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

Daniel Di Capua, Dara Bracken-Clarke, Karine Ronan, Anne-Marie Baird, Stephen Finn, Daniel Di Capua, Dara Bracken-Clarke, Karine Ronan, Anne-Marie Baird, Stephen Finn

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.

Keywords: circulating tumor DNA; circulating tumor cells; liquid biopsy; lung cancer; non-small cell lung carcinoma.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Technical considerations when acquiring tumor tissue and liquid biopsy specimens and preparing samples for diagnostic and monitoring purposes in NSCLC. Core tissue biopsy and EBUS requires careful consideration of patient factors such as comorbidity and frailty, and may be complicated by procedure risk. Technically skilled medical staff and significant healthcare resources are required for such procedures, which limits their availability. Acquisition of sufficient material for diagnosis, subtyping and molecular subtyping is not always straightforward and can lead to delays in “real-world” practice. Sample collection for liquid biopsy is minimally invasive, via blood draw or pleural fluid analysis, technically straightforward and minimizes patient risk. NSCLC = non-small cell lung carcinoma; EBUS = endobronchial ultrasound; CTCs = circulating tumor cells; ctDNA = circulating tumor DNA.
Figure 2
Figure 2
Graph demonstrating the potential roles of ctDNA and CTCs in the clinical course of a patient with NSCLC compared with standard approaches to patient care. Patient 1 demonstrates standard approaches to screening, diagnosis and monitoring of a patient with NSCLC. Patient 2 demonstrates the potential utility of ctDNA and CTCs in the disease course of a patient with NSCLC.

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