We Now Have a Treatment Strategy for ctDNA-Positive Colon Cancer Patients: Celecoxib
In this article
JAMA Oncology • December 4, 2025 • CALGB/SWOG 80702
After surgery for stage 3 colon cancer, circulating tumor DNA (circulating tumor DNA – ctDNA) testing has become one of the most important recent advances. Detecting tumor-specific DNA fragments in a simple blood sample, it reflects invisible minimal residual disease . We now know that postoperative ctDNA positivity, independently of conventional pathological staging and lymph node counts, is one of the strongest known prognostic factors—a relationship repeatedly demonstrated in colon cancer.
Whether ctDNA could move from a ‘prognostic’ to a ‘predictive’ biomarker —showing not only who has a poor prognosis but also which additional treatment might help —has long been an unanswered question. In this new CALGB/SWOG 80702 subgroup analysis in JAMA Oncology, researchers examined, in postoperative ctDNA-positive stage 3 colon cancer patients, whether adding celecoxib to standard adjuvant chemotherapy significantly improves recurrence-free time and overall survival. The study opens a door to using ctDNA as more than a risk indicator: as a compass for personalized treatment decisions.
What does this article explain?
How postoperative ctDNA testing can identify truly high-risk stage 3 colon cancer patients, and the survival contribution of celecoxib + adjuvant chemotherapy in this group.
Why does it matter?
After years of debate about aspirin/NSAID benefit in colon cancer, this study provides concrete numbers showing, for the first time, ctDNA-positive subgroups in which celecoxib actually provides benefit for these patients.
The Aspirin/NSAID Debate in Colon Cancer Enters the ctDNA Era
In colorectal cancer, aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) have long been known to reduce adenoma development and cancer risk. After diagnosis, observational studies have also reported lower recurrence risk among regular aspirin/NSAID users.
However, when these effects are examined across all patients , randomized trials have not shown a clear, consistent benefit. This raised a critical question:
‘Could it be that, rather than every stage 3 colon cancer patient, specific biological subgroups benefit more from COX-2 inhibition?’
This is where circulating tumor DNA (circulating tumor DNA – ctDNA) comes in. Postoperative tumor-derived DNA fragments in blood make ctDNA a strong biomarker of microscopic residual disease and actual recurrence risk.
CALGB/SWOG 80702: A Classic Trial Revisited Through ctDNA
This analysis reassesses data from an older, well-known phase 3 trial (CALGB/Alliance – SWOG 80702) through a fresh ctDNA lens for interpretation.
- Patient group: Treated between 2010–2015, 940 patients with stage 3 colon cancer were included
- Adjuvant treatment: 3 or 6 months of FOLFOX (5-FU, leucovorin, oxaliplatin)
- Additional treatment arm: For 3 years, celecoxib 400 mg daily or placebo
- ctDNA assessment: Between surgery and adjuvant chemotherapy initiation, using a tumor-specific, 16-target PCR–NGS (Signatera) test
The central question was: ‘Does postoperative ctDNA status (positive/negative) modify celecoxib’s effect on survival?’
ctDNA • PROGNOSTIC POWER
ctDNA Positivity: 6-Fold Higher Recurrence Risk
Among 940 patients, 81.6% were ctDNA-negative, 18.4% were ctDNA-positive . Approximately 1 in every 5 still had tumor DNA in their blood despite surgery.
- Disease recurrence / death risk (DFS): In ctDNA-positive patients, 6.12 times higher (AHR 6.12; 95% CI 4.66–8.03)
- Overall survival (OS) risk: In ctDNA-positive patients, 5.86 times worse (AHR 5.86; 95% CI 4.19–8.19)
These figures again confirm that, in stage 3 colon cancer, ctDNA is one of the strongest prognostic markers in this disease.
ctDNA-POSITIVE • CELECOXIB EFFECT
Significant Survival Gain in the High-Risk Group
In ctDNA-positive patients, adding celecoxib to adjuvant chemotherapy produced:
- Disease-free survival (DFS): AHR 0.61 → recurrence/death risk fell by approximately 39%
- Overall survival (OS): AHR 0.62 → mortality risk fell by approximately 38%
The abstract states that 3-year disease-free survival in ctDNA-positive patients rose from 22.6% to 41% . Thus, nearly one in two peopleappears to gain an additional opportunity to prevent recurrence with celecoxib.
ctDNA-NEGATIVE • CELECOXIB EFFECT
No Apparent Additional Benefit in the Low-Risk Group
Adding celecoxib in ctDNA-negative patients:
- DFS: AHR 0.76; 95% CI 0.53–1.09
- OS: AHR 0.85; 95% CI 0.54–1.36
Because confidence intervals cross 1 , no statistically significant benefit can be claimed in this group. Celecoxib therefore does not appear to be a routine additional treatment for ctDNA-negative patients without microscopic residual disease.
MSI, PIK3CA, and Safety: How Generalizable Are the Findings?
Researchers examined whether celecoxib’s effects were similar across biological subgroups:
- Microsatellite instability (MSI) status stratification produced consistent results.
- PIK3CA mutation status did not eliminate the celecoxib benefit in the ctDNA-positive group when considered.
The study also reports safety. Earlier CALGB 80702 analyses highlight concerns with long-term COX-2 inhibitors, particularly cardiovascular risks; however, this analysis reported no notable new safety signal with treatment.
Important note: Long-term celecoxib or other NSAID use may carry cardiovascular, renal, and gastrointestinal risks. This study therefore neither says ‘prescribe celecoxib to every stage 3 patient’ nor supports generalization independently of ctDNA results.
Personalizing Treatment Through ctDNA: Next Steps
This post hoc analysis offers several important messages:
- 1. ctDNA is an exceptionally strong prognostic marker in stage 3 colon cancer.
Positivity means, for disease-free and overall survival, a 5–6-fold worse course. - 2. Celecoxib may significantly improve survival in the ctDNA-positive subgroup.
An approximately 40% risk reductionis clinically noteworthy in these particularly high-risk patients. - 3. Additional celecoxib does not show enough benefit in ctDNA-negative patients for routine use.
This highlights the transition from ‘the same treatment for everyone’ toward biomarker-guided treatment in practice.
Because this study is post hoc , its findings generate hypotheses, and prospective, ctDNA-targeted randomized trials are needed. The direction is nevertheless clear: future adjuvant decisions will be shaped not only by stage or lymph node counts but by dynamic biomarkers such as ctDNA.
Source
Zhang GQ, Meyerhardt JA, Shi Q, et al. Predictive Role of Circulating Tumor DNA in Stage III Colon Cancer Treated With Celecoxib: A Post Hoc Analysis of the CALGB (Alliance)/SWOG 80702 Phase 3 Randomized Clinical Trial. JAMA Oncology. Published online: December 4, 2025; doi:10.1001/jamaoncol.2025.5144.
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