Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer

Takehiro Iwata, Shoji Kimura, Mohammad Abufaraj, Florian Janisch, Mehdi Kardoust Parizi, Andrea Haitel, Micheal Rink, Morgan Rouprêt, Harun Fajkovic, Veronica Seebacher, Peter Nyirady, Pierre I. Karakiewicz, Dmitry Enikeev, Leonid M. Rapoport, Yasutomo Nasu, Shahrokh F. Shariat

Research output: Contribution to journalArticle

Abstract

Objectives: To assess the role of the urokinase plasminogen activator (uPA) system as a prognostic biomarker in patients with nonmuscle invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB) with or without adjuvant intravesical therapy. Material and methods: We stained TURB tissue from 827 NMIBC patients with uPA, its receptor (uPAR) and its inhibitor (PAI-1). The status of these markers was categorized as normal vs. overexpressed using the cutoffs of 30% for uPA, 50% for uPAR, and 30% for PAI-1. Multivariable Cox regression analyses were performed to evaluate the prognostic value of these markers. Results: uPA was overexpressed in 37.7% of patients, uPAR in 44.7% and PAI-1 in 44.6%. Overexpression of these markers was associated with high tumor grade. Within a median follow-up was 60 months (interquartile range: 22–109), uPA (hazard ratio [HR]: 1.40; P = 0.006), uPAR (HR: 1.70; P < 0.001), PAI-1 (HR: 1.35; P = 0.014), and the combination of all 3 markers (HR: 3.38; P < 0.001) were associated with recurrence-free survival (RFS); uPA (HR: 1.68; P = 0.035) and the combination of all 3 markers (HR: 8.79; P = 0.005) were associated with progression-free survival (PFS). The addition of the uPA system to a base model improved the discrimination by 1.3% for RFS and 2.1% for PFS. In subgroup analyses, uPA (HR: 2.19; P = 0.018) was associated with PFS in T1G3 patients and its addition to a base model improved the discrimination by 2.5%. uPA (HR: 1.44; P = 0.019), uPAR (HR: 1.54; P = 0.006), PAI-1 (HR: 1.46; P = 0.013) and the combination of all 3 markers (HR: 3.48; P < 0.001) were associated with RFS in TaG1-2 patients and their addition to a base model improved the discrimination by 2.1%. Conclusion: uPA, uPAR, and PAI-1 are overexpressed in one-third to half of patients with NMIBC. Their overexpression is an independent prognosticator of RFS and PFS which improved the predictive accuracy of current clinicopathological characteristics. Biomarkers that capture the biological and clinical behavior of individual tumors may help personalize clinical decision-making in patients with NMIBC.

Original languageEnglish
JournalUrologic Oncology: Seminars and Original Investigations
DOIs
Publication statusPublished - Jan 1 2019

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Plasminogen Activators
Urokinase-Type Plasminogen Activator
Urinary Bladder Neoplasms
Plasminogen Activator Inhibitor 1
Disease-Free Survival
Recurrence
Urinary Bladder
Biomarkers
Urokinase Plasminogen Activator Receptors
Survival
Neoplasms
Regression Analysis

Keywords

  • Nonmuscle invasive bladder cancer
  • Progression
  • Recurrence
  • Urokinase plasminogen activator

ASJC Scopus subject areas

  • Oncology
  • Urology

Cite this

Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer. / Iwata, Takehiro; Kimura, Shoji; Abufaraj, Mohammad; Janisch, Florian; Parizi, Mehdi Kardoust; Haitel, Andrea; Rink, Micheal; Rouprêt, Morgan; Fajkovic, Harun; Seebacher, Veronica; Nyirady, Peter; Karakiewicz, Pierre I.; Enikeev, Dmitry; Rapoport, Leonid M.; Nasu, Yasutomo; Shariat, Shahrokh F.

In: Urologic Oncology: Seminars and Original Investigations, 01.01.2019.

