumor Dnamentioning

confidence: 99%

Liquid Biopsy Strategies to Distinguish Progression from Pseudoprogression and Radiation Necrosis in Glioblastomas

et al. 2020

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despite aggressive treatment. [1] Currently, maximal resection followed by radiation therapy with concurrent temozolomide (TMZ) and adjuvant TMZ treatment is the standard of care. Post-treatment surveillance involves serial MRI. A challenge faced by clinicians is the diagnosis and management of a gadolinium enhancing lesion on a follow-up MRI post-treatment. This suspicious lesion could be progressive disease (PD) or a mere post-treatment radiation effects such as pseudoprogression or radiation necrosis (RN). Pseudoprogression and RN are distinct clinical entities, which when identified and managed appropriately result in better outcomes, while PD of the tumor is often dismal. Patients with PD have a median survival of 3-6 months, [2] and there is no standard of care. Systemic options include TMZ rechallenge, lomustine, and antiangiogenic therapy such as bevacizumab, but their effectiveness is limited. Reradiation and reresection can be considered depending on the location of the tumor and the condition of the patient. [3] Conversely, antiangiogenic drugs like bevacizumab or cediranib decrease contrast enhancement by altering permeability of tumor vasculature without actual reduction in tumor burden, referred to as pseudoresponse. Distinguishing these clinical entities from PD is crucial to avoid unnecessary reoperations, premature discontinuation of adjuvant TMZ or its substitution with second line agents. MR imaging based monitoring is the current standard of care for post-surgical monitoring. Contrast enhancement on imaging is indicative of disrupted blood brain barrier (BBB), but not tumor presence. [4] Currently, MRI-based Response Assessment in Neuro-Oncology (RANO) criteria is used to monitor treatment response in GBM patients. The criteria included T1 gadolinium enhancing disease, T2/FLAIR changes, new lesions, corticosteroid use, and clinical status. [5] Adoption of RANO criteria for monitoring response is not without limitations. There is ambiguity in identifying radiation effects, enrolling patients into clinical trials and monitoring immunotherapy response. [6] Advanced imaging modalities including diffusion-tensor imaging, perfusion imaging, MR spectroscopy (MRS), and positron emission tomography (PET) imaging Liquid biopsy for the detection and monitoring of central nervous system 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, it can be challenging to distinguish between radiation treatment effects including pseudoprogression, radiation necrosis, and recurrent/progressive disease based on imaging alone. Tissue biopsy-based monitoring is high risk and not always feasible. However, distinguishing these entities is of critical im...

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Section: Circulating Tumor Dnamentioning

confidence: 99%

Liquid Biopsy Strategies to Distinguish Progression from Pseudoprogression and Radiation Necrosis in Glioblastomas

et al. 2020

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“…In addition, the availability of targeted therapy has increased the need for longitudinal monitoring of molecular changes within tumors in order to precisely guide anti-cancer treatment. Hence, there is a compelling need for the indirect assessment of tumors at certain time points via less-invasive tumor markers which can be gained from body fluids of the patient [ 6 , 7 ]. The most proximal source for liquid biopsy for pediatric brain tumors is the cerebrospinal fluid (CSF) followed by peripheral blood including its components serum/plasma and urine [ 8 ] ( Figure 1 ).…”

Section: Introductionmentioning

confidence: 99%

“…Multiple different molecular structures have been identified in the liquids of pediatric brain tumor patients and raised the interest of the scientific field. These biomarkers include circulating tumor cells (CTCs) [ 18 , 19 ], circulating tumor DNA (ctDNA) [ 7 , 18 , 19 ], cell-free DNA (cfDNA) [ 6 , 18 , 19 , 20 , 21 ], circulating proteins [ 6 , 8 , 19 , 20 ], extracellular vesicles and exosomes [ 5 , 18 , 22 , 23 , 24 , 25 , 26 ], micro-RNAs (miRNAs) [ 5 , 19 , 27 , 28 , 29 , 30 , 31 , 32 ], long non-coding RNA (lncRNA) [ 33 ] and other genetic alterations [ 28 , 34 , 35 , 36 , 37 , 38 ]. Detection of these biomolecules may offer advantages compared to surgical interventions.…”

Section: Introductionmentioning

confidence: 99%

Liquid Biomarkers for Pediatric Brain Tumors: Biological Features, Advantages and Perspectives

