Glioblastoma (GBM) is the most common type of primary brain cancer in adults.
Despite advances in surgery, radiotherapy, and chemotherapy, GBM remains one of the most aggressive malignancies, with a median survival of 15 months from diagnosis. GBM arises from glial cells, which support and protect neurons, and is distinct from secondary brain tumours which originate as metastases from cancers elsewhere in the body. Although other types of glioma can affect individuals of all ages—including children, adolescents, and young adults—GBM is most frequently diagnosed in older adults.
GBM’s highly invasive growth makes complete surgical resection virtually impossible, and its complex biology, including rapid proliferation, genetic heterogeneity, and resistance to standard therapies, severely limits the effectiveness of current treatment options.
Only a small number of drugs are currently approved for GBM treatment. However, a growing number of advanced therapies are entering clinical trials, driven by the identification of actionable biomarkers. This shift toward a biomarker-guided approach offers renewed hope for improving outcomes in this aggressive disease.
Key statistics
1st
GBM is the most common and aggressive primary malignant brain tumour in adults
~250,000
people living with GBM worldwide
<6%
5-year survival rate for GBM patients
15 months
median survival
Current challenges for GBM diagnostics and potential benefits of including liquid biopsy
Limitations of tissue-based biopsies
Tissue biopsy is challenging due to the location of glioblastomas and biomarker analysis is usually performed after surgical resection.
For this reason, repeated biopsies and longitudinal monitoring of biomarkers is impractical using tissue samples.
Furthermore, 16-40% of patients are inoperable due to the location of the tumour or co-morbidities, further reducing access to biomarker testing.
Benefits of liquid biopsy
In many other cancer types, blood-based liquid biopsies are already enabling minimally-invasive biomarker testing.
In GBM, circulating tumour cells (CTCs) from liquid biopsy would enable real-time tracking of tumour evolution through repeated sampling.
CTCs would also provide an alternative for patients who cannot undergo surgical biopsy due to tumour location or health status.
ctDNA is not a viable analyte for glioblastoma
A landmark study by Bettegowda et al. (2014) evaluated ctDNA detectability in over 600 patients across multiple cancer types. It demonstrated that ctDNA is detectable in fewer than 10% of glioma patients, compared to over 75% of patients with advanced cancers like colorectal, pancreatic, and breast. This finding highlights the limitations of ctDNA in brain tumours.
- Study revealed stage-dependent variability, with lower ctDNA detection in early-stage disease and brain tumours
- Detection rate of ctDNA in glioma was <10%.
- This highlights the need for an alternative liquid biopsy approach in cancers with low ctDNA yield.
Figure: Bar graph showing the percentage of patients with detectable ctDNA across cancer types. Error bars represent detection range. Glioma (circled) had the lowest ctDNA detection rate. Source: Bettegowda et al., Sci Transl Med, 2014.
CTCs for non-invasive GBM assessment
- Circulating tumour cells (CTCs) have been successfully identified in various glioma subtypes, including glioblastoma (GBM) with detection rates up to 77%, highlighting the strong potential of CTC-based liquid biopsies in GBM.
- Since the discovery of CTCs in GBM, they have been analysed using a wide range of assays including digital PCR, next-generation sequencing, immunofluorescence and DNA-FISH.
- ANGLE’s Parsortix® system is one of the most widely validated CTC isolation systems and multiple groups have successfully applied it with GBM CTCs.
- One of the key benefits of the Parsortix system is that it is label-free and therefore captures both epithelial and mesenchymal CTCs, which is essential in GBM where epithelial to mesenchymal transition is very common.
- By enabling both visualisation and molecular analysis of CTCs, the Parsortix system supports deeper understanding of GBM biology.
Key evidence for CTCs in GBM
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Circulating tumor cell is a common property of brain glioma and promotes the monitoring system
Gao F et al. 2016
-
Detection of circulating tumour cell clusters in human glioblastoma
Krol I et al 2018
-
Innovative Approach to Isolate and Characterize Glioblastoma Circulating Tumor Cells and Correlation with Tumor Mutational Status
Lessi et al. 2023
-
Use of circulating tumor cells and microemboli to predict diagnosis and prognosis in diffuse glioma
Qi et al. 2024
Circulating tumor cell is a common property of brain glioma and promotes the monitoring system
Gao F et al. 2016
- CTCs were tested in 31 patients with 7 different glioma subtypes (including GBM).
- CTCs were identified by copy number analysis of chromosome 8 & CD45 negativity.
- Circulating tumour cells (CTCs) were detected in 77% of patients across subtypes, suggesting CTCs are a common feature of brain gliomas.
- Detection was independent of glioma subtype or WHO grade, indicating broad applicability.
Detection of circulating tumour cell clusters in human glioblastoma
Krol I et al 2018
- The first published study to characterise CTCs and CTC clusters isolated from GBM patients’ blood using the Parsortix system.
- CTC clusters, ranging from 2 to 23 cells, were observed at multiple time points during disease progression.
- Exome sequencing revealed mutations in 58 cancer-associated genes, including ATM, JAK2, and ERBB4.
