Utility of Kynurenic Acid for Non-Invasive Detection of Metastatic Spread to Lymph Nodes in Non-Small Cell Lung Cancer

Background: Kynurenic acid (KYNA) is a side-stream product of the kynurenine metabolic pathway that plays a controversial role in malignancies either enabling escape of malignant cells from immune surveillance or exerting antiproliferative effect on cancer cells, and is associated with differences in invasiveness related to metastatic spread to lymph nodes in lung cancer. Nodal involvement is a significant negative prognostic factor usually considered a contraindication for primary surgical resection. Objective: To assess potential value of circulating KYNA for non-invasive identification of patients with metastatic lymph nodes (N+) in non-small cell lung cancer (NSCLC). Methods: KYNA level in venous blood serum was determined with use of high performance liquid chromatography (HPLC) in 312 subjects including 230 patients with NSCLC and 32 healthy controls. Results: Circulating KYNA level in NSCLC patients was higher than in controls (93.6±61.9pmol/ml vs. 31.4±16.6pmol/ml; p=2.2•10(-15)) and positively correlated with N (R=0.326; p=2•(10-6)) but not with T or M stage (p>0.05). In N+ patients it was higher than in N0 patients (137.7±51.8pmol/ml vs. 71.9±41.7pmol/ml; p=4.8•10(-16)). KYNA effectively discriminated N+ from N0 patients at a cut-off value 82.3 pmol/ml with sensitivity 94.7% (95%CI 87.1-98.5%), specificity 80.5% (95%CI 73.4-86.5%), negative predictive value NPV=96.8%, PPV=70.5% and area under the ROC curve AUC=0.900 (95%CI 0.854-0.935; p=0.0001). Discussion and Conclusion: Circulating KYNA level measurement offers reliable non-invasive discrimination between N0 and N+ patients in NSCLC. Robust discriminatory characteristics of KYNA assay predestines it for clinical use as an adjunct facilitating selection of candidates for primary surgical resection.