The Role of ctDNA for Diagnosis and Histological Prediction in Early Stage Non-Small-Cell Lung Cancer: A Narrative Review

Background: Circulating tumor DNA (ctDNA) may be released from neoplastic cells into biological fluids through apoptosis, necrosis, or active release. In patients with non-small-cell lung cancer (NSCLC), ctDNA analysis is being introduced in clinical practice only for advanced disease management. Nevertheless, an interesting and promising field of application is the analysis of ctDNA in the management of early stage non-small-cell lung cancer, both for evaluation before treatment, such as diagnosis and screening, and for prediction of histology or pathological features. Methods: A thorough review of the literature published between 2000 and 2024 was performed on PubMed, utilizing the advanced search feature to narrow down titles and abstracts containing the following keywords: ctDNA, early stage, and NSCLC. A total of 20 studies that met all inclusion criteria were chosen for this review. Results: In this review, we summarize the increasing evidence suggesting that ctDNA has potential clinical applications in the management of patients with early stage NSCLC. ctDNA levels in early stage cancers are very low, posing many technical challenges in improving the detection rate and sensitivity, especially in clinical practice, if it is to be implemented for early detection. Presently, the main limitation of ctDNA experimental and clinical studies, especially in early stage settings, is the lack of definitive standardization and consensus regarding methodology, the absence of systematically validated analyses, and the lack of adoption of sensitive approaches. Conclusions: Possible applications of this analyte open up new fields of diagnosis, treatment, and follow up, which are less invasive and more precise than other approaches currently in use, especially in early stage NSCLC patients.