How Liquid Biopsy Could Improve Brain Tumor Treatment and Diagnoses

Today, when surgeons operate on a brain tumor, they must consider how much tissue to remove without impairing vital brain functions including cognition, speech and language, movement and sensation of limbs or memory. Tumors inoperable due to their location require a surgical biopsy for tissue diagnosis, which carries risk. Bob Carter, MD, PhD, chief of Neurosurgery at Massachusetts General Hospital, warns, “Every time you pass a biopsy probe, even in the best of hands, there’s a chance of hemorrhage and other risks.”

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A liquid biopsy, which is the analysis of blood or cerebral spinal fluid to detect cancer, is poised to reduce the need for tissue biopsies that require a surgical procedure to open the skull. Ideally, liquid biopsies can be used for many types of cancers, but the potential advantages of a liquid biopsy are especially poignant for brain tumors.

Liquid biopsies have two significant advantages:

1. They provide ongoing real-time, accurate genetic and molecular information about a patient’s tumor as opposed to tissue biopsies, which are often done once or twice in a patient’s disease course. The ability to monitor and detect mutations in real-time may allow highly personalized treatment for each patient.
2. They are less invasive than traditional surgical biopsy. Mass General researchers have identified exosomes, circulating tumor cells and circulating DNA/RNA in the blood of patients with brain tumors, all of which can be sampled through a blood test. This simple blood draw spares a patient from having an invasive brain biopsy and may be able to provide a great deal of information about the patient’s tumor.

Roles of Exosomes and Circulating Tumor Cells in Brain Tumors

Leading the discovery of this promising new technology and its translation to clinical care is a multidisciplinary team of Mass General neurosurgeons, scientists and bioengineers who launched the liquid brain biopsy field. In 2008, they made their landmark finding that glioblastoma exosomes transport RNA and protein to promote tumor growth and can serve as diagnostic markers of the cancer. Mass General researchers have continued to advance the field with the development of the first device to identify and capture circulating tumor cells in the blood of patients with brain tumors.

Brian Nahed, MD, MSc, a neurosurgeon at Mass General, says, “Developing a blood test for brain tumors may provide patients the first ability in real-time to diagnose brain tumors, monitor the response to therapy and detect recurrence. It will be a game changer.”

Liquid Biopsy and the Brain

Brain tumors are heterogeneous masses with areas of varied mutations and genetic changes. For example, some brain biopsies might produce a sample of tissue that is negative for a specific oncogenic mutant form of protein known as EGFR vIII. However, the adjacent tissue might test positive for it. Missing the presence of EGFR vIII in a tissue biopsy is problematic because its manifestation is a powerful determinant for designing an optimal therapeutic course for a patient.

“With a normal biopsy we may not always get a full picture of a tumor’s mutational status due to heterogeneity within the tumor.” Dr. Carter says.

A liquid biopsy could more accurately characterize the tumor because as blood passes through the entire tumor, circulating tumor cells or exosomes shed from the tumor enter the blood. Also, liquid biopsies may help prevent additional invasive procedures to distinguish whether abnormal appearances on brain imaging are treatment-induced changes or disease recurrence; the two can appear the same but have very different prognostic implications. The Mass General team is focused on capturing these circulating tumor cells and exosomes. This will provide detailed information, which is not vulnerable to the “hit or miss” surgical removal of discrete tissue samples in a tissue biopsy. It will also help distinguish treatment-induced change from recurrent tumor.

However, currently, liquid biopsies are still imperfect at capturing and identifying the exosomes and circulating tumor cells from the other components in the blood. Liquid biopsies sensitivity therefore remains a pressing area of research as the Mass General team aims to translate liquid biopsies into widespread clinical use for brain tumors.

As a first clinical step, Dr. Carter and Dr. Nahed are studying brain tumor patients at diagnosis as well as during and after chemotherapy and radiation treatment. They intend to develop the first liquid biopsy to differentiate between normal inflammation and malignant tumor and cell death that occurs during treatment and active tumor growth; this capability will be a monumental step forward.

As the work of the Mass General Liquid Biopsy Center team progresses through initial phases of clinical trials, they hope to answer four key questions:

1. If a patient presents with an abnormal brain scan, can a liquid biopsy diagnose a brain tumor through a blood test? Will our blood test for brain tumors have a high enough sensitivity to accurately detect when a brain tumor is present, and specific enough to accurately confirm when no brain tumor is present?
2. Prior to surgery, can a liquid biopsy diagnose and characterize the brain tumor to plan for the optimal treatment and outcome for patients?
3. Can a liquid biopsy differentiate between a growing or recurrent brain tumor from a side effect from treatment (radiation necrosis)?
4. Can this blood test better match patients with clinical trials, helping to achieve better outcomes for all?

Conclusion

As liquid biopsies become more accurate, the potential for a precise and personalized treatment based upon a blood test will allow patients and their physicians to have a minimally invasive diagnostic test. The Mass General Liquid Biopsy Center’s team of physicians and researchers from the Departments of Neurosurgery, Neurooncology and the Mass General Cancer Center are dedicated to overcoming the limitations of liquid biopsy today to have an accurate, effective and powerful clinical test for patients and their care teams. There is a significant potential for liquid biopsy to revolutionize cancer diagnoses and treatments with the goal of turning a blood test for brain tumors into reality for our patients.

Learn more about the Neurosurgery Department

Learn more about the Mass General Cancer Center