Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with recurrence after treatment posing a significant challenge. The CALGB/SWOG 80702 trial explored the potential of circulating tumor DNA (ctDNA) as a biomarker for predicting disease recurrence and survival outcomes in patients with resected stage III CRC. Presented by Dr. Jonathan A. Nowak at the ASCO Gastrointestinal Cancers Symposium, the study assessed the prognostic value of ctDNA and its implications for guiding adjuvant treatment decisions.The CALGB/SWOG 80702 trial enrolled 2,526 patients with resected adenocarcinoma of the colon without metastatic disease. Of these, 1,752 patients consented to biospecimen collection, leading to the successful banking of tumor tissue. Whole exome sequencing data were generated for 1,197 patients, and sufficient plasma for ctDNA testing was available for 1,011 patients. After excluding samples collected outside the immediate post-surgical period, a total of 940 patients were evaluated for ctDNA status.
Among these patients, 18.4 percent were ctDNA-positive, while 81.6 percent were ctDNA-negative. The study aimed to determine the prognostic significance of ctDNA detection in post-resection CRC patients and its correlation with disease-free survival (DFS).
Baseline Characteristics
Baseline characteristics of the cohort revealed key clinical and demographic differences between ctDNA-positive and ctDNA-negative patients. The median age was similar across groups, with a mean of 60.8 years. However, sex distribution showed a higher prevalence of ctDNA positivity in males (64.7 percent) compared to females (35.3 percent), a difference that was statistically significant (p = 0.003).
Tumor staging analysis demonstrated that ctDNA-positive patients had a higher proportion of advanced T4 tumors (20.9 percent) compared to ctDNA-negative patients (11.9 percent), with a p-value of 0.001. Similarly, N-stage analysis indicated that 47.7 percent of ctDNA-positive patients had N2 disease, compared to 24.1 percent in the ctDNA-negative cohort, with a highly significant p-value of <0.0001. These findings suggest that ctDNA positivity is associated with more advanced disease at diagnosis.
Disease-Free and Overall Survival Outcomes
The study demonstrated a strong correlation between ctDNA positivity and poor DFS. Patients with ctDNA-negative status had a significantly higher three-year survival estimate of 86.5 percent (95% CI: 84.0 – 89.1 percent), whereas ctDNA-positive patients had a markedly lower survival rate of 33.7 percent (95% CI: 27.1 – 41.8 percent). The hazard ratio for ctDNA positivity was 7.14 (95% CI: 5.54 – 9.21), with a log-rank p-value of <0.0001, indicating a statistically significant association between ctDNA status and disease recurrence.
Similarly, overall survival analysis revealed that ctDNA-negative patients had a five-year survival estimate of 91.5 percent (95% CI: 89.5 – 93.6 percent), while ctDNA-positive patients had a substantially lower survival rate of 52.6 percent (95% CI: 45.3 – 61.0 percent). The hazard ratio for ctDNA positivity was 6.72 (95% CI: 4.91 – 9.18), with a log-rank p-value of <0.0001.
Impact of Adjuvant Celecoxib on Survival Outcomes
The study further investigated whether ctDNA status influenced the benefit of adjuvant celecoxib therapy. Among ctDNA-negative patients, there was no statistically significant difference in survival outcomes between those receiving celecoxib and those receiving placebo (hazard ratio: 0.81; 95% CI: 0.56 – 1.18, p = 0.277). However, in ctDNA-positive patients, celecoxib appeared to confer a survival benefit, with a hazard ratio of 0.61 (95% CI: 0.41 – 0.92, p = 0.016).
Similarly, in microsatellite stable tumors, ctDNA-positive patients receiving celecoxib had an improved three-year survival estimate of 39.7 percent (95% CI: 30.6 – 51.5 percent) compared to 22.3 percent (95% CI: 13.9 – 35.8 percent) in the placebo group (p = 0.0055). These findings suggest that celecoxib may be more beneficial in ctDNA-positive patients.
Conclusions and Future Directions
The findings from the CALGB/SWOG 80702 trial underscore the importance of ctDNA as a prognostic biomarker in CRC. CtDNA positivity after surgery and before adjuvant therapy was strongly associated with increased risk of recurrence and poor overall survival. Moreover, ctDNA status appeared predictive of the benefit of adjuvant celecoxib therapy, particularly in high-risk patients.
Ongoing studies are evaluating the predictive value of ctDNA for guiding treatment duration, specifically comparing three versus six months of adjuvant FOLFOX chemotherapy. Sensitivity and subgroup analyses are also underway to further refine the clinical utility of ctDNA testing. These findings highlight the potential for ctDNA-guided therapeutic strategies to improve patient outcomes and personalize CRC management in the future.
