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Review
. 2022 Aug 12;23(16):9006.
doi: 10.3390/ijms23169006.

Making the Rounds: Exploring the Role of Circulating Tumor DNA (ctDNA) in Non-Small Cell Lung Cancer

Misty Dawn Shields  1 , Kevin Chen  2 , Giselle Dutcher  3 , Ishika Patel  4 , Bruna Pellini  5   6
Affiliations
Review

Making the Rounds: Exploring the Role of Circulating Tumor DNA (ctDNA) in Non-Small Cell Lung Cancer

Misty Dawn Shields et al. Int J Mol Sci. .

Abstract

Advancements in the clinical practice of non-small cell lung cancer (NSCLC) are shifting treatment paradigms towards increasingly personalized approaches. Liquid biopsies using various circulating analytes provide minimally invasive methods of sampling the molecular content within tumor cells. Plasma-derived circulating tumor DNA (ctDNA), the tumor-derived component of cell-free DNA (cfDNA), is the most extensively studied analyte and has a growing list of applications in the clinical management of NSCLC. As an alternative to tumor genotyping, the assessment of oncogenic driver alterations by ctDNA has become an accepted companion diagnostic via both single-gene polymerase chain reactions (PCR) and next-generation sequencing (NGS) for advanced NSCLC. ctDNA technologies have also shown the ability to detect the emerging mechanisms of acquired resistance that evolve after targeted therapy. Furthermore, the detection of minimal residual disease (MRD) by ctDNA for patients with NSCLC after curative-intent treatment may serve as a prognostic and potentially predictive biomarker for recurrence and response to therapy, respectively. Finally, ctDNA analysis via mutational, methylation, and/or fragmentation multi-omic profiling offers the potential for improving early lung cancer detection. In this review, we discuss the role of ctDNA in each of these capacities, namely, for molecular profiling, treatment response monitoring, MRD detection, and early cancer detection of NSCLC.

Keywords: MRD; NSCLC; cell-free DNA; circulating tumor DNA; early cancer detection; liquid biopsy; minimal residual disease; molecular profiling; non-small cell lung cancer; treatment response monitoring.

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Conflict of interest statement

Bruna Pellini receives research support to the institution from Bristol Myers Squibb, has received speaker honoraria from BioAscend, OncLive/MJH Life Science, and has conducted consulting work/advisory board membership with Guidepoint, Guardant Health, and AstraZeneca. The other authors have nothing to disclose.

Figures

Figure 1
Figure 1
Overview of ctDNA detection and the workflow for NSCLC. The detection of ctDNA through liquid biopsies can be utilized for (A) molecular profiling, (B) treatment response monitoring, (C) detection of minimal residual disease, and (D) early cancer detection. (A) ctDNA can be readily used to identify cancer-related aberrations (e.g., detection of EGFR L858R) with ultrasensitive detection, for ease of use when tissue is limited or exhausted, or as a complementary diagnostic tool with rapid turn-around times. (B) The ease of ctDNA detection by serial blood draws permits treatment response monitoring of tumor biology evolution, via the detection of potential mechanisms of acquired resistance (e.g., EGFR T790M on first-generation EGFR TKIs). (C) ctDNA is a powerful tool for minimal residual disease (MRD) detection after curative-intent multimodal therapy (i.e., chemotherapy, radiation, and immunotherapy) in locally advanced NSCLC. ctDNA MRD positivity can be detected generally prior to radiographic progression to aid in decision making for patient care. (D) In an effort to improve early cancer detection in high-risk individuals, minimally invasive ctDNA analysis via mutational, methylation, and/or fragmentation profiles offers promising potential to complement radiographic screening with low-dose CT chest (LDCT chest).
Figure 2
Figure 2
Timeline of ctDNA MRD studies in patients with NSCLC. A timeline of studies that have advanced our understanding of ctDNA MRD as a prognostic and potentially predictive biomarker in patients with NSCLC, who were treated with a curative-intent [39,115,116,117,118,119,120,121,122].
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Grants and funding

This research is partially supported by the National Institutes of Health (NIH), National Cancer Institute (NCI), Geographic Management of Cancer Health Disparities Programs Region 2 (GMaP R2) 3P30CA076292-24S2 (John Cleveland, PI).