Research output: Contribution to journalArticle

Iwata, T, Kimura, S, Abufaraj, M, Janisch, F, Parizi, MK, Haitel, A, Rink, M, Rouprêt, M, Fajkovic, H, Seebacher, V, Nyirady, P, Karakiewicz, PI, Enikeev, D, Rapoport, LM, Nasu, Y & Shariat, SF 2019, 'Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer', Urologic Oncology: Seminars and Original Investigations. https://doi.org/10.1016/j.urolonc.2019.05.019
Iwata, Takehiro ; Kimura, Shoji ; Abufaraj, Mohammad ; Janisch, Florian ; Parizi, Mehdi Kardoust ; Haitel, Andrea ; Rink, Micheal ; Rouprêt, Morgan ; Fajkovic, Harun ; Seebacher, Veronica ; Nyirady, Peter ; Karakiewicz, Pierre I. ; Enikeev, Dmitry ; Rapoport, Leonid M. ; Nasu, Yasutomo ; Shariat, Shahrokh F. / Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer. In: Urologic Oncology: Seminars and Original Investigations. 2019.
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title = "Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer",
abstract = "Objectives: To assess the role of the urokinase plasminogen activator (uPA) system as a prognostic biomarker in patients with nonmuscle invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB) with or without adjuvant intravesical therapy. Material and methods: We stained TURB tissue from 827 NMIBC patients with uPA, its receptor (uPAR) and its inhibitor (PAI-1). The status of these markers was categorized as normal vs. overexpressed using the cutoffs of 30{\%} for uPA, 50{\%} for uPAR, and 30{\%} for PAI-1. Multivariable Cox regression analyses were performed to evaluate the prognostic value of these markers. Results: uPA was overexpressed in 37.7{\%} of patients, uPAR in 44.7{\%} and PAI-1 in 44.6{\%}. Overexpression of these markers was associated with high tumor grade. Within a median follow-up was 60 months (interquartile range: 22–109), uPA (hazard ratio [HR]: 1.40; P = 0.006), uPAR (HR: 1.70; P < 0.001), PAI-1 (HR: 1.35; P = 0.014), and the combination of all 3 markers (HR: 3.38; P < 0.001) were associated with recurrence-free survival (RFS); uPA (HR: 1.68; P = 0.035) and the combination of all 3 markers (HR: 8.79; P = 0.005) were associated with progression-free survival (PFS). The addition of the uPA system to a base model improved the discrimination by 1.3{\%} for RFS and 2.1{\%} for PFS. In subgroup analyses, uPA (HR: 2.19; P = 0.018) was associated with PFS in T1G3 patients and its addition to a base model improved the discrimination by 2.5{\%}. uPA (HR: 1.44; P = 0.019), uPAR (HR: 1.54; P = 0.006), PAI-1 (HR: 1.46; P = 0.013) and the combination of all 3 markers (HR: 3.48; P < 0.001) were associated with RFS in TaG1-2 patients and their addition to a base model improved the discrimination by 2.1{\%}. Conclusion: uPA, uPAR, and PAI-1 are overexpressed in one-third to half of patients with NMIBC. Their overexpression is an independent prognosticator of RFS and PFS which improved the predictive accuracy of current clinicopathological characteristics. Biomarkers that capture the biological and clinical behavior of individual tumors may help personalize clinical decision-making in patients with NMIBC.",
keywords = "Nonmuscle invasive bladder cancer, Progression, Recurrence, Urokinase plasminogen activator",
author = "Takehiro Iwata and Shoji Kimura and Mohammad Abufaraj and Florian Janisch and Parizi, {Mehdi Kardoust} and Andrea Haitel and Micheal Rink and Morgan Roupr{\^e}t and Harun Fajkovic and Veronica Seebacher and Peter Nyirady and Karakiewicz, {Pierre I.} and Dmitry Enikeev and Rapoport, {Leonid M.} and Yasutomo Nasu and Shariat, {Shahrokh F.}",
year = "2019",
month = "1",
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TY - JOUR

T1 - Prognostic role of the urokinase plasminogen activator (uPA) system in patients with nonmuscle invasive bladder cancer

AU - Iwata, Takehiro

AU - Kimura, Shoji

AU - Abufaraj, Mohammad

AU - Janisch, Florian

AU - Parizi, Mehdi Kardoust

AU - Haitel, Andrea

AU - Rink, Micheal

AU - Rouprêt, Morgan

AU - Fajkovic, Harun

AU - Seebacher, Veronica

AU - Nyirady, Peter

AU - Karakiewicz, Pierre I.

AU - Enikeev, Dmitry

AU - Rapoport, Leonid M.

