A new liquid biopsy approach developed by Johns Hopkins Kimmel Cancer Center investigators could revolutionize brain cancer detection by identifying circulating DNA fragments from tumors and immune cells in blood samples, potentially enabling earlier diagnosis.
A description of the work was published April 29 in Cancer Discovery. The research was partially supported by the National Institutes of Health.
Brain cancers are notoriously hard to detect. As a result, many patients receive a diagnosis at a late stage after experiencing symptoms like headaches, seizures or cognitive problems. Late diagnosis limits treatment options and often leads to worse patient outcomes. Previous attempts to find biomarkers in a patient's blood have failed because the blood-brain barrier that protects the brain from infection may also prevent potential biomarkers from reaching the blood.
To overcome this challenge, Victor E. Velculescu, M.D., Ph.D., co-director of cancer genetics and epigenetics at the cancer center, and his colleagues created a "next generation" liquid biopsy approach that they've previously shown effective for detecting lung cancer and is now in clinical use for lung cancer screening. The technique uses machine learning, a form of artificial intelligence (AI), to identify patterns of DNA fragments circulating in the blood linked to brain tumors. It also searches for repeating patterns in the genome linked to brain cancer.
Using this technique, investigators successfully detected brain cancer about three-quarters of the time in a cohort of 505 patients from the United States and South Korea. The team verified the results in a second set of about 95 patients from Poland. Previous liquid biopsy approaches have only been able to detect brain cancers less than 10% of the time.
"Our next-generation AI liquid biopsy approach combining DNA fragments and repeating genome patterns may accelerate brain cancer diagnosis," says Velculescu, senior author of the study. "It may ultimately allow patients to get care earlier, improving their treatment outcomes."
One factor that led to the success of this approach is that it detected immune changes associated with brain cancer. Patients with brain cancer have immune suppression throughout their body and a unique immune cell profile in the blood. These immune differences do not have to pass through the blood-brain barrier to be detected, explains lead study author Dimitrios Mathios, M.D., who completed the research during his fellowship in cancer immunology, genetics and epigenetics at Johns Hopkins.
"We finally have a way of detecting brain cancer that takes advantage of its unique characteristics, including genome-wide fragmentation from brain cancer and immune cell changes," says Mathios, who is now an assistant professor of neurosurgery and genetics at Washington University School of Medicine in St. Louis. "Some of the signals we detect come from the cancer itself in the brain, and some of them come from the immune system's response to the cancer."
Next, the team ran a computer simulation of what would happen if their liquid biopsy method were used to screen the estimated 10 million patients presenting with headaches to the emergency room or primary care clinics each year. Usually, these individuals are only referred for brain imaging if their physician suspects an underlying problem. But in the simulation, sending patients who received a liquid biopsy result suggestive of brain cancer for imaging would result in the detection of nearly 1,700 more cancer cases than the usual approach.
The next step for the team will be designing a prospective trial to confirm these findings in larger patient populations who are at increased risk of brain cancer.
Other co-authors included Noushin Niknafs, Akshaya V. Annapragada, Elaine J. Chiao, Kavya Boyapati, Keerti Boyapati, Sarah Short, Adrianna Bartolomucci, Stephen Cristiano, Shashikant Koul, Nicholas A. Vulpescu, Leonardo Ferreira, Jamie Medina, Daniel C. Bruhm, Vilmos Adleff, Judy Huang, Gary L. Gallia, Henry Brem, Debraj Mukherjee, Justin M. Caplan, Jon Weingart, Christopher Jackson, Jillian Phallen and Robert B. Scharpf of Johns Hopkins. Researchers from Washington University in St. Louis, the Medical University of Lodz in Poland, and Stanford University also contributed.
The study was supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Gray Foundation, the Commonwealth Foundation, the Mark Foundation for Cancer Research, Conquer Cancer, the American Society of Clinical Oncology Foundation, the American Association for Cancer Research, the Cole Foundation, a grant from Delfi Diagnostics, and grants from the NIH (grant numbers CA12113, CA006973, CA233259, CA062924, CA271896, 1T32GM136577 and T32GM148383).
Mathios, Niknafs, Scharpf and Velculescu have a patent application for cell-free DNA brain cancer detection submitted by The Johns Hopkins University. Mathios, Bruhm, Phallen, Scharpf and Velculescu have patent applications submitted by The Johns Hopkins University for cell-free DNA for cancer detection that have been licensed to DELFI Diagnostics. Phallen, Adleff and Scharpf are founders of DELFI Diagnostics, and Adleff and Scharpf are consultants for this organization. Velculescu is a founder of DELFI Diagnostics, serves on the board of directors and owns Delfi Diagnostics stock, which is subject to certain restrictions under university policy. In addition, The Johns Hopkins University owns equity in Delfi Diagnostics. Velculescu divested his equity in Personal Genome Diagnostics (PGDx) to LabCorp in February 2022. Velculescu is an inventor on patents and patent applications submitted by The Johns Hopkins University related to cancer genomic analyses and cell-free DNA for cancer detection that have been licensed to one or more entities, including DELFI Diagnostics, LabCorp, QIAGEN, Sysmex, Agios, Genzyme, Esoterix, Ventana and ManaT Bio. Under the terms of these license agreements, the university and inventors are entitled to fees and royalty distributions. Velculescu is an adviser to Viron Therapeutics and Epitope. These arrangements have been reviewed and approved by The Johns Hopkins University in accordance with its conflict-of-interest policies.
