ctDNA Status May Be Prognostic for DFS With Celecoxib for Stage III Resected Colon Cancer

Celecoxib improved disease-free survival in patients with stage III colon cancer who had circulating tumor DNA in their blood.

In patients with stage III resected colon cancer, positive circulating tumor DNA (ctDNA) was associated with worse disease-free survival (DFS) overall, although a subgroup analysis of the phase 3 CALGB (Alliance)/SWOG 80702 trial (NCT01150045) presented at the 2025 Gastrointestinal Cancers Symposium showed that celecoxib (Celebrex) significantly improved DFS in ctDNA-positive patients compared to placebo.¹

Among patients with ctDNA-negative colon cancer following surgery and before treatment with celecoxib or placebo (n = 767), the estimated 3-year DFS rate was 86.5% (95% CI, 84.0%-89.1%). Among those with ctDNA-positive disease (n = 173), this estimated rate was 33.7% (95% CI, 27.1%-41.8%; log-rank P < .0001).

“In a subset of patients enrolled in CALGB/SWOG 80702, ctDNA status after surgery and prior to starting adjuvant therapy was highly prognostic of DFS and overall survival [OS],” Jonathan Nowak, MD, PhD, lead study author, said in a press briefing ahead of the presentation of the data. “Additionally, ctDNA status appeared predictive of the benefit of adjuvant celecoxib.”

Nowak is an investigator at the Hale Family Center for Pancreatic Cancer Research at Dana-Farber Cancer Institute and an assistant professor of pathology at Harvard Medical School in Boston, Massachusetts.

When patients were stratified by treatment with celecoxib vs placebo, investigators showed that patients with ctDNA-negative disease at the time of study enrollment had similar outcomes regardless of whether they received celecoxib or placebo, with estimated 3-year DFS rates of 87.4% (95% CI, 84.0%-91.0%) and 85.6% (95% CI, 82.0%-89.4%), respectively (HR, 0.76; 95% CI, 0.54-1.08; P = .1293). However, among patients with ctDNA-positive disease, a significant DFS benefit was seen in the celecoxib arm vs the placebo arm, with estimated 3-year DFS rates of 41.0% (95% CI, 32.2%-52.2%) vs 22.6% (95% CI, 14.3%-35.5%), respectively (HR, 0.55; 95% CI, 0.39-0.80; P = .0013).

Trial Background and Rationale

“Approximately one-third of patients diagnosed with colon cancer have regional lymph node involvement,” Nowak said. “Despite optimal surgery and adjuvant chemotherapy, approximately 20% to 70% of patients with stage III disease will have a recurrence. Additional strategies beyond standard chemotherapy are needed to reduce risk of recurrent disease and improve survival. One promising option is to use post-resection ctDNA status, which can tell us if any residual micrometastatic disease is present in order to help guide adjuvant treatment decisions.”

Prior research has shown that patients with colon cancer and colon cancer survivors who receive aspirin or COX-2 inhibitors experience favorable DFS and OS outcomes. For instance, a prospective, observational study showed that among 843 evaluable patients with stage III colon cancer who were enrolled in an adjuvant chemotherapy trial, those who used COX-2 inhibitors had improved 5-year DFS rate (HR, 0.47; 95% CI, 0.24-0.91) and OS rate (HR, 0.26; 95% CI, 0.08-0.81) compared with nonusers.²

Trial Design and Previously Reported Findings

The CALGB/SWOG 80702 trial formally tested whether COX-2 inhibition with celecoxib improved survival in patients with colon cancer.¹ To be eligible for trial enrollment, patients needed to have resected stage III colon adenocarcinoma without metastatic disease, and at least 1 pathologically confirmed positive lymph node or N1c disease per American Joint Committee on Cancer version 7 criteria. Patients were not eligible for enrollment if they used nonsteroidal anti-inflammatory drugs at any dose more often than 2 times per week or aspirin more than 325 mg 3 times per week. However, patients using low-dose aspirin not exceeding a dose of 100 mg per day were permitted to enroll.

Patients were randomly assigned to receive daily treatment with either celecoxib at 400 mg or placebo in combination with either 6 or 12 treatments of FOLFOX (leucovorin calcium, fluorouracil, and oxaliplatin) as follows: placebo plus 12 FOLFOX treatments (arm A), celecoxib plus 12 FOLFOX treatments (arm B), placebo plus 6 FOLFOX treatments (arm C), or celecoxib plus 6 FOLFOX treatments (arm D). Celecoxib or placebo was continued for 3 years from study drug initiation.

The trial had a target sample size of 2500 patients; 2526 total patients were enrolled, and 2524 patients were included.³ DFS served as the trial’s primary end point. In the primary analysis, investigators observed no statistically significant DFS difference with celecoxib vs placebo (HR, 0.89; 95% CI, 0.76-1.03; stratified log-rank P = .12). Furthermore, the effects of celecoxib treatment were not significantly different based on assigned adjuvant FOLFOX duration.

ctDNA Analysis Rationale and Additional Findings

In the Gastrointestinal Cancers Symposium analysis, Nowak noted that the HR and Kaplan-Meier curves for DFS in the primary analysis indicated that a subgroup of patients may derive benefit from adjuvant celecoxib.¹

To identify whether any patient subgroup derived greater benefit from celecoxib treatment compared with the overall population, investigators retrospectively performed a ctDNA analysis using the Signatera minimal residual disease assay on banked plasma specimens from trial patients that were collected after surgery and before trial enrollment.

Nowak highlighted that findings from this subgroup analysis “also held true in multivariable adjusted models for both DFS and OS when the factors that are commonly known to predict colon cancer survival [were] included in the model.”

In the multivariable analysis, among ctDNA-negative patients, the HR for DFS with celecoxib vs placebo was 0.76 (95% CI, 0.53-1.08; adjusted P = .1262), and the HR for OS was 0.84 (95% CI, 0.53-1.34; adjusted P = .4593). Among ctDNA-positive patients, the HR for DFS with celecoxib vs placebo was 0.63 (95% CI, 0.43-0.92; adjusted P = .0167), and the HR for OS was 0.63 (95% CI, 0.40-0.98; adjusted P = .0419).

Nowak concluded by explaining that sensitivity and subgroup analyses of this trial are ongoing, as well as studies evaluating the predictive value of ctDNA for 3 vs 6 months of adjuvant FOLFOX in this patient population.

References

1. Nowak JA, Shi Q, Twombly T, et al. Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: findings from CALGB (Alliance)/SWOG 80702. J Clin Oncol. 2025;43(4):LBA14. Presented at: 2025 Gastrointestinal Cancers Symposium; January 23-25, 2025; San Francisco, CA. LBA14.
2. Ng K, Meyerhardt JA, Chan AT, et al. Aspirin and COX-2 inhibitor use in patients with stage III colon cancer. J Natl Cancer Inst. 2014;107(1):345. doi:10.1093/jnci/dju345
3. Meyerhardt JA, Shi Q, Fuchs CS, et al. Effect of celecoxib vs placebo added to standard adjuvant therapy on disease-free survival among patients with stage II colon cancer: the CALGB/SWOG 80702 (Alliance) randomized clinical trial. JAMA. 2021;325(13):1277-1286. doi:10.1001/jama.2021.2454