Field Cancerization and Microbiome Effects on Lung Cancer: A Source of Early Detection Biomarkers to Improve Patients’ Outcome

Abstract

Lung cancer results in more deaths than any other cancer in the United States and worldwide, with non-small cell lung cancer (NSCLC) accounting for most cases. Diagnosis typically involves chest imaging, molecular testing, and biopsy. However, most patients are diagnosed at advanced stages, with only a 6% chance of a 5-year survival rate. In contrast, early-stage diagnosis and treatment can result in a favorable prognosis, with a high 5-year survival rate of 70-90%. The concept of tumor field cancerization describes a phenomenon where exposure to carcinogens can cause histologic changes in large areas of tissue, creating a field of pre-malignant cells that can eventually develop into tumors. Additionally, microbiota dysbiosis might influence tumor development. Studies have identified several commensal bacteria present in the lower airway tracts, such as Streptococcus, Prevotella, and Veillonella.

The high mortality rate of lung cancer is often attributed to i) its late-stage diagnosis, ii) aggressive nature given its ability to metastasize early in the disease process complicating treatment and reducing survival rates, and iii) significant therapeutic challenges despite current treatments such as surgery, chemotherapy, radiation therapy, targeted therapy and immunotherapy. Despite advancements, the survival rate for advanced lung cancer remains low. To address this challenge, our research focuses on identifying risk protein biomarkers that are associated with the earliest molecular changes indicative of an ongoing tumorigenic process, thus offering significant potential for early intervention.

Our study investigates the phenotypic molecular changes in the bronchial tree of NSCLC patients in light of the field cancerization theory and correlates these findings with blood biomarkers to support the future development of a non-invasive risk assessment test. Using enhanced liquid chromatography tandem mass spectrometry (LC-MS/MS) proteomic analysis and two independent cohorts of lung cancer patients (N=18, and N=263) with matched plasma and bronchial tree tissue specimens, we identified a set of 6 and 13 candidate risk plasma biomarkers with tissue origin. Additionally, we explored the microbiome proteome composition in NSCLC patient tissue and plasma to support future characterization of its potential role in cancer development. Risk biomarkers will enable the evaluation of individuals at high risk, guiding necessary lifestyle adjustments and facilitating the development of personalized prevention plans and therapies.