Treatment Response Assessment in IDH-Mutant Glioma Patients by Noninvasive 3D Functional Spectroscopic Mapping of 2-Hydroxyglutarate.

Abstract

PURPOSE:

Measurements of objective response rates are critical to evaluate new glioma therapies. The hallmark metabolic alteration in gliomas with mutant isocitrate dehydrogenase (IDH) is the overproduction of oncometabolite 2-hydroxyglutarate (2HG), which plays a key role in malignant transformation. 2HG represents an ideal biomarker to probe treatment response in IDH-mutant glioma patients, and we hypothesized a decrease in 2HG levels would be measureable by in vivo magnetic resonance spectroscopy (MRS) as a result of antitumor therapy.

EXPERIMENTAL DESIGN:

We report a prospective longitudinal imaging study performed in 25 IDH-mutant glioma patients receiving adjuvant radiation and chemotherapy. A newly developed 3D MRS imaging was used to noninvasively image 2HG. Paired Student t test was used to compare pre- and posttreatment tumor 2HG values. Test-retest measurements were performed to determine the threshold for 2HG functional spectroscopic maps (fSM). Univariate and multivariate regression were performed to correlate 2HG changes with Karnofsky performance score (KPS).

RESULTS:

We found that mean 2HG (2HG/Cre) levels decreased significantly (median = 48.1%; 95% confidence interval = 27.3%-56.5%;P= 0.007) in the posttreatment scan. The volume of decreased 2HG correlates (R(2)= 0.88,P= 0.002) with clinical status evaluated by KPS.

CONCLUSIONS:

We demonstrate that dynamic measurements of 2HG are feasible by 3D fSM, and the decrease of 2HG levels can monitor treatment response in patients with IDH-mutant gliomas. Our results indicate that quantitative in vivo 2HG imaging may be used for precision medicine and early response assessment in clinical trials of therapies targeting IDH-mutant gliomas.

• Authors: Ovidiu C Andronesi, Franziska Loebel, Wolfgang Bogner, Małgorzata Marjańska, Matthew G Vander Heiden, A John Iafrate, Jorg Dietrich, Tracy T Batchelor, Elizabeth R Gerstner, William G Kaelin, Andrew S Chi, Bruce R Rosen, Daniel P Cahill
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 22 Issue 7 Pg. 1632-41 (Apr 01 2016) ISSN: 1557-3265 [Electronic] United States
• PMID: 26534967 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Biomarkers
• Glutarates
• alpha-hydroxyglutarate
• Isocitrate Dehydrogenase

Topics

• Biomarkers
• Brain (pathology)
• Brain Neoplasms (diagnosis, genetics, metabolism, therapy)
• Chemoradiotherapy, Adjuvant
• Female
• Glioma (diagnosis, genetics, metabolism, therapy)
• Glutarates (metabolism)
• Humans
• Image Processing, Computer-Assisted
• Imaging, Three-Dimensional
• Isocitrate Dehydrogenase (genetics, metabolism)
• Magnetic Resonance Spectroscopy (methods)
• Male
• Mutation
• Neoplasm Grading
• Neoplasm Staging