Liquid biopsy may improve detection of brain tumor mutations
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Key takeaways:
- An optimized digital droplet polymerase chain reaction blood test showed high sensitivity and specificity in detection of EGFRvIII mutations.
- Longitudinal monitoring of four patients also demonstrated the assay’s ability to detect EGFRvIII levels in plasma of patients with different clinical outcomes.
- If approved, the assay would provide a safer and more cost-effective method to genetically profile a patient’s tumor, according to researchers.
Researchers at Massachusetts General Hospital have developed a new blood test to detect epidermal growth factor receptor mutations in patients with glioma — one of the most common brain cancers in adults.
If successfully commercialized, the liquid biopsy technology — evaluated in a study published in Clinical Cancer Research — may allow clinicians to order a noninvasive blood test that will help more accurately diagnose the disease, guide treatment options and evaluate responses to therapy, the investigators noted.
Background
In previous research, the group at Mass General detected circulating tumor mRNA using a digital droplet polymerase chain reaction blood test. The test allowed researchers to identify two mutations of the gene TERT, another common mutation found in glioma tumors, Leonora Balaj, PhD, investigator at Mass General's Brain Tumor Research Center and assistant professor of neurosurgery at Harvard Medical School, told Healio.
Previous studies have shown that aggressive gliomas often express EGFRvIII and that the mutation can be detected in blood plasma “but with low sensitivity,” Balaj said.
“That was in 2008, and since then it has been extremely difficult to reproduce the results or improve on the detection rate,” she added.
Balaj’s group has successfully adapted the PCR assay so that it detects EGFRvIII with high sensitivity in both tumor tissue and in the circulating extracellular vesicle RNA of patients with glioma.
“The results of the study are proof of principle, and we are now working with regulators and our commercial partner to validate the findings to bring this test to the clinic,” Balaj said.
Methodology
Balaj and colleagues evaluated tumor tissue and blood specimens of 54 adults who underwent surgery at Mass General for biopsy or resection of a primary brain lesion. The study included 30 patients with confirmed EGFRvIII-positive disease, 10 with EGFR wild-type glioma and 14 age-matched healthy control patients.
Investigators used quantitative PCR to detect EGFRvIII mutations in tumor tissue and optimized digital droplet PCR to evaluate EGFRvIII mutations in patient plasma samples.
Key findings
The optimized digital droplet PCR assay showed sensitivity of 73% (95% CI, 64-82) and specificity of 98% (95% CI, 87-100) to detect EGFRvIII mutations compared with quantitative PCR tissue analysis in both discovery and blinded validation cohorts.
Longitudinal monitoring of four patients also demonstrated the digital droplet PCR assay’s ability to detect EGFRvIII levels in plasma of patients with different clinical outcomes. Results showed rising levels upon disease progression and decreasing levels as patients responded to treatment, the investigators noted.
Clinical implications
Balaj said the assay still needs to be validated by HHS’s Clinical Laboratory Improvement Amendments (CLIA) process before becoming available for clinical use — a process she said is underway with the help of a special NIH grant and the work of their commercial partner. Even after approval, both the TERT and EGFR assays will require utility studies in larger populations.
If approved, the assay would provide a safer and more cost-effective method to genetically profile a patient’s tumor, Balaj told Healio.
"Not all patients are good candidates for biopsy, whether because of age or comorbidities,” she said. “But if it is obvious from MRI that a patient has glioma, then a quick test to detect for mutations can help patients avoid possible biopsy and then go straight to chemoradiotherapy."
Another large application for the test will be monitoring after the start of treatment, Balaj noted.
"We can see the number of mutations go up and down with treatment, which is an indirect readout about whether the patient is responding," she said.
Because EGFRvIII is a cell surface marker, the assay can help stratify which patients may be eligible for ongoing clinical trials of targeted therapies, including chimeric antigen receptor T cells and multispecific T-cell engagers.
Balaj said her group is working on a third assay to detect IDH1. Once it is validated, they hope to combine all three assays into a single diagnostic that can provide a comprehensive genetic profile of glioma tumors and thereby guide patient-centered treatment to target specific mutations.
"This could be a huge advance that may allow us to stratify patients, monitor their progress and open them up to a world of possible studies to treat their disease,” she said.
For more information:
Leonora Balaj, PhD, can be reached at Brain Tumor Research Center, Massachusetts General Hospital, Simches Research Building, 185 Cambridge St., Boston, MA 02114; email: balaj.leonora@mgh.harvard.edu.
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