Circulating levels of glutamate predict brain disease in patients with advanced lung and breast cancer: a prospective study

Purpose: Brain metastases (BM) from lung and breast cancer are a major clinical challenge. Circulating Glutamate (Glut), a key neurotransmitter, may reflect interactions between the tumor and the central nervous system (CNS). The study aims to evaluate its diagnostic value in patients undergoing Gamma Knife Radiosurgery (GKRS) for BMs. Methods: In this prospective study, pre-treatment serum Glut, Glut-scavengers, and catabolites were quantified in patients with BMs and compared to primary lung/breast cancer patients without BMs and those with benign intracranial tumors. Data were correlated with clinical and radiological features. Results: Thirty-six patients with BMs (lung 75%, breast 25%) were enrolled (median age 66.5 years; median brain tumor volume 4.35 cc). Most patients had extracranial metastases (94.4%) and had received prior systemic therapy (58.3%). During a median follow-up of 7.6 months, 50% of patients experienced disease progression. Peripheral Glut levels were significantly associated with the presence of BMs (p = 0.003), independently of lesion number or brain tumor burden. No correlation was found with other clinical or radiological features. ROC analysis identified a 68.5 µM cut-off for Glut for discriminating between patients with and without BM. In multivariable logistic regression, Glut remained independently associated with BM. Conclusions: Circulating Glut levels are associated with BM presence in advanced lung and breast cancer patients. This measurement is non-invasive and straightforward, and may help identify patients who require brain imaging. Further prospective validation is warranted. Trial registration: The study was registered in ClinicalTrials.gov with the accession number NCT04785521.