Stacey Cohen, MD, Fred Hutchinson Cancer Center at University of Washington, Seattle, WA, reviews the results of a study she presented at the 2023 ASCO Gastrointestinal Cancers Symposium, evaluating how the fluctuating levels of post-operative cell-free DNA may impact the ability to detect circulating tumor DNA among patients with colorectal cancer.

Dr Cohen explained the results suggest that while there is a significant increase of cell-free DNA in the first 2 weeks following surgery, there is no correlation between higher cell-free DNA and the ability to detect ctDNA. Further, molecular residual disease testing had a similar sensitivity in weeks 2 to 4 post-surgery and weeks 4 to 8. Dr Cohen noted this suggests “standard MRD testing windows could begin as early as 2 weeks after surgery.”

Transcript:

Hi, I'm Stacey Cohen and I'm an associate professor at Fred Hutchinson Cancer Center at the University of Washington in Seattle, Washington. And I wanted to share some highlights from my recent talk at the 2023 ASCO GI Symposium evaluating the kinetics of postoperative circulating cell-free DNA and impact on MRD [molecular residual disease] detection in patients with resected stage one to three colorectal cancer.

So as background, we know that ctDNA [circulating tumor DNA] has emerged as a strong prognostic and predictive biomarker, but we've not yet figured out whether frequencies of cell-free DNA fluctuating after, say surgery or chemotherapy, have those affect or ability to detect ctDNA. We sought to answer this question by evaluating a large database of patients with commercially ordered ctDNA testing, the Signatera Tumor-Informed ctDNA Assay, and evaluating their DNA kinetics and its impact on ctDNA detection.

In taking all patients with commercial testing, we excluded patients with rectal cancer to avoid the impact of neoadjuvant therapy, and ended up with a database of 14 425 patients with stage 1 to 3 colon cancer with at least one ctDNA result. And then we have a fully annotated subset of 450 patients. About 60% of these patients had MRD testing in the first 12 weeks after surgery, but we did have heterogeneity across our sample as this was commercially driven real-world data. In evaluating the cell-free DNA dynamics, as expected, we saw an increase compared to baseline or preoperative draws. We saw an increase in the time period of 0 to 2 weeks, which decreased at 2 to 4 weeks and further decreased at 4 to 8 weeks. And these changes were statistically significant. We saw similar trends in the full cohort and in the annotated cohort.

Additionally, when we evaluated the impact of chemotherapy, we did see higher levels of cell-free DNA in patients on chemotherapy compared to patients who were not on chemotherapy. Then we looked at the ability to detect ctDNA, and we saw a lot of variability, especially in week 1 after surgery on cell-free DNA, and also variability in ctDNA positivity, which was less in week 2 and more consistent thereafter. About 17% to 18% of our group had ctDNA positivity after 2 weeks, and this decreased somewhat after 8 weeks, likely the result of adjuvant chemotherapy. And again, the most variability was in the first week, so we're not sure that at that time point it's reliable to detect ctDNA. But after 2 weeks, our rates were pretty consistent.

We did perform a multivariate analysis looking at the impact of cell-free DNA concentration, as well as timing and other clinical features, and did not see that these impacted our ability to detect ctDNA. And similarly, when we looked in the fully annotated cohort, we saw that MRD remained a strong predictive feature for rapport recurrence. While cell-free DNA concentration did not affect our ability to detect ctDNA or have impact on recurrence-free survival.

Our conclusion from this study is that cell-free DNA concentration does significantly increase in the first 2 weeks after surgery, but that higher cell-free DNA concentrations do not impact our ability to detect ctDNA, and that MRD testing between weeks 2 to 4 had fairly similar sensitivity to weeks 4 to 8. Therefore, standard MRD testing windows could start as early as 2 weeks after surgery, which would be day 15 and beyond.

Thank you.

Source:

Cohen SA, Kasi PM, Aushev VN, et al. Kinetics of postoperative circulating cell-free DNA and impact on minimal residual disease detection rates in patients with resected stage I-III colorectal cancer. Presented at ASCO Gastrointestinal Cancers Symposium; January 19-21; San Francisco, CA. Abstract 5