Combining multiple approaches and omics technologies to detect circulating tumor cells (CTCs): a real clinical application in patients with early-stage non-small-cell lung cancer (NSCLC)?

Non-small cell lung cancer (NSCLC) remains one of the most aggressive human malignancies worldwide. While tissue biopsy has long been considered the gold standard for diagnosing NSCLC, the past two decades have seen the emergence of various circulating biomarkers as key components of plasma-based liquid biopsy in NSCLC. These include circulating tumor cells (CTCs), circulating cell-free nucleic acids such as circulating tumor DNA and microRNAs, extracellular vesicles (exosomes), tumor-educated platelets, circulating proteins, and immune cells or immune system components. Despite their promise, CTCs are not yet routinely used in clinical practice for early-stage NSCLC. This commentary highlights the current understanding and detection of CTCs in early-stage NSCLC patients. To date, identifying reliable blood-based biomarkers - whether associated with CTCs or not - remains a major hurdle to diagnosing NSCLC across both early and advanced stages. Monitoring CTC levels could provide important clues on tumor heterogeneity and complexity, including pathologic staging, primary tumor characteristics, and treatment response, particularly in advanced disease. Currently, multiple techniques exist for isolating, characterizing, and enumerating CTCs. Among them, the CellSearch System is the most widely used and remains the only US FDA-approved method, despite certain limitations. In addition, this commentary explores the potential of combining other diagnostic modalities, such as 18-FDG PET/CT, with emerging nanotechnologies to monitor lung nodules - even at early stages - offering deeper insights into disease onset, progression, and therapeutic response.