Circulating tumor DNA dynamics and clinical outcomes in patients with advanced Colorectal Cancer treated with cetuximab-based induction and maintenance treatment.
prospective_cohort · Level II
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- Record sourced from PubMed, PMID 41671078.
- Also identified by DOI 10.1158/1078-0432.CCR-25-3555.
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Abstract
We investigated whether circulating tumor DNA (ctDNA) changes may be useful to assess clinical outcomes in metastatic colorectal cancer (mCRC) patients randomized in the TIME-PRODIGE28 trial comparing bi-weekly maintenance with cetuximab alone to observation after 4-month FOLFIRI plus cetuximab induction chemotherapy. 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 markers approaches. Progression-free (PFS) and overall (OS) survival from randomization were analyzed according to ctDNA kinetics and EGFR-MAPK pathway alterations. 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 to patients with ctDNA decrease of ≥ 80% (3.4 months) or 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 17/63 (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). Our findings show the prognostic impact of both ctDNA kinetics and EGFR-MAPK pathway alterations dynamics following induction chemotherapy with FOLFIRI-cetuximab in mCRC patients. 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. TRIAL REGISTRATION clinicaltrials.gov identifier NCT02404935.