AU - Nasu, Yasutomo

AU - Shariat, Shahrokh F.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Objectives: To assess the role of the urokinase plasminogen activator (uPA) system as a prognostic biomarker in patients with nonmuscle invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB) with or without adjuvant intravesical therapy. Material and methods: We stained TURB tissue from 827 NMIBC patients with uPA, its receptor (uPAR) and its inhibitor (PAI-1). The status of these markers was categorized as normal vs. overexpressed using the cutoffs of 30% for uPA, 50% for uPAR, and 30% for PAI-1. Multivariable Cox regression analyses were performed to evaluate the prognostic value of these markers. Results: uPA was overexpressed in 37.7% of patients, uPAR in 44.7% and PAI-1 in 44.6%. Overexpression of these markers was associated with high tumor grade. Within a median follow-up was 60 months (interquartile range: 22–109), uPA (hazard ratio [HR]: 1.40; P = 0.006), uPAR (HR: 1.70; P < 0.001), PAI-1 (HR: 1.35; P = 0.014), and the combination of all 3 markers (HR: 3.38; P < 0.001) were associated with recurrence-free survival (RFS); uPA (HR: 1.68; P = 0.035) and the combination of all 3 markers (HR: 8.79; P = 0.005) were associated with progression-free survival (PFS). The addition of the uPA system to a base model improved the discrimination by 1.3% for RFS and 2.1% for PFS. In subgroup analyses, uPA (HR: 2.19; P = 0.018) was associated with PFS in T1G3 patients and its addition to a base model improved the discrimination by 2.5%. uPA (HR: 1.44; P = 0.019), uPAR (HR: 1.54; P = 0.006), PAI-1 (HR: 1.46; P = 0.013) and the combination of all 3 markers (HR: 3.48; P < 0.001) were associated with RFS in TaG1-2 patients and their addition to a base model improved the discrimination by 2.1%. Conclusion: uPA, uPAR, and PAI-1 are overexpressed in one-third to half of patients with NMIBC. Their overexpression is an independent prognosticator of RFS and PFS which improved the predictive accuracy of current clinicopathological characteristics. Biomarkers that capture the biological and clinical behavior of individual tumors may help personalize clinical decision-making in patients with NMIBC.

AB - Objectives: To assess the role of the urokinase plasminogen activator (uPA) system as a prognostic biomarker in patients with nonmuscle invasive bladder cancer (NMIBC) treated with transurethral resection of the bladder (TURB) with or without adjuvant intravesical therapy. Material and methods: We stained TURB tissue from 827 NMIBC patients with uPA, its receptor (uPAR) and its inhibitor (PAI-1). The status of these markers was categorized as normal vs. overexpressed using the cutoffs of 30% for uPA, 50% for uPAR, and 30% for PAI-1. Multivariable Cox regression analyses were performed to evaluate the prognostic value of these markers. Results: uPA was overexpressed in 37.7% of patients, uPAR in 44.7% and PAI-1 in 44.6%. Overexpression of these markers was associated with high tumor grade. Within a median follow-up was 60 months (interquartile range: 22–109), uPA (hazard ratio [HR]: 1.40; P = 0.006), uPAR (HR: 1.70; P < 0.001), PAI-1 (HR: 1.35; P = 0.014), and the combination of all 3 markers (HR: 3.38; P < 0.001) were associated with recurrence-free survival (RFS); uPA (HR: 1.68; P = 0.035) and the combination of all 3 markers (HR: 8.79; P = 0.005) were associated with progression-free survival (PFS). The addition of the uPA system to a base model improved the discrimination by 1.3% for RFS and 2.1% for PFS. In subgroup analyses, uPA (HR: 2.19; P = 0.018) was associated with PFS in T1G3 patients and its addition to a base model improved the discrimination by 2.5%. uPA (HR: 1.44; P = 0.019), uPAR (HR: 1.54; P = 0.006), PAI-1 (HR: 1.46; P = 0.013) and the combination of all 3 markers (HR: 3.48; P < 0.001) were associated with RFS in TaG1-2 patients and their addition to a base model improved the discrimination by 2.1%. Conclusion: uPA, uPAR, and PAI-1 are overexpressed in one-third to half of patients with NMIBC. Their overexpression is an independent prognosticator of RFS and PFS which improved the predictive accuracy of current clinicopathological characteristics. Biomarkers that capture the biological and clinical behavior of individual tumors may help personalize clinical decision-making in patients with NMIBC.

KW - Nonmuscle invasive bladder cancer

KW - Progression

KW - Recurrence

KW - Urokinase plasminogen activator

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