Following surgery to remove a colorectal tumor, patients may have molecular measurable residual disease (MRD). Circulating tumor DNA (ctDNA), or liquid biopsy, may be used to detect molecular MRD in patients who underwent surgery for colorectal cancer and to determine whether they may benefit from receiving adjuvant chemotherapy. The research will be presented at the 2024 ASCO Gastrointestinal Cancers Symposium by Yukami et al (Abstract 6).
About the Study
“Since the current treatment paradigm for postoperative chemotherapy is largely based on cancer stage and other clinicopathologic risk factors, monitoring ctDNA status with a highly validated assay allows us to develop a personalized treatment plan for each patient,” said lead study author Hiroki Yukami, MD, of the Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University.
In this updated analysis from the GALAXY study, researchers used a blood test that is custom-built based on the somatic variants found in each patient’s tumor tissue to detect ctDNA following surgery (Signatera). These variants were then tracked in the patient’s plasma samples during serial blood draws at 1, 3, 6, 9, 12, 18, and 24 months after surgery or until disease recurrence. Patients also underwent computed tomography scans of the chest, abdomen, and pelvis every 6 months.
The analysis included 2,998 patients; 1,130 patients received adjuvant chemotherapy, and 1,868 patients underwent observation. The primary endpoint was disease-free survival, defined as the time between the date of surgery and the date of cancer recurrence or death from any cause.
Key Findings
During the 2- to 10-week window to detect molecular MRD after surgery, ctDNA results were available for 2,860 patients; 369 (2.9%) were ctDNA-positive, and 2,491 (87.1%) were ctDNA-negative. Patients who were ctDNA-positive had significantly inferior disease-free survival compared with patients who were ctDNA-negative.
An analysis of ctDNA dynamics from postoperative molecular MRD detection to a 6-month time point revealed that patients who remained ctDNA-positive were over five times more likely to experience a cancer recurrence than those who had ctDNA clearance, meaning there was no molecular MRD detected.
Among the 445 ctDNA-positive patients in the full study population, 240 received adjuvant chemotherapy, 66.3% of whom had ctDNA clearance. For patients whose ctDNA was positive after surgery, and whose ctDNA turned negative upon chemotherapy, 58% had sustained clearance compared with 42% of patients who eventually returned to ctDNA-positive status. Patients with sustained ctDNA clearance had significantly better disease-free survival than did those who achieved ctDNA clearance temporarily, meaning ctDNA negativity turned to ctDNA positivity (24-month disease-free survival rate = 90.1% vs 2.3%).
Among ctDNA-positive patients treated with adjuvant chemotherapy, a decrease in ctDNA levels of at least 50% at 6 months was associated with better disease-free survival compared with patients with a < 50% decrease or increase in ctDNA levels (24-month disease-free survival rate = 51% vs 29%).
“These findings may allow us to spare a considerable number of ctDNA-negative patients the toxicity of chemotherapy without compromising their long-term survival and identify ctDNA-positive patients who should receive chemotherapy. Monitoring ctDNA during surveillance allows for early detection of cancer recurrence, which can potentially enable early intervention, improve the chances of a cure, and/or extend survival,” said Dr. Yukami.
Next Steps
The authors plan to further validate the use of ctDNA to guide patient management by studying the addition of trifluridine/tipiracil compared with placebo in patients with colorectal cancer who are ctDNA-positive at any time after surgery. They are also studying the possibility of omitting adjuvant chemotherapy in patients with colorectal cancer who are ctDNA-negative during the window to detect molecular MRD after surgery.
ASCO Expert Perspective
“This is the first study to not only demonstrate the significance of sustained ctDNA clearance, but also that a dynamic change in ctDNA of more than 50% at 6 months of adjuvant chemotherapy was associated with improved disease-free survival,” said Cathy Eng, MD, FACP, FASCO, an ASCO Expert in gastrointestinal gancers.
Disclosure: This research was funded by the Japan Agency for Medical Research and Development. For full disclosures of the study authors, visit coi.asco.org.
