Sputum-based DNA methylation biomarkers to guide lung cancer screening decisions

Lung cancer is the leading cause of cancer-related deaths worldwide (1). Exposure to tobacco smoke is the main risk factor (2). Early detection and timely treatment have been shown to greatly improve lung cancer survival. In 2011, the National Lung Screening Trial (NLST) reported a 20% reduction in lung cancer mortality when low dose computed tomography (LDCT) was used repeatedly to screen highrisk individuals (i.e., 55–74 years of age, ≥30 pack-year smoking history, and if ex-smokers, had quit within the past 15 years) (3). As of 2014, annual LDTC has become the only recommended screening test for lung cancer by the U.S. Preventive Services Task Force (USPSTF) in this high-risk population (4), but several concerns have been raised. Although LDCT is highly sensitive and detects early stage tumors, it has a low specificity. In the NLST study, among the 24.2% of subjects classified as being positive, 96.4% of them were eventually diagnosed with benign nodules. This high false positive rate can cause a lot of anxiety to patients and caregivers, and lead to unnecessary exposure to additional radiation or invasive procedures (i.e., bronchoscopy and surgical lung biopsy), to ultimately confirm or rule out a cancer diagnosis. A screening program only based upon LDCT has additional limitations, including the current USPSTF eligibility criteria that may only capture a third of newly diagnosed lung cancer patients (5), and the cost of yearly LDCT screens. Almost 9 million individuals satisfy the USPSTF criteria for screening in the US (6), and the projected coverage for screening will increase total Medicare expenditure by nearly $7 billion per month over 5 years (7). Therefore, non-invasive tests are critically needed to identify individuals at higher risk that are best suited for LDCT. Development of highly sensitive risk biomarkers used prior to LDCT would reduce the number of false positive scans later on, and therefore improve the cost-effectiveness of a LDCT screening program. Screening biomarkers should complement the ability of LDCT to rule out lung cancer among high-risk individuals, and, thus, focus resources on those more likely to benefit.