Around 70% of lung cancers are diagnosed at stage III or IV, where treatment options with curative intent are significantly reduced. The ground-breaking US National Lung Screening Trial enrolled 53,454 patients at high risk for lung cancer and compared annual computed tomography scans with an annual chest radiograph.

The screening took place in the community where respiratory symptoms, spirometry, and cancer risk were assessed. Those considered at high lung cancer risk were offered to screen. A year later, follow-up scans identified a lung cancer incidence of 1.6%, and 79% of tumors were stage I. These findings have led to NHS England’s roll-out targeted lung health checks at 14 pilot sites in 10 schemes across England. Various strategies are being evaluated for the earlier detection of lung cancer, including transcriptomics, proteomics, and circulating tumor cells. ctDNA has the potential to provide information regarding tumor origin, genetic profile, and disease burden. In early-stage disease, the detection of ctDNA is far more challenging. Most patients will have less than one copy of the tumor genome detected per 5 ml plasma.

The analysis of DNA methylation patterns within the ctDNA may further improve early-stage disease detection and help identify tumors’ anatomic location through tissue-specific cell death. Breath and blood testing will probably be acceptable to the general public, can be carried out in a familiar community setting, and limit unnecessary exposure to ionizing radiation. Using a sequential investigation algorithm, ctDNA analysis, and a positive breath test could identify cases where low-dose computed tomography may be useful. Questions about sensitivity, specificity, positive and negative predictive value of these approaches have to be answered before reaching this stage, but these are now being investigated.