Evaluation of Circulating Tumor DNA as a Biomarker for Chemoresistance in Colorectal Cancer

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Background: Colorectal cancer (CRC) is a leading cause of cancer-related mortality globally. Resistance to chemotherapy, particularly to first-line regimens such as FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin), remains a critical barrier to successful treatment. Methods: This prospective observational study enrolled 96 patients with stage II–IV colorectal adenocarcinoma receiving first-line FOLFOX chemotherapy. Plasma samples were collected at baseline, post-cycle 3, and post-cycle 6 for ctDNA quantification and sequencing of KRAS, NRAS, and TP53 mutations. Radiological tumor response was assessed by RECIST v1.1 criteria. Statistical analysis included ANOVA, Chi-square tests, and logistic regression. Results: Among 96 patients (mean age 60.3 ± 8.2 years; 58.3% male), 34 (35.4%) exhibited chemoresistance. Baseline ctDNA levels were significantly higher in resistant patients (38.7 ± 10.5 ng/mL) compared to responders (25.4 ± 9.3 ng/mL, P < 0.001). TP53 mutations were more frequent in resistant patients (58.8% vs. 27.9%, P = 0.004). A >20% reduction in ctDNA by cycle 3 was associated with treatment response (OR 4.12, 95% CI 1.76–9.67, P = 0.001). ROC curve analysis yielded an AUC of 0.84 for ctDNA reduction as a predictor of chemoresistance. Conclusion: Elevated baseline ctDNA levels and persistent TP53 mutations are associated with chemoresistance in colorectal cancer. Early reduction in ctDNA during therapy may serve as a robust predictor of response, supporting its integration into personalized treatment strategies.