MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors

Ying Meng; Christopher B Pople; Suganth Suppiah; Maheleth Llinas; Yuexi Huang; Arjun Sahgal; James Perry; Julia Keith; Benjamin Davidson; Clement Hamani; Yutaka Amemiya; Arun Seth; Hon Leong; Chinthaka C Heyn; Isabelle Aubert; Kullervo Hynynen; Nir Lipsman

doi:10.1093/neuonc/noab057

MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors

Neuro Oncol. 2021 Oct 1;23(10):1789-1797. doi: 10.1093/neuonc/noab057.

Authors

Ying Meng^{1

2}, Christopher B Pople¹, Suganth Suppiah², Maheleth Llinas¹, Yuexi Huang¹, Arjun Sahgal^{1

3

4}, James Perry^{1

3

5}, Julia Keith^{1

6}, Benjamin Davidson^{1

2}, Clement Hamani^{1

2}, Yutaka Amemiya¹, Arun Seth^{1

6}, Hon Leong^{1

7}, Chinthaka C Heyn^{1

8}, Isabelle Aubert^{1

6}, Kullervo Hynynen^{1

7}, Nir Lipsman^{1

2}

Affiliations

¹ Sunnybrook Research Institute, Toronto, Ontario, Canada.
² Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.
³ Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
⁴ Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁵ Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
⁶ Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
⁷ Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
⁸ Department of Medical Imaging, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Abstract

Background: Liquid biopsy is promising for early detection, monitoring of response, and recurrence of cancer. The blood-brain barrier (BBB) limits the shedding of biomarker, such as cell-free DNA (cfDNA), into the blood from brain tumors, and their detection by conventional assays. Transcranial MR-guided focused ultrasound (MRgFUS) can safely and transiently open the BBB, providing an opportunity for less-invasive access to brain pathology. We hypothesized that MRgFUS can enrich the signal of circulating brain-derived biomarkers to aid in liquid biopsy.

Methods: Nine patients were treated in a prospective single-arm, open-label trial to investigate serial MRgFUS and adjuvant temozolomide combination in patients with glioblastoma (NCT03616860). Blood samples were collected as an exploratory measure within the hours before and after sonication, with control samples from non-brain tumor patients undergoing BBB opening (BBBO) alone (NCT03739905).

Results: Brain regions averaging 7.8 ± 6.0 cm3 (range 0.8-23.1 cm3) were successfully treated within 111 ± 39 minutes without any serious adverse events. We found MRgFUS acutely enhanced plasma cfDNA (2.6 ± 1.2-fold, P < .01, Wilcoxon signed-rank test), neuron-derived extracellular vesicles (3.2 ± 1.9-fold, P < .01), and brain-specific protein S100b (1.4 ± 0.2-fold, P < .01). Further comparison of the cfDNA methylation profiles suggests a signature that is disease- and post-BBBO-specific, in keeping with our hypothesis. We also found cfDNA-mutant copies of isocitrate dehydrogenase 1 (IDH1) increased, although this was in only one patient known to harbor the tumor mutation.

Conclusions: This first-in-human proof-of-concept study shows MRgFUS enriches the signal of circulating brain-derived biomarkers, demonstrating the potential of the technology to support liquid biopsy for the brain.

Keywords: blood-brain barrier; brain tumor; focused ultrasound; glioblastoma; liquid biopsy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biomarkers
Brain Neoplasms* / diagnostic imaging
Brain Neoplasms* / therapy
Humans
Liquid Biopsy
Magnetic Resonance Imaging*
Prospective Studies

Substances

Biomarkers

Associated data

ClinicalTrials.gov/NCT03739905
ClinicalTrials.gov/NCT03616860