by Michael D. O’Neill, Editor & Publisher, BioQuick News
The development of a tumor-derived extracellular vesicle (EV) mRNA blood-based assay for the detection of IDH1.R132H-mutant glioma has been described August 16, 2024 in Nature Communications and is particularly relevant given the FDA’s recent approval of vorasidenib (VORANIGO) as the first and only FDA-approved targeted treatment in Grade 2 IDH-mutant glioma. The new blood-based test (liquid biopsy) allows minimally invasive detection of tumor-derived EV mRNA using only 2 mL plasma volume. The open-access article is titled “Clinical Utility of a Blood Based Assay for the Detection of IDH1.R132H-Mutant Gliomas.” The authors are from Mass General Hospital, Harvard Medical School, and Exosome Diagnostics. “I am extremely proud of this work led by the brilliant future neurosurgeon, Syeda Maheen Batool, MD, and while this is incredibly exciting, our work is far from done, and I look forward to pushing it through until it can directly benefit patients, especially in light of the recent FDA approval of vorasidenib for IDH1-mutant gliomas,” said corresponding author Leonora Balaj, PhD, Assistant Professor of Neurosurgery at Mass General Hospital and Harvard Medical School. “This assay could be a game changer–if we could measure the mutation in blood and then give the patient the drug and monitor the status over time with a blood test.”
Glioma is the most common primary central nervous system (CNS) neoplasm in adults with an overall incidence of 6 cases per 100,000 people in the US every year. The 2021 WHO classification of brain tumors provides a new framework for comprehensive characterization of gliomas based on histology and independently by hallmark molecular alterations. Importantly, IDH1 mutant alteration represents a key diagnostic biomarker, prevalent in >80% of WHO grade II/III gliomas, >70% of secondary glioblastoma (GBM), and <10% of primary GBM (all previous IDH1 mutant GBM lesions are now classified as Grade 4, astrocytoma). This point mutation is found in codon 132, characterized by a G>A transition (CGT>CAT) at nucleotide position 395, resulting in the substitution of arginine for histidine. IDH1 mutant gliomas represent a distinctive subtype with important clinical implications, most importantly improved prognosis and survival outcomes.
In healthy human cells, a family of genes called isocitrate dehydrogenases (IDHs) help break down nutrients and generate energy for cells. Mutations in IDH1 and IDH2 are associated with a variety of cancers, where they prevent cells from differentiating, or specializing, into the kind of cells they are ultimately supposed to become. When cells cannot differentiate properly, they may begin to grow out of control. It is thought that mutant IDH leads to the production of the oncometabolite 2-hydroxyglutarate, which interferes with the methylation of histones and has consequent effects on gene expression. In IDH-mutant gliomas, vorasidenib works by reducing the activity of the mutant IDH1 and IDH2 enzymes, to help control the disease.
In their Nature Communications paper, the authors show that a droplet digital PCR (ddPCR) assay, called mt-IDH1dx, can be used for robust detection of IDH1.R132H in patient plasma derived EV mRNA. To evaluate the assay performance in their study population (N = 133), the authors performed blinded validation testing across three independent cohorts. Baseline plasma testing from IDH1.R132H patients (n = 80), IDH1 wild-type gliomas (n = 44), and age matched healthy controls (n = 9) demonstrates clinically relevant diagnostic sensitivity and specificity. Finally, they show the utility of the proposed blood-based in longitudinal disease monitoring and surveillance in (n = 8) patients with IDH1.R132H alteration. Overall, the authors say that the proposed mt-IDH1dx assay can be utilized for blood-based diagnosis, prognostication, and longitudinal monitoring. Finally, the optimized workflow enables rapid and efficient completion of both tumor tissue and plasma testing in under 4 hours from the time of sampling.