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Prognostic implications of the co-detection of the urokinase plasminogen activator system and osteopontin in patients with non-small-cell lung cancer undergoing radiotherapy and correlation with gross tumor volume

Prognostische Auswirkungen der Detektion von Urokinase-Plasminogen-Aktivator-System in Kombination mit Osteopontin bei Patienten mit nicht-kleinzelligem Bronchialkarzinom nach Radiotherapie und Korrelation mit dem makroskopischen Tumorvolumen

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Abstract

Background

The urokinase plasminogen activator system (uPA, uPAR, PAI‑1) is upregulated in cancer and high plasma levels are associated with poor prognosis. Their interaction with hypoxia-related osteopontin (OPN) which is also overexpressed in malignant tumors suggests potential clinical relevance. However, the prognostic role of the uPA system in the radiotherapy (RT) of non-small-cell lung cancer (NSCLC), particularly in combination with OPN, has not been investigated so far.

Methods

uPA, uPAR, PAI‑1 and OPN plasma levels of 81 patients with locally advanced or metastasized NSCLC were prospectively analyzed by ELISA before RT and were correlated to clinical patient/tumor data and prognosis after RT.

Results

uPAR plasma levels were higher in M1; uPA and PAI‑1 levels were higher in M0 NSCLC patients. uPAR correlated with uPA (p < 0.001) which also correlated with PAI‑1 (p < 0.001). The prognostic impact of OPN plasma levels in the RT of NSCLC was previously reported by our group. PAI‑I plasma levels significantly impacted overall (OS) and progression-free survival (PFS). Low PAI‑1 levels were associated with a significantly reduced OS and PFS with a nearly 2‑fold increased risk of death (p = 0.029) and tumor progression (p = 0.029). In multivariate analysis, PAI‑1 levels remained an independent prognostic factor for OS and PFS with a 3‑fold increased risk of death (p = 0.001). If PAI‑1 plasma levels were combined with OPN or tumor volume, we found an additive prognostic impact on OS and PFS with a 2.5- to 3‑fold increased risk of death (p = 0.01).

Conclusion

Our results suggest that PAI-1 but not uPA and uPAR might add prognostic information in patients with advanced NSCLC undergoing RT. High pretreatment PAI-1 plasma levels were found predominantly in M0-stage patients and indicate a favorable prognosis as opposed to OPN where high plasma levels are associated with poor survival and metastasis. In combination, PAI-1 and OPN levels successfully predicted outcome and additively correlated with prognosis. These findings support the notion of an antidromic prognostic impact of OPN and PAI-1 plasma levels in the RT of advanced NSCLC.

Zusammenfassung

Hintergrund

Das Urokinase-Plasminogen-Aktivator-System (uPA, uPAR, PAI‑1) ist in malignen Tumoren hochreguliert und hohe Plasmaspiegel mit schlechter Prognose assoziiert. Deren Zusammenspiel mit hypoxieassoziierten Proteinen wie Osteopontin (OPN), welches ebenfalls in malignen Tumoren überexprimiert ist, legt eine potenzielle klinische Relevanz nahe. Die prognostische Bedeutung des uPA-Systems für die RT des NSCLC („non-small-cell lung cancer“), insbesondere in Kombination mit OPN, wurde bisher noch nicht untersucht.

Methoden

Bei 81 Patienten mit lokal fortgeschrittenem bzw. metastasiertem NSCLC wurden Plasmaspiegel von uPA, uPAR, PAI-1 und OPN vor RT prospektiv mittels ELISA bestimmt und mit klinischen Patienten- und Tumorparametern sowie der Prognose nach RT korreliert.

