The Liquid Biopsy for Lung Cancer: State of the Art, Limitations and Future Developments

SIMPLE SUMMARY: During the development and progression of lung tumors, processes such as necrosis and vascular invasion shed tumor cells or cellular components into various fluid compartments. Liquid biopsies consist of obtaining a bodily fluid, typically peripheral blood, in order to isolate and investigate these shed tumor constituents. Circulating tumor cells (CTCs) are one such constituent, which can be isolated from blood and can act as a diagnostic aid and provide valuable prognostic information. Liquid-based biopsies may also have a potential future role in lung cancer screening. Circulating tumor DNA (ctDNA) is found in small quantities in blood and, with the recent development of sensitive molecular and sequencing technologies, can be used to directly detect actionable genetic alterations or monitor for resistance mutations and guide clinical management. While potential benefits of liquid biopsies are promising, they are not without limitations. In this review, we summarize the current state and limitations of CTCs and ctDNA and possible future directions. ABSTRACT: Lung cancer is a leading cause of cancer-related deaths, contributing to 18.4% of cancer deaths globally. Treatment of non-small cell lung carcinoma has seen rapid progression with targeted therapies tailored to specific genetic drivers. However, identifying genetic alterations can be difficult due to lack of tissue, inaccessible tumors and the risk of complications for the patient with serial tissue sampling. The liquid biopsy provides a minimally invasive method which can obtain circulating biomarkers shed from the tumor and could be a safer alternative to tissue biopsy. While tissue biopsy remains the gold standard, liquid biopsies could be very beneficial where serial sampling is required, such as monitoring disease progression or development of resistance mutations to current targeted therapies. Liquid biopsies also have a potential role in identifying patients at risk of relapse post treatment and as a component of future lung cancer screening protocols. Rapid developments have led to multiple platforms for isolating circulating tumor cells (CTCs) and detecting circulating tumor DNA (ctDNA); however, standardization is lacking, especially in lung carcinoma. Additionally, clonal hematopoiesis of uncertain clinical significance must be taken into consideration in genetic sequencing, as it introduces the potential for false positives. Various biomarkers have been investigated in liquid biopsies; however, in this review, we will concentrate on the current use of ctDNA and CTCs, focusing on the clinical relevance, current and possible future applications and limitations of each.