Minimal Residual Disease Detection using a Plasma-only Circulating Tumor DNA Assay in Patients with Colorectal Cancer

Abstract

Statement of Translational RelevanceDetection of persistent circulating tumor DNA (ctDNA) after curative-intent surgery to identify patients with minimal residual disease (MRD) who will ultimately recur has emerged as a potentially transformative approach in oncology. Early identification of patients with MRD through ctDNA detection could identify patients in whom additional therapy might salvage the chance of cure. To date, ctDNA MRD assays have employed a tumor-informed approach, requiring initial sequencing of tumor tissue to guide ctDNA detection, and thus cannot be used when a patient has insufficient tumor tissue for analysis. Here, we evaluate the first tumoruninformed, plasma-only ctDNA assay integrating genomic and epigenomic signatures to detect MRD in post-operative colorectal cancer (CRC) patients, without requiring parallel tumor sequencing, which produced favorable sensitivity and specificity, comparable to tumor-informed approaches. These data highlight the feasibility and potential clinical utility of plasma-only ctDNA-guided MRD detection.

Clinical Applications of Minimal Residual Disease Assessments by Tumor-Informed and Tumor-Uninformed Circulating Tumor DNA in Colorectal Cancer

“…These are well above those for CEA (69% and 64%, respectively) in the same cohort [24]. The longitudinal sensitivity and specificity for recurrence approach 69% and 91%, respectively, for a recent tumor-uninformed plasma ctDNA panel [30]. The differences in analytical sensitivity between these assays are likely due to differences inherent to the tumor-informed NGS detection of top-ranked hits that are then deployed for plasma ctDNA detection.…”

“…There may be complementarity between methylation and NGS-based ctDNA assays to further improve upon the sensitivity of ctDNA assays as well. This was recently demonstrated in a prospective CRC cohort whereby incorporating methylation or epigenomic signatures increased the sensitivity of the ctDNA assay by 25-36% over targeted genomic alterations alone [30]. Specifically, across all ctDNA-positive samples, 28% and 25% of samples were individually positive by methylation and NGS-based testing, respectively, while 47% were positive by both epigenomic and genomic measures.…”

“…A separate group evaluated the feasibility of tumor-uninformed MRD detection using the plasma-only ctDNA assay (Guardant Reveal TM , Guardant Health) in a cohort of stage I-IV CRC patients undergoing curative intent surgeries [30]. Here, the ctDNA assay was designed to look for a combination of aberrant DNA methylation and targeted NGS of standard genomic alterations employed by most MRD assays without requiring parallel assessment of tumor tissue in blood samples collected at a landmark of 1 month following definitive therapy.…”

Liquid Biopsy to Detect Minimal Residual Disease: Methodology and Impact

“…In the post-curative treatment setting, the success rate of the technique drops. Although it shows a good positive predictive value, the negative predictive value still has room for improvement: when ctDNA is detected post-treatment, patients are significantly more likely to experience relapse in the following months [ 87 , 120 , 121 ]. However, due mainly to technical limitations, not detecting ctDNA after curative-intent treatment does not predict the tumor’s definitive elimination (cf/ Table 2 ).…”

Liquid Biopsies for Molecular Biology-Based Radiotherapy

“…Because these non-genetic signatures are unique to their cells of origin, they could provide a novel marker of tissue-specific pathologies. There is growing interest in using these new approaches as cancer biomarkers that may be complementary to tracking tumor mutations [ 82 , 106 , 150 , 151 , 152 , 153 , 154 , 155 ]. Furthermore, cell-free DNA epigenetic markers have been shown to be associated with normal tissue injury [ 92 , 156 , 157 , 158 ], raising the possibility that cell-free DNA methylation, fragmentomics, and/or cell-free RNA could identify radiation-induced normal tissue toxicity.…”