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

Line S Tarpgaard, Ib J 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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

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.

OriginalsprogEngelsk
TidsskriftInternational Journal of Cancer
Vol/bind137
Udgave nummer10
Sider (fra-til)2470–2477
ISSN0020-7136
DOI
StatusUdgivet - 2015

Fingeraftryk

oxaliplatin
Urokinase Plasminogen Activator Receptors
Urokinase-Type Plasminogen Activator
Colorectal Neoplasms
Disease-Free Survival
Cetuximab
Immunoassay
Epidermal Growth Factor Receptor

Citer dette

Tarpgaard, Line S ; Christensen, Ib J ; Høyer-Hansen, Gunilla ; Lund, Ida K ; Guren, Tormod K ; Glimelius, Bengt ; Sorbye, Halfdan ; Tveit, Kjell M ; Nielsen, Hans Jørgen ; Moreira, José M A ; Pfeiffer, Per ; Brünner, Nils. / Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab. I: International Journal of Cancer. 2015 ; Bind 137, Nr. 10. s. 2470–2477.
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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.",
author = "Tarpgaard, {Line S} and Christensen, {Ib J} and Gunilla H{\o}yer-Hansen and Lund, {Ida K} and Guren, {Tormod K} and Bengt Glimelius and Halfdan Sorbye and Tveit, {Kjell M} and Nielsen, {Hans J{\o}rgen} and Moreira, {Jos{\'e} M A} and Per Pfeiffer and Nils Br{\"u}nner",
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year = "2015",
doi = "10.1002/ijc.29476",
language = "English",
volume = "137",
pages = "2470–2477",
journal = "International Journal of Cancer",
issn = "0020-7136",
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Tarpgaard, LS, Christensen, IJ, Høyer-Hansen, G, Lund, IK, Guren, TK, Glimelius, B, Sorbye, H, Tveit, KM, Nielsen, HJ, Moreira, JMA, Pfeiffer, P & Brünner, N 2015, 'Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab', International Journal of Cancer, bind 137, nr. 10, s. 2470–2477. https://doi.org/10.1002/ijc.29476

Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab. / Tarpgaard, Line S; Christensen, Ib J; Høyer-Hansen, Gunilla; Lund, Ida K; Guren, Tormod K; Glimelius, Bengt; Sorbye, Halfdan; Tveit, Kjell M; Nielsen, Hans Jørgen; Moreira, José M A; Pfeiffer, Per; Brünner, Nils.

I: International Journal of Cancer, Bind 137, Nr. 10, 2015, s. 2470–2477.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Intact and cleaved plasma soluble urokinase receptor in patients with metastatic colorectal cancer treated with oxaliplatin with or without cetuximab

AU - Tarpgaard, Line S

AU - Christensen, Ib J

AU - Høyer-Hansen, Gunilla

AU - Lund, Ida K

AU - Guren, Tormod K

AU - Glimelius, Bengt

AU - Sorbye, Halfdan

AU - Tveit, Kjell M

AU - Nielsen, Hans Jørgen

AU - Moreira, José M A

AU - Pfeiffer, Per

AU - Brünner, Nils

N1 - © 2015 UICC.

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1002/ijc.29476

DO - 10.1002/ijc.29476

M3 - Journal article

C2 - 25664394

VL - 137

SP - 2470

EP - 2477

JO - International Journal of Cancer

JF - International Journal of Cancer

SN - 0020-7136

IS - 10

ER -