title: Circulating DNA Demonstrates Convergent Evolution and Common Resistance Mechanisms during Treatment of Colorectal Cancer.
abstract: Purpose:Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment.Experimental Design:We evaluated under blinded conditions the ability of cell-free DNA (cfDNA) to detectRAS/BRAFmutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab.Results:Prior to treatment, sequencing of archival tissue detected mutations in 25 of 42 patients (60%), while the cfDNA assay detected mutations in 37 of 42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41 of 42 patients (98%) had a cfDNA-detectedRAS/BRAFmutation. Of 21 patients followed with serial measurements who wereRAS/BRAFmutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. OfRAS/BRAFwild-type tumors at baseline, 4 of 5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation.Conclusions:Our findings demonstrate the development of newRAS/BRAFmutations in patients regardless of whether they had preexisting mutations in the pathway, demonstrating a convergent evolutionary pattern.Clin Cancer Res; 23(16); 4578-91. ©2017 AACR.
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France. alain.thierry@inserm.fr.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Institut Régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Alain R
authors.initials: AR
authors.lastname: Thierry
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Institut Régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Brice
authors.initials: B
authors.lastname: Pastor
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: Jiang
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Anastasia D
authors.initials: AD
authors.lastname: Katsiampoura
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Christine
authors.initials: C
authors.lastname: Parseghian
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Loree
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Institut Régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Sanchez
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|DiaDx SAS, Montpellier, France.
authors.forename: Safia El
authors.initials: SE
authors.lastname: Messaoudi
authors.affiliation: IRCM, Institut de Recherche en Cancérologie de Montpellier, Montpellier, France.|INSERM, U1194, Montpellier, France.|Université de Montpellier, Montpellier, France.|Service de Chirurgie Digestive, Institut Régional du Cancer de Montpellier, Montpellier, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Ychou
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000073888:Cell-Free Nucleic Acids / Q000032:analysis* / Q000235:genetics; D000068818:Cetuximab / Q000008:administration & dosage; D060965:Clonal Evolution; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics; D000069439:Dasatinib / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005472:Fluorouracil / Q000008:administration & dosage; D005787:Gene Frequency; D006801:Humans; D002955:Leucovorin / Q000008:administration & dosage; D009154:Mutation; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D017063:Outcome Assessment, Health Care / Q000379:methods; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D018631:ras Proteins / Q000235:genetics
chemical_list: D000073888:Cell-Free Nucleic Acids; D009944:Organoplatinum Compounds; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins; D000068818:Cetuximab; D002955:Leucovorin; D000069439:Dasatinib; D005472:Fluorouracil