SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.
It is estimated that approximately 30% of patients with Stage II or III CRC and 60-70% of patients after oligometastatic resection experience recurrence. Adjuvant chemotherapy for patients with resected, locally advanced, node-positive (Stage III) colon cancer has been the standard of care since the 1990s. However, not all patients with Stage III disease benefit from adjuvant chemotherapy. In the IDEA trial, the absolute Disease Free Survival benefit of adjuvant chemotherapy for the lowest-risk Stage III group and the highest-risk group was 8% and 20%, respectively, suggesting that a substantial number of patients with low-risk Stage III cancer can safely forgo adjuvant chemotherapy or be considered for treatment de-escalation.
More recent data suggests that platelets may play a role in tumorigenesis as well, through the release of angiogenic and growth factors due to overexpression of Cyclooxygenase 2 (COX-2). Aspirin and COX-2 inhibitors such as Celecoxib have been associated with a reduced risk of colorectal polyps and cancer in observational and randomized studies.
The CALGB/SWOG 80702 is a randomized Phase III trial conducted to determine if the addition of Celecoxib to adjuvant chemotherapy with Fluorouracil, Leucovorin, and Oxaliplatin (FOLFOX) improves Disease-Free Survival (DFS) in patients with Stage III colon cancer. Patients were randomized to receive adjuvant FOLFOX (every 2 weeks) for 3 versus 6 months with or without 3 years of Celecoxib (400 mg orally daily; N=1263) versus placebo; N=1261). In this study, the addition of Celecoxib for 3 years to standard adjuvant chemotherapy did not significantly improve Disease-Free Survival (DFS).
The present analysis evaluated the prognostic and predictive value of circulating tumor DNA (ctDNA) in identifying a subpopulation of patients in the above study, who may potentially benefit from Celecoxib therapy. A subset of 1,011 patients from the CALGB/SWOG 80702 trial with adequate biospecimen availability was included in this analysis. ctDNA status was assessed using a tumor-informed, clinically validated 16-plex multiplex Polymerase Chain Reaction Next-Generation Sequencing (mPCR-NGS) assay (Signatera(TM), Natera, Inc.). Plasma samples were collected post-surgery and before the initiation of adjuvant chemotherapy. Survival outcomes, including DFS and Overall Survival (OS), were analyzed using Kaplan-Meier estimates and Cox proportional hazards models.
Results:
- Of the 1,011 patients with ctDNA data, 189 (18.7%) tested ctDNA-positive.
- ctDNA positivity correlated with male sex, advanced T stage, and N2 nodal disease.
- Patients with detectable ctDNA had significantly worse outcomes:
- DFS: Hazard Ratio (HR)=6.52; P<0.0001
- OS: HR=6.28; P<0.0001
- Three-year DFS rates were:
- 6% in ctDNA-negative patients
- 8% in ctDNA-positive patients
- Celecoxib did not significantly impact DFS in ctDNA-negative patients (HR=0.75; P=0.095, 3-year DFS: 87.7% vs. 85.5%).
- However, in ctDNA-positive patients, Celecoxib was associated with a notable improvement in DFS (HR=0.59; P=0.004, 3-year DFS: 44.1% vs. 26.6%).
- OS trends mirrored those observed for DFS:
- ctDNA-negative group: HR=0.86 (P=0.49) with Celecoxib versus placebo.
- ctDNA-positive group: HR=0.63 (P=0.028) with Celecoxib versus placebo.
- Multivariate analysis confirmed a statistically significant benefit of Celecoxib in ctDNA-positive patients.
Conclusion: ctDNA serves as a strong prognostic biomarker for both DFS and OS in Stage III colon cancer. Furthermore, ctDNA positivity appears to predict a significant therapeutic benefit from adjuvant Celecoxib, suggesting its potential role in stratifying patients for COX-2 inhibitor therapy. These findings highlight the utility of ctDNA assessment in guiding adjuvant treatment decisions and optimizing personalized therapeutic strategies in colon cancer.
Clinical Implications:
- Post-surgical ctDNA testing can help identify patients at elevated risk of recurrence.
- Celecoxib may offer a survival advantage for ctDNA-positive patients when used alongside standard FOLFOX chemotherapy.
- Further research is warranted to elucidate the role of ctDNA-guided treatment in personalizing colon cancer therapy.
Prognostic and predictive role of circulating tumor DNA (ctDNA) in stage III colon cancer treated with celecoxib: Findings from CALGB (Alliance)/SWOG 80702. Nowak JA, Shi Q, Twombly T, et al. J Clin Oncol. 2025;43(4):LBA14.
