The Airway Transcriptome as a Biomarker for Early Lung Cancer Detection

Abstract

Lung cancer remains the leading cause of cancer-related death due to its advanced stage at diagnosis. Early detection of lung cancer can be improved by better defining who should be screened radiographically and determining which imaging-detected pulmonary nodules are malignant. Gene expression biomarkers measured in normal-appearing airway epithelium provide an opportunity to use lung cancer-associated molecular changes in this tissue for early detection of lung cancer. Molecular changes in the airway may result from an etiologic field of injury and/or field cancerization. The etiologic field of injury reflects the aberrant physiologic response to carcinogen exposure that creates a susceptible microenvironment for cancer initiation. In contrast, field cancerization reflects effects of "first-hit" mutations in a clone of cells from which the tumor ultimately arises or the effects of the tumor on the surrounding tissue. These fields might have value both for assessing lung cancer risk and diagnosis. Cancer-associated gene expression changes in the bronchial airway have recently been used to develop and validate a 23-gene classifier that improves the diagnostic yield of bronchoscopy for lung cancer among intermediate-risk patients. Recent studies have demonstrated that these lung cancer-related gene expression changes extend to nasal epithelial cells that can be sampled noninvasively. While the bronchial gene expression biomarker is being adopted clinically, further work is necessary to explore the potential clinical utility of gene expression profiling in the nasal epithelium for lung cancer diagnosis, lung cancer risk assessment, and precision medicine for lung cancer treatment and chemoprevention. Clin Cancer Res; 24(13); 2984-92. ©2018 AACR.

Figure 1:

Molecular alterations found throughout the respiratory tract can be attributed to field effects. A) The physiologic effect of smoking occurs predictably, commonly, immediately, and largely reversibly. This field of injury consists of molecular alterations present throughout the respiratory tract upon exposure to tobacco smoke. B) The etiological field of injury consists of processes at the molecular level that contribute to lung carcinogenesis. Molecular alterations related to inflammation, oxidative stress, and xenobiotic metabolism are among these processes which potentiate the establishment and expansion of cells harboring the genetic or epigenetic alterations that are directly required for tumorigenesis. C) Field cancerization refers to tumor-associated abnormalities (e.g. gene expression pathways related to immune response, DNA repair, and cell proliferation) in tumor-adjacent normal appearing cells. These abnormalities may reflect clonal expansion of cells harboring cancer-initiating alterations that are insufficient, on their own, to lead to transformation; or may be a consequence of the tumor on surrounding tissue. D) These fields are not mutually exclusive, and histologically normal-appearing tissue exhibiting cancer-associated alterations due to the etiologic field of injury and / or field cancerization can be leveraged for developing gene-expression based biomarkers for the early detection of lung cancer.

Figure 2:

Potential clinical applications of airway molecular biomarkers for the early detection of lung cancer. A) In current practice, pulmonary nodules are discovered either due to lung cancer screening based on clinical risk factors, as findings incidental to other imaging studies, or during the work up of symptomatic patients. In the current diagnostic algorithm for indeterminate pulmonary nodules established by the American College of Chest Physicians (ACCP), based on the pretest probability of malignancy, patients determined to be low risk will typically undergo continued surveillance while higher risk patients will undergo invasive testing. However, there is a clinical unmet need to better stratify those subjects at intermediate pre-test risk into CT surveillance vs. invasive biopsy as well as an unmet need to identify which subjects should undergo CT screening. B) Molecular biomarkers have the potential to impact the current diagnostic workflow of patients with indeterminate pulmonary nodules. Current biomarkers measured in histologically normal-appearing bronchial airway tissue can serve to identify patients with non-diagnostic bronchoscopies who are at low risk for lung cancer and can be followed with continued imaging surveillance. Future biomarkers measured in histologically normal-appearing nasal airway tissue could help identify at-risk individuals for CT-based lung cancer screening or direct diagnostic workup in individuals with suspect lung nodules who are not otherwise undergoing bronchoscopy. CT = Computed Tomography. LDCT = Low Dose Computed Tomography.