Differential early diagnosis of benign versus malignant lung cancer using systematic pathway flux analysis of peripheral blood leukocytes

Abstract

Early diagnosis of lung cancer is critically important to reduce disease severity and improve overall survival. Newer, minimally invasive biopsy procedures often fail to provide adequate specimens for accurate tumor subtyping or staging which is necessary to inform appropriate use of molecular targeted therapies and immune checkpoint inhibitors. Thus newer approaches to diagnosis and staging in early lung cancer are needed. This exploratory pilot study obtained peripheral blood samples from 139 individuals with clinically evident pulmonary nodules (benign and malignant), as well as ten healthy persons. They were divided into three cohorts: original cohort (n = 99), control cohort (n = 10), and validation cohort (n = 40). Average RNAseq sequencing of leukocytes in these samples were conducted. Subsequently, data was integrated into artificial intelligence (AI)-based computational approach with system-wide gene expression technology to develop a rapid, effective, non-invasive immune index for early diagnosis of lung cancer. An immune-related index system, IM-Index, was defined and validated for the diagnostic application. IM-Index was applied to assess the malignancies of pulmonary nodules of 109 participants (original + control cohorts) with high accuracy (AUC: 0.822 [95% CI: 0.75-0.91, p < 0.001]), and to differentiate between phases of cancer immunoediting concept (odds ratio: 1.17 [95% CI: 1.1-1.25, p < 0.001]). The predictive ability of IM-Index was validated in a validation cohort with a AUC: 0.883 (95% CI: 0.73-1.00, p < 0.001). The difference between molecular mechanisms of adenocarcinoma and squamous carcinoma histology was also determined via the IM-Index (OR: 1.2 [95% CI 1.14-1.35, p = 0.019]). In addition, a structural metabolic behavior pattern and signaling property in host immunity were found (bonferroni correction, p = 1.32e - 16). Taken together our findings indicate that this AI-based approach may be used for "Super Early" cancer diagnosis and amend the current immunotherpay for lung cancer.