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  • Liquid Biopsy Can Distinguish Recurrent GBM from Pseudoprogression and Radiation Necrosis After Concurrent Radiochemotherapy

    Final Number:

    Andrew E. Sloan MD FACS; David Soler Ph.D.; Anne B. Young BS; Kelvin D Cooper MD, PhD; Thomas McCormic Ph.D.

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2016 Annual Meeting

    Introduction: Glioblastoma (GBM) is the most lethal primary brain tumor with a median survival of 15 months despite resection and concurrent radio-chemotherapy. Among the many challenges in treating glioblastoma patients is the ability to differentiate pseudoprogression (PsP) and “radiation necrosis” (RN) from true recurrent GBM (rGBM). While PsP and RN occur in 15-30% of glioblastoma treated with concurrent radiochemotherapy, they are difficult to distinguish from recurrent GBM (rGBM) with magnetic resonance imaging (MRI). Thus, despite various MRI grading classifications, biopsy remains the gold standard. We and others have recently identified myeloid derived suppressor cells (MDSC) in both tumor microenvironment and peripheral blood of GBM patients. Our recent studies also identified the MDSC related protein VN2 on CD14+ monocytes in various conditions.

    Methods: Fresh peripheral blood was collected per IRB-approved protocol and monocytes isolated by density gradient centrifugation. CD14+ were then isolated using magnetic CD14 micro beads. HLA-DR- and/or VN2+ cells were quantitated using multi-color flow cytometry with isotype-matched antibody controls. Analysis was performed using Winlist software; statistical significance was determined using Student’s t test.

    Results: Median MDSC (CD14+ HLA-DR-) comprised 52% of monocytes in peripheral blood of GBM patients (N=12) but only 4-5% of patients with PsP, RN or normal controls (N=5 & N=11 respectively; p< 0.0001). Conversely CD14+VN2+ monocytes were found in 26% of patients with verified RN (N = 5), while the level in rGBM and normal controls was 8 & 12% (N = 12 & N=11 respectively; p< 0.0004). Together, MDSC and VN2 were 100% sensitive and 100% specific in differentiating rGBM from PsP and RN in our retrospective studies of 16 patients.

    Conclusions: This novel, quick and inexpensive "liquid biopsy" performed on peripheral blood could replace invasive brain biopsy if preliminary results are confirmed in prospective studies currently underway.

    Patient Care: If our preliminary findings are confirmed, operative brain biopsy for rGBM after concurrent radiochemotherapy (Stupp protocol) will be replaced by this liquid "blood biopsy."

    Learning Objectives: 1. Recognize the challenges in discriminating recurrent GBM (rGBM), pseudoprogression (PsP), and radiation necrosis (RN) in the setting of GBM patients treated by standard radio-chemotherapy (Stupp protocol)for which current SOC is brain biopsy; 2). Identify the potential of a "liquid biopsy" utilizing peripheral blood to replace the invasive biopsy if sensitivity and specificity of 100% are confirmed.

    References: 1). Chamberlain MC, Glantz MJ, Chalmers L, Van Horn A, Sloan AE. Early necrosis following concurrent Temodar and radiotherapy in patients with glioblastoma. Journal of Neuro-Oncology. 2007 Mar;82(1):81-3. Epub 2006 Aug 31. 2). 212. Sloan AE, Nock CJ, Ye X, Desideri S, Fisher JD, Pardos M, Grossman SA: A Biomarker and Phase II study of vismodegib (GDC-0449) in patients with recurrent GBM. 2012 ASCO Annual Meeting, Chicago, IL June 2012 (poster discussion); Journal of Clinical Oncology, 2012.

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