title: Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab.
abstract: Circulating forms of the urokinase plasminogen activator receptor (uPAR) are associated with prognosis in patients with colorectal cancer. Preclinical studies have shown that uPAR can influence the state of phosphorylation and signalling activity of the epidermal growth factor receptor (EGFR) in a ligand-independent manner. The purpose of the study was to evaluate whether plasma soluble intact and cleaved uPAR(I-III)+(II-III) levels could identify a subpopulation of patients with metastatic colorectal cancer (mCRC) where treatment with cetuximab would have a beneficial effect. Plasma samples were available from 453 patients treated in the NORDIC VII study. Patients were randomized between FLOX and FLOX + cetuximab. The levels of uPAR(I-III)+(II-III) were determined by time-resolved fluorescence immunoassay. We demonstrated that higher baseline plasma uPAR(I-III)+(II-III) levels were significantly associated with shorter progression-free survival (PFS) (HR = 1.30, 1.14-1.48, p = 0.0001) and overall survival (OS) (HR = 1.75, 1.52-2.02, p < 0.0001). Multivariate Cox analysis showed that plasma uPAR(I-III)+(II-III) was an independent biomarker of short OS (HR = 1.45, 1.20-1.75, p = 0.0001). There were no significant interactions between plasma uPAR(I-III)+(II-III) levels, KRAS mutational status and treatment either PFS (p = 0.43) or OS (p = 0.095). However, further explorative analyses indicated that patients with low levels of circulating suPAR and a KRAS wild-type tumor have improved effect from treatment with FLOX + cetuximab as compared to patients with KRAS wild-type and high levels of suPAR. These results thus support the preclinical findings and should be further tested in an independent clinical data set.
authors: Department of Oncology, Odense University Hospital, Odense, Denmark.|Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors: Line S
authors: LS
authors: Tarpgaard
authors: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Ib J
authors: IJ
authors: Christensen
authors: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Gunilla
authors: G
authors: Høyer-Hansen
authors: The Finsen Laboratory, Rigshospitalet, Copenhagen, Denmark.|Biotech Research and Innovation Center (BRIC), University of Copenhagen, Copenhagen, Denmark.
authors: Ida K
authors: IK
authors: Lund
authors: Department of Oncology and K. G. Jebsen Centre for Colorectal Cancer Research, Oslo University Hospital, Oslo, Norway.
authors: Tormod K
authors: TK
authors: Guren
authors: Department of Radiology, Uppsala University, Uppsala, Sweden.|Department of Oncology, Uppsala University, Uppsala, Sweden.|Department of Radiation Science, Uppsala University, Uppsala, Sweden.|Department of Oncology and Pathology, Karolinska Institutet, Stockholm, Sweden.
authors: Bengt
authors: B
authors: Glimelius
authors: Department of Oncology, Haukeland University Hospital, Bergen, Norway.
authors: Halfdan
authors: H
authors: Sorbye
authors: Department of Oncology and K. G. Jebsen Centre for Colorectal Cancer Research, Oslo University Hospital, Oslo, Norway.
authors: Kjell M
authors: KM
authors: Tveit
authors: Department of Surgical Gastroenterology, Copenhagen University Hospital, Hvidovre, Denmark.
authors: Hans Jørgen
authors: HJ
authors: Nielsen
authors: Institute of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: José M A
authors: JM
authors: Moreira
authors: Department of Oncology, Odense University Hospital, Odense, Denmark.|Institute of Clinical Research, University of Southern Denmark, Odense, Denmark.
authors: Per
authors: P
authors: Pfeiffer
authors: Institute of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
authors: Nils
authors: N
authors: Brünner
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D014408:Biomarkers, Tumor / Q000097:blood; D000068818:Cetuximab / Q000008:administration & dosage* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000401:mortality*; D005260:Female; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D009944:Organoplatinum Compounds / Q000008:administration & dosage* / Q000627:therapeutic use; D000077150:Oxaliplatin; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood*; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D009944:Organoplatinum Compounds; D055293:Receptors, Urokinase Plasminogen Activator; D000077150:Oxaliplatin; D000068818:Cetuximab
keywords: EGFR inhibition; cetuximab; metastatic colorectal cancer; suPAR forms