Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor

// Caroline Vandeputte 1, * , Pashalina Kehagias 1, * , Hakim El Housni 2 , Lieveke Ameye 3 , Jean-Francois Laes 4 , Christine Desmedt 5 , Christos Sotiriou 5 , Amelie Deleporte 1 , Francesco Puleo 1 , Karen Geboes 6 , Thierry Delaunoit 7 , Gauthier Demolin 8 , Marc Peeters 9 , Lionel D’Hondt 10 , Jos Janssens 11 , Javier Carrasco 12 , Raphael Marechal 13 , Maria Gomez Galdon 14 , Pierre Heimann 2 , Marianne Paesmans 3 , Patrick Flamen 15 and Alain Hendlisz 1 1 Gastro Intestinal Oncology Unit, Medical Oncology, Institut Jules Bordet, Brussels, Belgium 2 Department of Medical Genetics, Hopital Erasme-ULB, Brussels, Belgium 3 Data Centre, Institut Jules Bordet, Brussels, Belgium 4 OncoDna, Gosselies, Belgium 5 Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium 6 Service of Digestive Oncology, Universitair Ziekenhuis Gent, Gent, Belgium 7 Oncology Department, Hopital de Jolimont, La Louviere, Belgium 8 Gastroenterology Department, Centre Hospitalier Chretien St-Joseph, Liege, Belgium 9 Oncology Department, Universitair Ziekenhuis Antwerpen, Antwerpen, Belgium 10 Oncology Department, Centre Hospitalier Universitaire, UCL Namur (site de Godinne), Dinant, Belgium 11 Department of Gastroenterology, AZ Turnhout, Turnhout, Belgium 12 Oncology Department, Grand Hopital de Charleroi, Charleroi, Belgium 13 Department of Gastroenterology, GI Cancer Unit, ULB-Erasme, Brussels, Belgium 14 Department of Pathology, Jules Bordet Institute, Free University of Brussels, Brussels, Belgium 15 Nucleair Medicine Imaging and Therapy Department, Institut Jules Bordet, Brussels, Belgium * Shared first authors Correspondence to: Alain Hendlisz, email: alain.hendlisz@bordet.be Keywords: early-response; biomarker; multi-kinase inhibitor; colorectal cancer; ctDNA Received: June 08, 2017     Accepted: March 01, 2018     Published: April 03, 2018 ABSTRACT Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which ≥50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome. High baseline cell free DNA (cfDNA) levels are associated with shorter overall survival (OS) (HR 7.38, P=0.001). An early increase (D14) in mutated copies/mL is associated with a significantly worse PFS (HR 6.12, P=0.008) and OS (HR 8.02, P=0.004). These data suggest a high prognostic value for early ctDNA level changes and support the use of blood-born genomic markers as a tool for treatment.