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

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.