Metabolomic Profiling and Machine Learning Models for Tumor Classification in Patients with Recurrent IDH-Wild-Type Glioblastoma: A Prospective Study

Background/Objectives: The recurrence of glioblastoma is an inevitable event in this disease's course. In this study, we sought to identify the metabolomic signature in patients with recurrent glioblastomas undergoing surgery and radiation therapy. Methods: Blood samples collected prospectively from six patients with recurrent IDH-wildtype glioblastoma who underwent one surgery at diagnosis and a second surgery at relapse were analyzed using untargeted gas chromatography-time-of-flight mass spectrometry to measure metabolite abundance. The data analysis techniques included univariate analysis, correlation analysis, and a sample t-test. For predictive modeling, machine learning (ML) algorithms such as multinomial logistic regression, gradient boosting, and random forest were applied to predict the classification of samples in the correct treatment phase. Results: Comparing samples after the first surgery and after the relapse surgeries to the pre-operative samples showed a significant decrease in sorbitol and mannitol; there was a significant increase in urea, oxoproline, glucose, and alanine. After chemoradiation, two metabolites, erythritol and 6-deoxyglucitol, showed a decrease, with a cut-off of three and a significant reduction for 6-deoxyglucitol, while 2,4-difluorotoluene and 9-myristoleate showed an increase post radiation, with a fold-change cut-off of three. The gradient-boosting ML model achieved a high performance for the prediction of tumor conditions in patients with glioblastoma who had undergone relapse surgery. Conclusions: We developed an ML predictor for tumor phase based on the plasma metabolomic profile. Our study suggests the potential of combining metabolomics with ML as a new tool to stratify the risk of tumor progression in patients with glioblastoma.