Ergebnisse

uPAR-Plasmalevel waren bei M1-Patienten höher; uPA- und PAI-1-Plasmaspiegel waren bei nichtmetastasierten Patienten (M0) erhöht. uPAR korrelierte mit uPA (p < 0,001), das ebenfalls mit PAI‑1 korrelierte (p < 0,001). Der prognostische Effekt von OPN-Plasmaspiegeln in der RT von NSCLC wurde bereits in unseren Vorarbeiten gezeigt. PAI-1-Plasmaspiegel korrelierten signifikant mit Gesamtüberleben (OS) und progressionsfreiem Überleben (PFS). Niedrige PAI-1-Spiegel waren mit reduziertem OS und PFS verbunden sowie mit einem fast 2‑fach erhöhtem Risiko zu versterben (p = 0,029) bzw. einen Tumorprogress im Verlauf zu erleiden (p = 0,029). In der multivariaten Analyse zeigten sich PAI-1-Plasmaspiegel als unabhängiger prognostischer Marker für OS und PFS, wobei bei erhöhten PAI-1-Spiegeln ein 3‑fach erhöhtes Risiko zu versterben vorlag (p = 0,001). Bei der Kombination von PAI‑1 mit OPN-Plasmaspiegeln bzw. Tumorvolumen zeigte sich ein additiver prognostischer Effekt für OS und PFS sowie ein 2,5- bis 3‑fach erhöhtes Risiko zu versterben (p = 0,01).

Schlussfolgerung

Die Ergebnisse zeigen, dass PAI-1-Plasmaspiegel im Gegensatz zu uPA- bzw. uPAR-Plasmaspiegeln zusätzliche prognostisch relevante Informationen für die RT beim fortgeschrittenen NSCLC liefern könnten. Hohe prätherapeutische PAI-1-Plasmaspiegel liegen v. a. bei nichtmetastasierten Patienten vor und zeigen eine günstige Prognose an – im Gegensatz zu hohen OPN-Plasmaspiegeln, die mit reduziertem OS nach RT und Metastasierung assoziiert sind. In der Kombination mit OPN prädizierten PAI-1-Plasmaspiegel erfolgreich das prognostische Outcome nach RT. Die Resultate sprechen für eine differenzielle prognostische Bedeutung von OPN- und PAI-1-Plasmaspiegeln bei der RT des fortgeschrittenen NSCLC.

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Abbreviations

BRMS1:

Breast cancer metastasis suppressor gene 1

CAIX:

Carbonic anhydrase IX

CCRT:

Concurrent chemoradiotherapy

CI:

Confidence interval

CT:

Computed tomography

EDTA:

Ethylenediaminetetraacetate

ELISA:

Enzyme-linked immunosorbent assay

Fx:

Fractions

GTV:

Gross tumor volume

M0:

Non-metastasized

M1:

Metastasized

mRNA:

Messenger RNA

NSCLC:

Non-small-cell lung cancer

OPN:

Osteopontin

OS:

Overall survival

P :

p-value

PAI-1:

Plasminogen activator inhibitor-1

PET:

Positron emission tomography

PFS:

Progression-free survival

RR:

Relative risk

rs :

Spearman’s rank correlation coefficient

RT:

Radiotherapy

SABR:

Stereotactic ablative radiotherapy

SD:

Standard deviation

SPSS:

Statistical package for the social sciences

UICC:

Union internationale contre le cancer

uPA:

Urokinase-type plasminogen activator

uPAR:

Urokinase-type plasminogen activator receptor

VEGF:

Vascular endothelial growth factor

WHO:

World Health Organization

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Funding

The authors declare that there is no external funding of the study. The study was entirely financially covered by the Department of Radiation Oncology of the Martin Luther University Halle-Wittenberg.

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  1. Dept. of Radiation Oncology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle, Germany

    C. Ostheimer, C. Evers, M. Bache, T. Reese & D. Vordermark

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C. Ostheimer, C. Evers, M. Bache, T. Reese and D. Vordermark declare that they have no competing interests.

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C. Ostheimer and C. Evers contributed equally to the manuscript and shared first authorship.

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Ostheimer, C., Evers, C., Bache, M. et al. Prognostic implications of the co-detection of the urokinase plasminogen activator system and osteopontin in patients with non-small-cell lung cancer undergoing radiotherapy and correlation with gross tumor volume. Strahlenther Onkol 194, 539–551 (2018). https://doi.org/10.1007/s00066-017-1255-1

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