ctDNA may identify stage III colon cancer patients who benefit from celecoxib

Celecoxib use in stage III colon cancer treatment may lead to improvement in disease-free survival (DFS) and outcomes survival (OS), according to published research in JAMA Oncology this month. Circulating tumor DNA (ctDNA) positive patients who used adjuvant celecoxib with conventional chemotherapy demonstrated statistically significant DFS and OS over placebo.

Colorectal cancer remains one of the most common and deadly malignancies in the United States. Despite advances in surgery and chemotherapy, recurrence rates for stage III colon cancer remain high, with up to 40% of patients experiencing relapse after curative resection. This persistent risk has fueled interest in biomarkers that can refine treatment strategies and identify patients most likely to benefit from adjunctive therapies.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and selective cyclooxygenase-2 (COX-2) inhibitors, have been studied for their potential protective role in colorectal cancer. Observational data suggested reduced recurrence and improved survival, but randomized trials have failed to demonstrate consistent benefit across all patients. The Cancer and Leukemia Group B (CALGB) and Southwest Oncology Group Trial (SWOG 80702) phase 3 trial was designed to evaluate celecoxib, a COX-2 inhibitor, in combination with standard chemotherapy. While initial results showed only modest benefits, investigators hypothesized that certain subgroups might derive greater advantage.

George Zhang M.D., M.P.H., from the department of surgery at Brigham and Women’s Hospital in Boston, and team examined the predictive role of ctDNA in patients enrolled in CALGB/SWOG 80702. Circulating tumor DNA is a portion of the cancer cell’s DNA that is released into the blood when the cell dies.

Researchers assessed postoperative ctDNA status in 940 patients with stage III colon cancer who had undergone curative resection and were randomized to receive either celecoxib or placebo alongside fluorouracil, leucovorin, and oxaliplatin (FOLFOX). Testing of ctDNA was performed with Signatera, a ctDNA assay designed to detect minimal residual disease.

Patients were followed for a median of six years. The primary endpoints were disease-free survival (DFS) and overall survival (OS), stratified by ctDNA status and treatment assignment.

Zhang and the team found that ctDNA positivity was strongly associated with worse outcomes. Patients who were ctDNA positive had an adjusted hazard ratio (aHR) of 6.12 for DFS and 5.86 for overall survival compared with ctDNA-negative patients. Point estimates for 3-year DFS ctDNA negative patients was 86.5% versus 33.7% for ctDNA positive patients. Among ctDNA-positive patients, celecoxib use correlated with improved survival. Three-year DFS was 41.0% with celecoxib versus 22.6% with placebo (aHR, 0.61). Five-year OS was 61.6% versus 39.9% (aHR, 0.62).

In contrast, ctDNA-negative patients did not experience significant survival benefit from celecoxib. Their outcomes remained favorable regardless of treatment assignment, with five-year overall survival exceeding 91%. The findings persisted when stratified by microsatellite instability status and PIK3CA mutational status, suggesting broad applicability of ctDNA as a predictive biomarker. For tumors that were categorized as MSI stable, ctDNA positive patients in the celecoxib cohort achieved an estimated 3year DFS of 39.7% vs 22.3% in the placebo group. Similarly, for tumors marked with high microsatellite instability, the celecoxib group demonstrated improvement in DFS.

The results highlight ctDNA’s potential to refine treatment decisions in stage III colon cancer. For payers, the ability to identify patients who benefit from celecoxib could support more targeted coverage policies, avoiding unnecessary drug costs and exposure in patients unlikely to benefit. Given celecoxib’s established safety profile and relatively low cost compared with newer targeted agents, its use in a biomarker-defined subgroup may represent a cost-effective strategy.

Zhang noted that there are still important questions regarding “optimal integration of COX inhibitors in adjuvant therapy for locally advanced colon cancer.” He adds, “ctDNA may help inform decision-making by identifying a subset of patients who benefit most from adjuvant COX-inhibition alongside conventional chemotherapy, offering opportunities for personalized approaches in CRC treatment.”