The Myriad Ways ctDNA Analysis Using Liquid Biopsy Can Be Applied in NSCLC

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A literature review examined the many clinical applications for circulating tumor DNA (ctDNA) analysis in non–small cell lung cancer (NSCLC) and provided insight into how liquid biopsy can help avoid certain limitations presented by other ctDNA analysis methods.

A new review of the evidence spotlights the myriad clinical ways that analysis of circulating tumor DNA (ctDNA) using liquid biopsy can be used in patients with non–small cell lung cancer (NSCLC), delving into the advantages and limitations with certain applications.

The review, published in Current Treatment Options in Oncology, focused on the clinical applications and the potential use of ctDNA as well as where research on ctDNA applications should be targeted.

“Specifically, the analysis of ctDNA has shown tremendous advantages in the management of lung cancer patients, enabling for noninvasive biomarker testing, tumor response to treatment monitoring, early detection of resistance mutations, the study of clonal evolution, and early detection of molecular relapse or residual disease,” wrote the authors.

Lung cancer is the leading cause of cancer-related deaths, and NSCLC accounts for 85% of lung cancer cases. NSCLC is often diagnosed at an advanced stage and carries a 5-year survival rate of about 5%. Biomarker testing was developed to be a crucial part of ensuring adequate management for patients with lung cancer.


However, biomarker testing can be challenging in patients with lung cancer, as the anatomical location of the tumor may limit access to targeted therapies. Additionally, the growing number of biomarkers that have been associated with NSCLC means that it may be necessary to obtain multiple biopsies to conduct several analyses, which is not always possible. At the time of disease progression, providers may want to know the molecular profile of a tumor in order to tailor therapeutic regimens. Liquid biopsies can serve as an avenue to avoid such limitations.

Most noninvasive biomarker tests using liquid biopsies are based on quantitative polymerase chain reaction (QPCR); digital PCR (dPCR); beads, emulsion, amplification, and magnetics (BEAMing); or next-generation sequencing (NGS) technology. QPCR tests can lack the level of sensitivity needed to detect genetic mutations. Some of the benefits of NGS analyses include that a larger number of mutations can be tested simultaneously compared with dPCR or BEAMing and that it may provide valuable insight into ALK-positive patients with NSCLC after treatment failure.

The authors noted that ctDNA can be used for selecting patients for clinical trials and serve as a trial end point because it can be reached sooner than survival time end points. ctDNA can also aid in detecting immune checkpoints that are known biomarkers of NSCLC, including tumor mutational burden.

Research has shown that the amount of ctDNA observed correlates with tumor bulk and can be used to determine treatment outcomes and quantify targetable mutations in EGFR-positive patients with NSCLC. Although longitudinal ctDNA quantification is not standard practice yet, increasingly evidence is showing that the amount of ctDNA has a prognostic significance.

ctDNA analyses can serve as a tool for early detection of resistance mutation, especially for T790M mutations, which can be effectively identified in plasma collected from patients with advanced lung cancer several months prior to clinical progression. However, there is still a lack of clinical trials examining whether changing of therapy is needed upon molecular progression rather than clinical progression.

“Intratumor heterogeneity is a key factor underlying treatment failure. It is important to recognize that the advent of liquid biopsies has improved our understanding of tumor evolution under the course of treatment,” the authors wrote.

Liquid biopsy technology can also detect residual disease after receiving local treatment during the early stages of several cancer types. Additionally, liquid biopsies through GNS can aid in the reliable detection of minimal residual disease (MRD) in patients with lung cancer.

“While the use of ctDNA for MRD detection appears promising, whether ctDNA detection is reliable enough to determine subsequent treatments has not been proven. Likewise, the interpretation of undetectable ctDNA levels remains unclear. In this way, clinical trials addressing these issues are of particular interest,” the authors noted.

Although liquid biopsies are a promising approach for cancer screening, the authors said that they may not be powerful enough yet to accurately detect early-stage lung cancer in patients and that technical improvements are needed to implement ctDNA NGS profiling as an effective screening tool.


Romero A, Serna-Blasco R, Calvo V, Provencio M. Use of liquid biopsy in the care of patients with non-small cell lung cancer. Curr Treat Options in Oncol. Published online August 23, 2021. doi:10.1007/s11864-021-00882-9