SAN FRANCISCO — In patients who have undergone surgery for colorectal cancer, monitoring levels of circulating tumor DNA (ctDNA) in the weeks after the operation can provide prognostic information.
For example, patients who showed ctDNA positivity during the molecular residual disease (MRD) time window of 2-8 weeks and during surveillance (defined as > 6 months postoperatively and subsequent to any adjuvant therapy) had significantly worse recurrence-free survival compared with patients who were ctDNA negative (MRD HR, 14.1; P < .0001; surveillance HR, 20.6; P < .0001).
However, during this postsurgery period, there is an increase in the concentration of cell-free DNA (cfDNA), which is significantly increased in the first 2 weeks after surgery and then gradually declines. So far, it has not been clear whether or not rising cfDNA interferes with the measurement of ctDNA in this patient population. Results from a new study suggest they do not.
“In our analysis, ctDNA can be reliably evaluated starting in week 3 after surgery, regardless of underlying cfDNA concentration,” said lead author Stacey A. Cohen, MD, of the Fred Hutchinson Cancer Center and University of Washington, Seattle. “Positive ctDNA is highly associated with poor recurrence-free survival, and for patients seeking to include ctDNA in their medical decision-making, these results suggest that earlier testing of ctDNA is possible.”
“Earlier testing may improve feasibility of ctDNA testing by minimizing time to receipt of results,” she added. The study used the Signatera assay, manufactured by Natera, to measure ctDNA.
Cohen presented the new results here at the ASCO Gastrointestinal Cancers Symposium (GICS) 2023.
Strong Prognostic Factor
Cohen explained that ctDNA has emerged as a strong prognostic and predictive biomarker in colorectal cancer, but added that there has been concern that in some scenarios, such as after surgery or during systemic chemotherapy, an increase in cfDNA could decrease the ability to detect ctDNA.
As recently reported by Medscape Medical News, updated results from the GALAXY study showed that patients with colorectal cancer who were MRD-positive 4 weeks after surgery (18%) had significant benefit from receiving adjuvant chemotherapy, but conversely, those who were MRD-negative (82%) did not.
GALAXY is part of the ongoing CIRCULATE-Japan trial, which according to the authors, is one of the largest and most comprehensive prospective studies of MRD testing in resectable colorectal cancer and is using the Signatera assay to monitor ctDNA.
During her presentation, Cohen noted that the ideal timing for testing ctDNA to best get assay sensitivity has been unclear. “So that prompted us to evaluate cfDNA kinetics and the impact on detecting molecular residual disease in a large group of colon cancer patients who had commercially ordered the assay,” she said.
Study Details
Cohen and colleagues conducted a retrospective study that included 14,425 patients with stage I-III colorectal cancer who had undergone surgical resection. This study was conducted in a “real-world setting,” and patients had ctDNA detected at the recommendation and timing of their provider, the authors commented.
There was an annotated subset of 450 patients from whom clinicians had submitted clinical information, providing details about treatment regimen and recurrence.
The median follow-up for relapsed and nonrelapsed patients was 730 and 615 days, respectively, and the Signatera assay was used to quantify ctDNA prior to surgery and postoperatively. The kinetics of total cfDNA was analyzed and then compared with the ctDNA MRD positivity rates at various time points after surgery.
“Importantly, about 60% or over 8000 patients had their first ctDNA draw within the classic MRD time window of 0 to 12 weeks,” said Cohen.
Even though cfDNA levels were higher, 30.6% of patients with immediate postoperative draws were ctDNA positive. They observed similar ctDNA detection rates within the conventional MRD windows after resection, whether defined as 2-6 weeks (20.8%) or 2-8 weeks (20.9%).
“Within our annotated cohort, we are able to look at the effect of chemotherapy versus not being on chemotherapy,” said Cohen. “So we have the patients who are actively on treatment, and we saw a higher level of cfDNA as expected than patients who were on surveillance.”
In the overall cohort, although data on chemotherapy was unavailable, researchers were able to estimate that patients who were 8 weeks or up to 8 months from surgery might have been on chemotherapy.
An analysis of cfDNA dynamics during adjuvant therapy showed that cfDNA levels gradually increased between 8 weeks and 8 months after surgery (P = .0001), suggesting a potential impact of treatment on cell death and shedding of cfDNA.
“In the multivariate analysis, we saw no impact on cfDNA concentration, and MRD remained the strongest predictor of recurrence-free survival,” Cohen concluded. “cfDNA concentration is significantly increased in the first 2 weeks after surgery, and higher levels of cfDNA do not seem to impact our ability to detect ctDNA. “
She added that high ctDNA positivity is seen in the first week after surgery and then declines, “so we suspect that may relate to micrometastatic disease that’s cleared by the immune system, and further investigation needs to be done in this area.”
No Changes in Clinical Practice
During a discussion of the paper, Dustin Deming, MD, of the University of Wisconsin–Madison, pointed out that the study had several limitations, including being a retrospective real-world study, and that patients were not analyzed serially, “meaning we don’t have data based on how these patients did at the 2- to 4-week and the 4- to 8-week time points as far as their ctDNA analysis,” he said. “And the analysis was not able to be done comparing the prognostic significance of MRD testing at 2 to 4 weeks versus at 4 to 8 weeks.”
Overall, this study does not change standard clinical practice. “MRD testing is still not the standard of care for patients with resectable colorectal cancer,” Deming said.
“However, this research does have significant implications for clinical trials,” he added. “The timing of the MRD testing and the timing to adjuvant therapy are important areas that need to be prospectively examined, or at least post-hoc examined, as part of the ongoing clinical trials to see if the timing of MRD testing or the timing or adjuvant therapy alters the clinical outcomes for those patients.”
Deming added that if he was designing a new ctDNA study, he would consider actually initiating the testing at 2 weeks “because I feel very comfortable that if a patient had a blood draw at 2 weeks and the DNA was positive that I would want to escalate therapy as part of the clinical trial for that patient.”
“But if the test was negative for an individual patient at this time, I’m still concerned that potentially the cfDNA for that individual patient could have altered that result and would want an additional assay drawn at a later time point when the cfDNA would be less.”
The study was funded by Natera. Cohen has reported relationships with the Association of Community Cancer Centers, Bayer, Istari Oncology, Kallyope, Pfizer, Taiho Oncology, Boston Biomedical, EMD Serono/Merck, Isofol Medical, Natera, Polaris, Helsell Fetterman, and Robins Kaplan. Deming has reported relationships with Bayer, Lilly, Pfizer, Seattle Genetics, Aadi Bioscience, Arcus Ventures, Bristol-Myers Squibb, Curegenix, Genentech, Merck, Millennium, Natera, Promega, Revolution Medicines, and Strata Oncology.
ASCO GICS 2023. Abstract 5. Presented January 21, 2023.
Roxanne Nelson is a registered nurse and an award-winning medical writer who has written for many major news outlets and is a regular contributor to Medscape.
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