Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab

Line S Tarpgaard, Ib Jarle Christensen, Gunilla Høyer-Hansen, Ida K Lund, Tormod K Guren, Bengt Glimelius, Halfdan Sorbye, Kjell M Tveit, Hans Jørgen Nielsen, José M A Moreira, Per Pfeiffer, Nils Brünner

11 Citations (Scopus)

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 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. This article is protected by copyright. All rights reserved.

Original languageEnglish
JournalInternational journal of cancer. Journal international du cancer
Volume137
Issue number10
Pages (from-to)2470-77
ISSN0020-7136
DOIs
Publication statusPublished - 15 Nov 2015

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