Circulating Tumor DNA Dynamics and Clinical Outcomes in Patients with Advanced Colorectal Cancer Treated with Cetuximab-Based Induction and Maintenance Treatment

Clinical Snapshot

Key Findings

• P Value: P = 0.013 for PFS comparison; P = 0.025 for OS with acquired alterations

• Effect Size: PFS: 9.6 months (ctDNA negative throughout) vs 3.4 months (≥80% decrease) vs 2.1 months (<80% decrease)

• Primary Outcome: Progression-free survival stratified by ctDNA kinetics

• Nnt Or Sensitivity: 26.9% of patients developed acquired EGFR-MAPK pathway alterations at progression

• Confidence Interval: Not reported in abstract

Clinical Application

ctDNA testing increasingly available but requires specialized laboratory infrastructure and standardized protocols Relevant to Australian practice where cetuximab is PBS-listed for mCRC; ctDNA testing emerging but not yet routine standard of care Patients with metastatic colorectal cancer receiving first-line cetuximab-based therapy

Abstract

PURPOSE: We investigated whether circulating tumor DNA (ctDNA) changes may be useful to assess clinical outcomes in patients with metastatic colorectal cancer (mCRC) randomized in the TIME-PRODIGE-28 trial comparing biweekly maintenance with cetuximab alone with observation after 4-month fluorouracil, folinic acid, and irinotecan (FOLFIRI) plus cetuximab induction chemotherapy. EXPERIMENTAL DESIGN: ctDNA samples were collected at four time points from baseline until disease progression during the first chemotherapy-free interval and analyzed using next-generation sequencing and methylation marker approaches. Progression-free survival (PFS) and overall survival (OS) from randomization were analyzed according to ctDNA kinetics and EGFR-MAPK pathway alterations. RESULTS: Among 139 randomized patients, 104 (74.8%) had paired samples available. Patients with negative baseline ctDNA remaining negative after 4-month induction chemotherapy had significantly longer PFS from randomization (9.6 months) as compared with patients with a ctDNA decrease of ≥80% (3.4 months) or a ctDNA decrease of <80% (2.1 months; P = 0.013). Patients with EGFR-MAPK pathway alterations identified either in tissue or baseline ctDNA had worse PFS and OS from randomization. Acquired alterations found in 17 of 63 (26.9%) patients at disease progression during the first chemotherapy-free interval were associated with worse OS from reintroduction of the full induction chemotherapy (14.9 vs. 19.4 months; P = 0.025). CONCLUSIONS: Our findings show the prognostic impact of both ctDNA kinetics and EGFR-MAPK pathway alteration dynamics following induction chemotherapy with FOLFIRI-cetuximab in patients with mCRC. Prospective studies evaluating ctDNA-guided treatment strategies are needed to validate the clinical utility of ctDNA monitoring to improve patient selection for first-line treatment de-escalation and anti-EGFR-based maintenance regimens, including treatment adaptation over time.

References

1. 1.Boige, V., Bouché, O., Mulot, C., Evesque, L., Ben Abdelghani, M., Phelip, J.-M., Mineur, L., Galais, M.-P., Villing, A.-L., Hautefeuille, V., De La Fouchardiere, C., Genet, D., Lassoued, S., Carnot, A., Mitry, E., Jacquot, S., Serazin, D., Bourreau, C., Abdelli, J., Brument, E., Laurent-Puig, P., Roca, L., & Blons, H. (2026). Circulating Tumor DNA Dynamics and Clinical Outcomes in Patients with Advanced Colorectal Cancer Treated with Cetuximab-Based Induction and Maintenance Treatment. Clinical Cancer Research. https://doi.org/10.1158/1078-0432.CCR-25-3555