title: CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial).
abstract: To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab.
  
  
  
  CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated.
  
  
  
  Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%; IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%; IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months; hazard ratio (HR) 1.53; 95% Cl, 1.15-2.04; P = 0.004] and longer overall survival (36.6 versus 21.3 months; HR 1.73; 95% Cl, 1.24-2.43; P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results.
  
  
  
  In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab.
  
  
  
  NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.
authors.affiliation: Department of Hematology and Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center Munich, Ludwig-Maximilians-University Munich, Munich marlies.michl@med.uni-muenchen.de.
authors.forename: M
authors.initials: M
authors.lastname: Michl
authors.affiliation: Department of Hematology and Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center Munich, Ludwig-Maximilians-University Munich, Munich German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg.
authors.forename: S
authors.initials: S
authors.lastname: Stintzing
authors.affiliation: Practice for Hematology and Medical Oncology, Gesundheitszentrum St Marien, Amberg.
authors.forename: L
authors.initials: L
authors.lastname: Fischer von Weikersthal
authors.affiliation: Practice for Hematology and Medical Oncology, Onkonet-Onkologie Ravensburg, Ravensburg.
authors.forename: T
authors.initials: T
authors.lastname: Decker
authors.affiliation: Department of Hematology and Medical Oncology, Klinik Herzoghöhe, Bayreuth.
authors.forename: A
authors.initials: A
authors.lastname: Kiani
authors.affiliation: Practice for Hematology and Medical Oncology, Landshut.
authors.forename: U
authors.initials: U
authors.lastname: Vehling-Kaiser
authors.affiliation: Department of Hematology and Medical Oncology, Krankenhaus Nordwest, University Cancer Center Frankfurt, Frankfurt.
authors.forename: S-E
authors.initials: SE
authors.lastname: Al-Batran
authors.affiliation: Department of Gastroenterology and Oncology, Medical Department II, Lukaskrankenhaus, Städtisches Klinikum Neuss, Neuss.
authors.forename: T
authors.initials: T
authors.lastname: Heintges
authors.affiliation: Practice for Hematology and Medical Oncology, Muenster.
authors.forename: C
authors.initials: C
authors.lastname: Lerchenmueller
authors.affiliation: Department of Hematology and Medical Oncology, Klinikum Magdeburg, Magdeburg.
authors.forename: C
authors.initials: C
authors.lastname: Kahl
authors.affiliation: Practice for Hematology and Medical Oncology, Bad Soden.
authors.forename: G
authors.initials: G
authors.lastname: Seipelt
authors.affiliation: Department of Gastroenterology, Hematology and Medical Oncology, Klinikum Weiden, Weiden.
authors.forename: F
authors.initials: F
authors.lastname: Kullmann
authors.affiliation: Practice for Hematology and Medical Oncology, Kronach, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Stauch
authors.affiliation: Department of Hematology and Medical Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Scheithauer
authors.affiliation: Department of Surgery, Klinikum Chemnitz, Chemnitz.
authors.forename: J
authors.initials: J
authors.lastname: Hielscher
authors.affiliation: Department of Medicine, Klinikum Stuttgart, Stuttgart.
authors.forename: M
authors.initials: M
authors.lastname: Scholz
authors.affiliation: Practice for Hematology and Medical Oncology, Ansbach.
authors.forename: S
authors.initials: S
authors.lastname: Mueller
authors.affiliation: Department of Medicine A, University Medicine Greifswald, Greifswald.
authors.forename: M M
authors.initials: MM
authors.lastname: Lerch
authors.affiliation: Department of Hematology and Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center Munich, Ludwig-Maximilians-University Munich, Munich German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg.
authors.forename: D P
authors.initials: DP
authors.lastname: Modest
authors.affiliation: Department of Pathology, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg.
authors.forename: T
authors.initials: T
authors.lastname: Kirchner
authors.affiliation: Department of Pathology, Klinikum Grosshadern, Ludwig-Maximilians-University Munich, Munich, Germany German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg.
authors.forename: A
authors.initials: A
authors.lastname: Jung
authors.affiliation: Department of Hematology and Medical Oncology, Klinikum Grosshadern and Comprehensive Cancer Center Munich, Ludwig-Maximilians-University Munich, Munich German Cancer Consortium (DKTK), German Cancer Research Centre (DKFZ), Heidelberg.
authors.forename: V
authors.initials: V
authors.lastname: Heinemann
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D002272:Carcinoembryonic Antigen / Q000235:genetics*; D000068818:Cetuximab / Q000008:administration & dosage* / Q000009:adverse effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018572:Disease-Free Survival; D005091:Exons / Q000235:genetics; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D053208:Kaplan-Meier Estimate; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D002272:Carcinoembryonic Antigen; C117307:KRAS protein, human; D000068258:Bevacizumab; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin
keywords: CEA; FIRE-3 trial; KRAS exon 2 wild-type; extended RAS wild-type; metastatic colorectal cancer; tumor marker