Clinical trial and real-world evidence of circulating tumor DNA monitoring to predict recurrence in patients with resected colorectal cancer

Abstract

Background

Circulating tumor DNA (ctDNA) is a novel biomarker to predict recurrence in colorectal cancer (CRC). However, clinical validation data in underrepresented patient populations like Southeast Asians are lacking.

Materials and methods

In our prospective clinical trial, 92 patients with stage I-IVA CRC and eligible for curative-intent surgery were recruited. Blood samples were collected before surgery, after surgery and during surveillance. ctDNA analysis was carried out using a personalized tumor-informed approach. Performance of ctDNA monitoring was further evaluated in a retrospective analysis of 32 patients who had commercial ctDNA testing.

Results

Before surgery, the ctDNA detection rate was 91.2%, significantly higher than the carcinoembryonic antigen (CEA) elevation rate at 42.9%. At 2-4 weeks after surgery, ctDNA detection, not CEA, was significantly associated with shorter disease-free survival (DFS) [hazard ratio (HR) = 30.3, 95% confidence interval (CI) 3.3-278.9, P = 0.002]. Longitudinally, ctDNA positivity showed the strongest prognostic value with 100% sensitivity and specificity to detect recurrence (HR = 173.6, 95% CI 19.7 to >1000, P = 0.001); the median lead time was 8.0 months. In the real-world data analysis, post-operative ctDNA remained the only significant prognostic biomarker for DFS (HR = 44.2, 95% CI 9.2-212.0, P < 0.0001). Among relapsed patients, the most common mutations found in ctDNA were in TP53 (58.8%), APC (52.9%) and KRAS (41.2%), with high frequency of co-mutations.

Conclusion

Our analysis from both clinical trial and real-world data indicated that ctDNA was an independent and strong prognostic biomarker to predict recurrence in CRC. ctDNA testing could be helpful for clinical decision making by enabling personalized intervention and surveillance strategies.