Circulating tumor (ct)DNA could be used to identify which patients with stage III colon cancer (CRC) are most likely to benefit from treatment with the cyclooxygenase (COX) inhibitor celecoxib in addition to conventional chemotherapy, say researchers.
“These findings are the first to implicate MRD [molecular residual disease], as assessed by ctDNA, as a potential predictor of therapeutic response to adjuvant COX-inhibition in CRC,” write George Zhanh, MD, MPH, (Brigham and Women’s Hospital, Boston, Massachusetts) and study co-authors of in JAMA Oncology.
They explain that although ctDNA has a well-established role in predicting prognosis, its value in guiding treatment remains unclear.
To investigate, the team carried out a post-hoc analysis of the Phase III CALGB/SWOG 80702 trial, which was developed, in part, to prospectively evaluate adjuvant celecoxib based on the rationale that observational studies have associated selective COX inhibitor use with decreased recurrence and improved survival in patients with colon cancer.
The trial randomly assigned patients with stage III CRC who had undergone curative surgery to receive either three or six months of adjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) alongside either celecoxib 400 mg daily or placebo for three years.
The primary analysis found no statistically significant difference in disease-free survival (DFS) rates between patients given celecoxib and those who received placebo. However, the researchers note that the hazard ratio (HR) of 0.89 they observed suggests a potential benefit in some patients and highlights the need for tailored therapeutic approaches based on risk stratification.
The current post-hoc analysis included data for 940 patients (mean age, 61 years, 55% men) who were tested for ctDNA using 16-plex-polymerase chain reaction next generation sequencing (Signatera; Natera) on plasma samples that were taken after surgery but before the initiation of adjuvant therapy. Of these, 18.4% were ctDNA positive.
Zhang and co-investigators report that, across all patients, ctDNA status was highly predictive of DFS and overall survival (OS) during a median six years of follow-up.
Specifically, patients who were ctDNA positive were a significant 6.1 times more likely to experience disease recurrence or death and 5.9 times more likely to die than those who were ctDNA negative, after adjustments for baseline demographic, pathologic, and molecular factors.
Estimated three-year DFS was 33.7% for ctDNA positive patients compared with 86.5% for those who were ctDNA negative, while estimated five-year OS rates were 52.6% and 91.5% respectively.
Among the patients who were ctDNA positive, the researchers found that celecoxib use was associated with significantly improved DFS relative to placebo, with estimated three-year DFS rates of 41.0% versus 22.6%. The difference between the two groups corresponded to a significant 39% lower risk for recurrence or death among the patients given celecoxib.
Similarly, celecoxib use was associated with a significant 38% lower risk for all-cause death versus placebo among the ctDNA positive patients, with estimated five-year OS rates of 61.6% and 39.9%, respectively.
By contrast, among patients who were ctDNA negative, there was no statistically significant difference in DFS between those given celecoxib or placebo (87.4 vs 85.6%), nor was there a difference in OS (91.8 vs 91.3%).
Zhang et al. acknowledge that the interaction between ctDNA status and treatment group did not reach statistical significance in the full cohort but was significant in a subanalysis restricted to high quality ctDNA results.
They also point out that the 18.4 percentage point improvement in estimated three-year DFS among patients who were ctDNA positive suggests “a potentially clinically meaningful effect” when compared with the 1.8 percentage point difference in those who were ctDNA negative.
The authors conclude that “ctDNA may help inform decision-making by identifying a subset of patients who benefit most from adjuvant COX-inhibition alongside conventional chemotherapy and may offer opportunities for personalized approaches in CRC treatment.
They add: “Analyses examining ctDNA status and the CALGB/SWOG 80702 trial’s second randomization factor of three vs. six months of adjuvant FOLFOX are under way and will be reported separately.”
