While the goal of treatment for most patients with early-stage cancers is cure, there remains a notable chance for relapse after definitive therapy across solid tumor types. This is attributed to the persistence of a small amount of tumor cells after primary treatment, undetectable by conventional imaging, known as minimal residual disease (MRD) (Luskin et al., 2018). Systemic treatments, such as chemotherapy, immunotherapy, and targeted therapy can reduce the risk of relapse by eliminating MRD for some patients, but this comes with the cost of additional toxicity. Despite escalated therapeutic regimens, some patients still relapse, while others, who are already cured, are subjected to overtreatment. Thus, there is an urgent clinical need for reliable assessment of MRD after treatment in early-stage cancers.

Liquid biopsies have emerged as a non-invasive approach that can be utilized to monitor MRD in real-time through circulating tumor DNA (ctDNA) assessments. ctDNA represents the tumor-derived portion of cell-free DNA (cfDNA), which is non-encapsulated DNA released into the blood stream primarily from cells that have undergone cell death through apoptosis and necrosis (Thierry et al., 2016). Multiple methods exist for ctDNA detection using genomic and epigenetic alterations, including sequence mutations, structural variations such as fusions and focal copy number alterations, larger chromosomal arm variations, methylation patterns and physical properties of cfDNA fragments such as fragment length and end motifs. The most commonly used liquid biopsy approaches are mutation-based and detecting ctDNA during or after definitive treatment can provide assessment of therapeutic response (Christensen et al., 2019) and may predict recurrence (Chaudhuri et al., 2017, Garcia-Murillas et al., 2015, Tie et al., 2016). The use of MRD assessments to detect recurrence at an earlier timepoint could potentially provide clinicians the opportunity to intercept treatment when the recurrent tumor burden is at its lowest (Moding et al., 2021). Additionally, assessment of ctDNA could be utilized to provide information about therapeutic response in both the neoadjuvant and adjuvant therapy settings, as failure to decrease or clear ctDNA may indicate need for additional or alternative therapies (Magbanua et al., 2023, Tie et al., 2022). Due to the small number of residual tumor cells present after curative-intent therapy for early stage disease, biomarker approaches in this setting must be highly sensitive (Vellanki et al., 2023). Here, we discuss the approaches and clinical utility of ctDNA to assess minimal residual disease across various cancer types.