Detection of Minimal Residual Disease Using ctDNA in Lung Cancer: Current Evidence and Future Directions

Abstract

Advances in DNA sequencing methods have significantly expanded the potential clinical applications of analyzing circulating tumor DNA (ctDNA). This genetic information can identify the presence of targetable mutations and has been explored for cancer screening purposes. ctDNA can be obtained without the risks inherent to biopsy, allowing for serial assessments over time. Several studies have additionally suggested that ctDNA can be used to detect the presence of minimal residual disease (MRD) after surgical resection in several cancer types, including lung cancer. The ability to detect MRD would allow clinicians to tailor adjuvant therapies, which carry risks of significant toxicities and may benefit only select groups of patients. Here, we review the current state of ctDNA profiling methods and evaluate the evidence supporting the use of ctDNA analysis to assess for MRD. We discuss how MRD detection could help identify patients at increased risk of disease recurrence and thus guide treatment decisions for resectable lung cancer. Finally, we propose future steps to validate such approaches and expand the utility of these rapidly progressing technologies.

Early circulating tumour DNA kinetics measured by ultra-deep next-generation sequencing during radical radiotherapy for non-small cell lung cancer: a feasibility study

“…Similarly, following surgery ctDNA levels are known to plummet within 1 day [36]. Levels immediately postsurgery can indicate minimal residual disease detection, which may guide the clinical management [37]. Radiological relapse post-surgery has been predicted by ctDNA increases up to 5.2 months prior [38].…”

Implementing ctDNA Analysis in the Clinic: Challenges and Opportunities in Non-Small Cell Lung Cancer

“…The genomic coverage (i.e., targeting specific genomic alterations versus broader panels of genes or a combination of these approaches) should also be considered when choosing a ctDNA assay [22]. ctDNA genotyping can be targeted to known mutations in predefined genes or non-targeted and aim at whole exome screening (discussed below) [41]. Targeted approaches are generally more sensitive than non-targeted assays; however, ultrasensitive technologies have been described [19].…”

“…For patients with advanced disease, ctDNA test results appear more reliable when performed at disease progression rather than during response to therapy [32]. This implies that confirmation of ctDNA negative tests is still recommended using tumor biopsy [1,41,49]. At the other end, false-positive findings can be introduced due to the presence of cfDNA from multiple sources, including age-related mutations from hematopoietic cells that and ctDNA mutations that are shared between cancer and benign conditions [41].…”

“…This implies that confirmation of ctDNA negative tests is still recommended using tumor biopsy [1,41,49]. At the other end, false-positive findings can be introduced due to the presence of cfDNA from multiple sources, including age-related mutations from hematopoietic cells that and ctDNA mutations that are shared between cancer and benign conditions [41]. In conclusion of this section, tissue and liquid biopsies may be considered as two complementary methods, and clinical aspects are crucial to take into account when interpreting ctDNA results [50][51][52][53][54] (Figure 2).…”

Epidermal Growth Factor Receptor (EGFR)-Mutated Non-Small-Cell Lung Cancer (NSCLC)

“…Moreover, studies have demonstrated that ctDNA can be used to detect minimal residual disease (MRD) after surgical resection and, therefore, identify patients at an increased risk of disease recurrence ahead of standard-of-care imaging surveillance [ 85 ]. With the recent data from the TRACERx (tracking non-small-cell lung cancer evolution through therapy (Rx)) study available, independent predictors of ctDNA release and phylogenetic ctDNA tracking provided insights into the subclonal nature of lung cancer relapse and metastasis [ 86 ].…”