Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor
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Caroline Vandeputte1,*, Pashalina Kehagias1,*, Hakim El Housni2, Lieveke Ameye3, Jean-François Laes4, Christine Desmedt5, Christos Sotiriou5, Amélie Deleporte1, Francesco Puleo1, Karen Geboes6, Thierry Delaunoit7, Gauthier Demolin8, Marc Peeters9, Lionel D’Hondt10, Jos Janssens11, Javier Carrasco12, Raphaël Marechal13, Maria Gomez Galdon14, Pierre Heimann2, Marianne Paesmans3, Patrick Flamen15 and Alain Hendlisz1
1Gastro Intestinal Oncology Unit, Medical Oncology, Institut Jules Bordet, Brussels, Belgium
2Department of Medical Genetics, Hôpital Erasme-ULB, Brussels, Belgium
3Data Centre, Institut Jules Bordet, Brussels, Belgium
4OncoDna, Gosselies, Belgium
5Breast Cancer Translational Research Laboratory, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
6Service of Digestive Oncology, Universitair Ziekenhuis Gent, Gent, Belgium
7Oncology Department, Hôpital de Jolimont, La Louvière, Belgium
8Gastroenterology Department, Centre Hospitalier Chrétien St-Joseph, Liège, Belgium
9Oncology Department, Universitair Ziekenhuis Antwerpen, Antwerpen, Belgium
10Oncology Department, Centre Hospitalier Universitaire, UCL Namur (site de Godinne), Dinant, Belgium
11Department of Gastroenterology, AZ Turnhout, Turnhout, Belgium
12Oncology Department, Grand Hôpital de Charleroi, Charleroi, Belgium
13Department of Gastroenterology, GI Cancer Unit, ULB-Erasme, Brussels, Belgium
14Department of Pathology, Jules Bordet Institute, Free University of Brussels, Brussels, Belgium
15Nucleair Medicine Imaging and Therapy Department, Institut Jules Bordet, Brussels, Belgium
*Shared first authors
Alain Hendlisz, email: firstname.lastname@example.org
Keywords: early-response; biomarker; multi-kinase inhibitor; colorectal cancer; ctDNA
Received: June 08, 2017 Accepted: March 01, 2018 Published: April 03, 2018
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.
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