- “These findings highlight the use of CTCs as a blood-based analyte for non-invasive GBM assessment”
Innovative Approach to Isolate and Characterize Glioblastoma Circulating Tumor Cells and Correlation with Tumor Mutational Status
Lessi et al. 2023
- In this study the authors used the Parsortix system to optimise a method to characterise circulating tumour cells (CTCs) in glioblastoma (GBM) patients.
- Single CTCs were genetically profiled and compared with primary and recurrent tumour tissue.
- CTCs shared key mutations with the parental tumour, confirming their origin and supporting their relevance in disease monitoring.
Use of circulating tumor cells and microemboli to predict diagnosis and prognosis in diffuse glioma
Qi et al. 2024
- CTCs were detected in over 84% of glioma patients.
- High CTC levels were linked to IDH-wildtype status and higher grade.
- Elevated postoperative CTCs predicted shorter survival in GBM patients (median OS: 124 days vs. not reached).
- These findings demonstrate that CTCs are a predictor of the prognosis of diffuse glioma.
Circulating tumor cell is a common property of brain glioma and promotes the monitoring system
Gao F et al. 2016
- CTCs were tested in 31 patients with 7 different glioma subtypes (including GBM).
- CTCs were identified by copy number analysis of chromosome 8 & CD45 negativity.
- Circulating tumour cells (CTCs) were detected in 77% of patients across subtypes, suggesting CTCs are a common feature of brain gliomas.
- Detection was independent of glioma subtype or WHO grade, indicating broad applicability.
Detection of circulating tumour cell clusters in human glioblastoma
Krol I et al 2018
- The first published study to characterise CTCs and CTC clusters isolated from GBM patients’ blood using the Parsortix system.
- CTC clusters, ranging from 2 to 23 cells, were observed at multiple time points during disease progression.
- Exome sequencing revealed mutations in 58 cancer-associated genes, including ATM, JAK2, and ERBB4.
- “These findings highlight the use of CTCs as a blood-based analyte for non-invasive GBM assessment”
Innovative Approach to Isolate and Characterize Glioblastoma Circulating Tumor Cells and Correlation with Tumor Mutational Status
Lessi et al. 2023
- In this study the authors used the Parsortix system to optimise a method to characterise circulating tumour cells (CTCs) in glioblastoma (GBM) patients.
- Single CTCs were genetically profiled and compared with primary and recurrent tumour tissue.
- CTCs shared key mutations with the parental tumour, confirming their origin and supporting their relevance in disease monitoring.
Use of circulating tumor cells and microemboli to predict diagnosis and prognosis in diffuse glioma
Qi et al. 2024
- CTCs were detected in over 84% of glioma patients.
- High CTC levels were linked to IDH-wildtype status and higher grade.
- Elevated postoperative CTCs predicted shorter survival in GBM patients (median OS: 124 days vs. not reached).
- These findings demonstrate that CTCs are a predictor of the prognosis of diffuse glioma.
Potential applications for CTCs in GBM research and clinical development
Biomarker detection
Genomic, transcriptomic, epigenetic & proteomic profiling of CTCs may help classify patients for selection of targeted therapies & enrolment into clinical trials.
The ability to capture and harvest CTCs is especially valuable for biomarker testing in cases where tissue is not available.
Determination of MGMT promoter hyper-methylation in CTCs may aid in the selection of patients most likely to benefit from temozolomide (TMZ) treatment when no tissue sample is available.
Longitudinal monitoring
Invasive tissue biopsies make monitoring of GBM biomarkers over time impractical.
CTCs from blood samples enable longitudinal monitoring of therapeutic resistance & sensitivity.
Prognosis
Mesenchymal CTCs are a prominent feature in GBM & their presence & characterisation offer insights into disease progression & treatment resistance in GBM patients.8
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Resources related to glioblastoma
Publications
June, 2023
Innovative Approach to Isolate and Characterize Glioblastoma Circulating Tumor Cells and Correlation with Tumor Mutational Status
Fondazione Pisana per la Scienza, San Giuliano Terme, Pisa, Italy, published by International Journal of Molecular Sciences
For Research Use Only. Not For Use in Diagnostic Procedures.
References
1. Bettegowda C, Sausen M, Leary RJ, et al. Detection of circulating tumor DNA in early- and late-stage human malignancies. Sci Transl Med. 2014;6(224):224ra24. 2. Circulating tumor cell is a common property of brain glioma and promotes the monitoring system. Gao F, Cui Y, Jiang H, et al. Oncotarget. 2016;7(44):71330-71340. 3. Detection of circulating tumour cell clusters in human glioblastoma. Krol I, Castro-Giner F, Maurer M, et al. Br J Cancer. 2018;119(4):487-491. doi:10.1038/s41416-018-0186-7. 4. Innovative Approach to Isolate and Characterize Glioblastoma Circulating Tumor Cells and Correlation with Tumor Mutational Status. Lessi F, Morelli M, Franceschi S, et al. Int J Mol Sci. 2023;24(12):10147. 5. Use of circulating tumor cells and microemboli to predict diagnosis and prognosis in diffuse glioma. Qi Y, Xu Y, Yan T, et al. J Neurosurg. 2024;141(3):673-683.