Early Detection of Glioblastoma

Historical context and biological basis

Early detection of solid tumors is vital for extending survival and possibly curing patients with cancer. This idea is especially relevant to patients with the most common and most lethal malignant brain tumor, glioblastoma (GBM), because earlier detection would likely increase not only survival but also quality of life. Historically, the more common malignancies, such as breast and colon cancer, paved the way for early discovery of these solid tumors, with mammogram and colonoscopy screenings saving countless lives. However, detecting solid tumors of the brain is a far more difficult task given that it is enclosed in the calvarium and imaging studies are not yet at the technical level to be considered fully diagnostic. In this regard, population-based screening with neurologic examinations and imaging is neither beneficial nor cost-effective. As with other cancers, screening for GBM would require a diagnostic test that has low false-positive rates in order to prevent unnecessary and costly imaging studies and further clinical work-up. Thus, clinicians and researchers have been pursuing biomarkers in the serum and cerebrospinal fluid (CSF) in order to detect GBM early enough for meaningful treatment.

Analyzing biofluids for markers of malignancy was initially pioneered in colorectal cancer with the detection of increased carcinoembryonic antigen (CEA) levels in the serum. However, levels of this normal physiologic protein were not always increased and were associated with numerous other cancer types, limiting its use as a diagnostic biomarker. Other biomarkers soon came to the forefront, such as prostate-specific antigen for prostate cancer and cancer antigen 125 (CA-125) for ovarian cancer; however, the specificities of these tests again failed to meet requirements for a diagnostic test. At present there are more than 20 US Food and Drug Administration–approved tumor biomarker proteins, most of which are used to monitor disease progression and response to therapy. However, GBM does not have a reliable serum biomarker, and initial detection currently relies solely on the presentation of symptoms related to the tumor size and/or location. For this reason, early detection is essential in order to initiate treatment before the patient is symptomatic, which is likely to affect quality of life and progression-free survival.

The ability to detect GBM early, ideally before clinical symptoms arise, is beneficial in 2 distinct ways in the current paradigm of therapeutic management. First, early discovery results in surgical resection of a smaller tumor volume, with likely less impact on surrounding structures compared with that of a larger tumor that is detected only after clinical symptoms are presented (eg, symptoms of speech difficulty, seizures, paralysis). Given that GBM invades into the surrounding tissue, the primary resection of a smaller tumor may necessitate less removal of normal brain parenchyma to prevent recurrence. Secondly, on a molecular genetic level, the total cell count of smaller tumors indicates less genetic variation between the tumor stem cells and their progeny, which can affect their ability to escape both chemotherapy and radiation treatment. Larger tumors have more genetic diversity in their cells, some of which aids in resistance to therapy, evasion of immunosurveillance, and initiation of recurrence.

Specific surface markers and mutations present in GBM may allow early detection in the serum and/or CSF. CSF is especially interesting given that the brain is bathed in this fluid, and there is a greater chance of finding relevant biomarkers because there is no blood-brain barrier to cross. However, collecting CSF is a more invasive process than collecting blood, hence discovery of a serum biomarker would be ideal. In addition, not all GBMs are alike and some respond better to different chemotherapeutic/radiation therapeutic regimens, so an ideal biomarker would be able to distinguish between the various molecular subtypes. Certain aberrations found in many GBMs, such as in the epithelial growth factor receptor (EGFR) and RNA profiling, as well as circulating tumor cells (CTCs) and extracellular vesicles (EVs), have the potential to diagnose GBM and also discriminate between classic, mesenchymal, and proneural subtypes. Thus, a reliable liquid biopsy from the serum or CSF would serve not only to improve GBM diagnosis but also would also affect treatment and surveillance for recurrence.

Development and evidence for biomarkers

Early detection of GBM has focused on the search for tumor-specific biomarkers in the blood and CSF. In this regard, current research concentrates on identifying 3 distinct tumor-related elements; extracellular macromolecules, EVs, and CTCs. Investigations into these 3 categories span the range of biological locales for tumor-specific biomarker discovery, and combined have the potential to affect GBM screening and diagnosis.