Journal Article Ahead of print
PubMed: 41671078 DOI: 10.1158/1078-0432.CCR-25-3555
Circulating tumor DNA dynamics and clinical outcomes in patients with advanced Colorectal Cancer treated with cetuximab-based induction and maintenance treatment.
Clin Cancer Res
Authors: Valérie Boige, Olivier Bouché, Claire Mulot, Ludovic Evesque, Meher Ben Abdelghani, Jean-Marc Phelip, Laurent Mineur, Marie-Pierre Galais, Anne-Laure Villing, Vincent Hautefeuille, Christelle De La Fouchardière, Dominique Genet, Slim Lassoued, Aurélien Carnot, Emmanuel Mitry, Stéphane Jacquot, Delphine Serazin, Camille Bourreau, Justine Abdelli, Emilie Brument, Pierre Laurent-Puig, Lise Roca, Hélène Blons
Affiliations
- Institut Gustave Roussy Villejuif France.
- University of Reims Champagne-Ardenne REIMS France.
- Paris Descartes University France.
- Centre Antoine Lacassagne Nice France.
- Paul Strauss Centre Strasbourg France.
- Centre Hospitalier Universitaire de Saint-Étienne Saint Etienne France.
- Institut Sainte Catherine Avignon France.
- Centre François Baclesse Caen France.
- Centre Hospitalier d'Auxerre Auxerre France.
- Centre Hospitalier Universitaire Amiens-Picardie Amiens France.
- Institute Paoli-Calmettes Marseille France.
- Clinique François Chénieux Limoges France.
- Centre Hospitalier Jean Rougier Cahors France.
- Centre Oscar Lambret France.
- Clinique Clémentville Montpellier France.
- Hôpital Européen Georges-Pompidou Paris France.
- Université Paris Cité France.
- Inserm France.
- UniCancer Group Paris France.
- Université Paris Cité PARIS, France France.
- Institut Regional du Cancer de Montpellier Montpellier France.
- Assistance Publique - Hôpitaux de Paris paris France.
Abstract
PURPOSE
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.
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 markers approaches. Progression-free (PFS) and overall (OS) survival 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 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).
CONCLUSIONS
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.
MeSH
Circulating Tumor Dna, Cetuximab, Induction Chemotherapy, Neoplasms, Disease Progression, Drug Therapy, Maintenance, Therapeutics, Colorectal Neoplasms, Random Allocation, Chemotherapy