Madlener

Gojo

2020

JPM

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Tumors of the central nervous system are the most frequent solid tumor type and the major cause for cancer-related mortality in children and adolescents. These tumors are biologically highly heterogeneous and comprise various different entities. Molecular diagnostics are already well-established for pediatric brain tumors and have facilitated a more accurate patient stratification. The availability of targeted, biomarker-driven therapies has increased the necessity of longitudinal monitoring of molecular alterations within tumors for precision medicine-guided therapy. Nevertheless, diagnosis is still primarily based on analyses of the primary tumor and follow-up is usually performed by imaging techniques which lack important information on tumor biology possibly changing the course of the disease. To overcome this shortage of longitudinal information, liquid biopsy has emerged as a promising diagnostic tool representing a less-invasive source of biomarkers for tumor monitoring and therapeutic decision making. Novel ultrasensitive methods for detection of allele variants, genetic alterations with low abundance, have been developed and are promising tools for establishing and integrating liquid biopsy techniques into clinical routine. Pediatric brain tumors harbor multiple molecular alterations with the potential to be used as liquid biomarkers. Consequently, studies have already investigated different types of biomarker in diverse entities of pediatric brain tumors. However, there are still certain pitfalls until liquid biomarkers can be unleashed and implemented into routine clinical care. Within this review, we summarize current knowledge on liquid biopsy markers and technologies in pediatric brain tumors, their advantages and drawbacks, as well as future potential biomarkers and perspectives with respect to clinical implementation in patient care.

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“…Current applications of liquid biopsy for glioblastoma diagnosis have to be improved for two main reasons: although in normal physiological conditions the BBB prevents ctDNA circulating into the blood, in pathological situations (i.e., presence of glioblastoma) the BBB is disrupted, which allows for EVs and other cell-free nucleic acids to cross it; and the detection of all cell-free nucleic acids remains a challenge due to the low amounts in the blood in the early course of the disease [2]. However, various new approaches and methods are being developed, such as detecting cell-free nucleic acids (cfDNA and cfRNA) with digital droplet PCR (ddPCR) [99,100] and stabilizing cell-free nucleic acids in the blood [101]. With the development of more sensitive methods, the forthcoming diagnosis of glioblastomas with liquid biopsy will be less demanding.…”

Section: Cell Free Circulating Tumor Dnamentioning

confidence: 99%

Nanomedicine and Immunotherapy: A Step Further towards Precision Medicine for Glioblastoma

et al. 2020

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Owing to the advancement of technology combined with our deeper knowledge of human nature and diseases, we are able to move towards precision medicine, where patients are treated at the individual level in concordance with their genetic profiles. Lately, the integration of nanoparticles in biotechnology and their applications in medicine has allowed us to diagnose and treat disease better and more precisely. As a model disease, we used a grade IV malignant brain tumor (glioblastoma). Significant improvements in diagnosis were achieved with the application of fluorescent nanoparticles for intraoperative magnetic resonance imaging (MRI), allowing for improved tumor cell visibility and increasing the extent of the surgical resection, leading to better patient response. Fluorescent probes can be engineered to be activated through different molecular pathways, which will open the path to individualized glioblastoma diagnosis, monitoring, and treatment. Nanoparticles are also extensively studied as nanovehicles for targeted delivery and more controlled medication release, and some nanomedicines are already in early phases of clinical trials. Moreover, sampling biological fluids will give new insights into glioblastoma pathogenesis due to the presence of extracellular vesicles, circulating tumor cells, and circulating tumor DNA. As current glioblastoma therapy does not provide good quality of life for patients, other approaches such as immunotherapy are explored. To conclude, we reason that development of personalized therapies based on a patient’s genetic signature combined with pharmacogenomics and immunogenomic information will significantly change the outcome of glioblastoma patients.

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Liquid biopsy for pediatric diffuse midline glioma: a review of circulating tumor DNA and cerebrospinal fluid tumor DNA

Cited by 52 publications

References 57 publications

Liquid Biopsy Strategies to Distinguish Progression from Pseudoprogression and Radiation Necrosis in Glioblastomas

Liquid Biopsy Strategies to Distinguish Progression from Pseudoprogression and Radiation Necrosis in Glioblastomas

Liquid Biomarkers for Pediatric Brain Tumors: Biological Features, Advantages and Perspectives

Nanomedicine and Immunotherapy: A Step Further towards Precision Medicine for Glioblastoma

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