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Urokinase-Type Plasminogen Activator and Its Inhibitor Type 1 Predict Disease Outcome and Therapy Response in Primary Breast Cancer

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      Abstract

      Combined determination of urokinase-type plasminogen activator (uPA) and its inhibitor, activator inhibitor type 1 (PAI-1), supports risk-adapted individualized therapy concepts, particularly in node-negative breast cancer. The prognostic impact of both factors in primary breast cancer was substantiated by a pooled analysis of > 8000 patients with breast cancer and a multicenter prospective randomized therapy trial in nodenegative breast cancer; findings achieved the highest level of evidence for tumor biomarkers. Patients with node-negative breast cancer with low antigen levels of uPA and PAI-1 in their primary tumor tissue have a very good prognosis and therefore may be spared the burden of adjuvant chemotherapy, whereas those with elevated uPA/PAI-1 antigen levels carry an increased risk of disease recurrence. Recent retrospective analysis of > 3000 patients indicated that patients with breast cancer with high uPA/PAI-1 values derive a significantly greater benefit from adjuvant chemotherapy than patients with low uPA/PAI-1 levels. Similarly, in the multicenter prospective Chemo N0 trial, administration of cyclophosphamide/methotrexate/5-fluorouracil— based chemotherapy led to a substantial reduction in risk of disease recurrence in patients with high uPA/PAI-1. However, benefit from adjuvant endocrine therapy appears to be independent of a patient's uPA/PAI-1 status. In metastatic breast cancer, retrospective studies showed that elevated uPA or PAI-1 present in the primary tumor tissue are associated with a poor response to later palliative endocrine therapy. These findings suggest that high levels of uPA and/or PAI-1 do reflect an aggressive phenotype that may be overcome or suppressed by early systemic therapy in the adjuvant setting but may be too advanced for response to palliative therapy at a later stage.

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      References

        • Andreasen PA
        • Kjöller L
        • Christensen L
        • et al.
        The urokinase-type plasminogen activator system in cancer metastasis: a review.
        Int J Cancer. 1997; 72: 1-22
        • Schmitt M
        • Harbeck N
        • Thomssen C
        • et al.
        Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy.
        Thromb Haemost. 1997; 78: 285-296
        • Harbeck N
        • Schmitt M
        • Kates RE
        • et al.
        Clinical utility of uPA/PAI-1 determination in primary breast cancer tissue for individualized therapy concepts.
        Clin Breast Cancer. 2002; 3: 196-200
        • Sweep CGJ
        • Geurts-Moespot J
        • Grebenschikov N
        • et al.
        External quality assessment of trans-European multicentre antigen determinations (ELISA) of urokinase-type plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) in human breast cancer tissue extracts.
        Br J Cancer. 1998; 78: 1434-1441
        • Look MP
        • van Putten WLJ
        • Duffy MJ
        • et al.
        Pooled analysis of prognostic impact of uPA and PAI-1 in 8,377 breast cancer patients.
        J Natl Cancer Inst. 2002; 94: 116-128
        • Goldhirsch A
        • Wood WC
        • Gelber RD
        • et al.
        Meeting highlights: updated international expert consensus on the primary therapy of early breast cancer.
        J Clin Oncol. 2003; 21: 3357-3365
        • Jänicke F
        • Prechtl A
        • Thomssen C
        • et al.
        For the German Chemo N0 Study Group: randomized adjuvant therapy trial in high-risk lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type I.
        J Natl Cancer Inst. 2001; 93: 913-920
        • Harbeck N
        • Meisner C
        • Prechtl A
        • et al.
        For the German Chemo-N0 Study Group. Level-I evidence for prognostic and predictive impact of uPA and PAI-1 in node-negative breast cancer provided by second scheduled analysis of multicenter Chemo-N0 therapy trial.
        Breast Cancer Res Treat. 2001; 69: 213
        • Harbeck N
        • Kates R
        • Schmitt M
        Clinical relevance of invasion factors uPA and PAI-1 for individualized therapy decisions in primary breast cancer is greatest when used in combination.
        J Clin Oncol. 2002; 20: 1000-1009
        • Jänicke F
        • Thomssen C
        • Pache L
        • et al.
        Urokinase (uPA) and PAI-1 as selection criteria for adjuvant chemotherapy in axillary node-negative breast cancer patients.
        in: Schmitt M Graeff H Jänicke F Prospects in Diagnosis and Treatment of Cancer. Elsevier Science, Amsterdam1994: 207-218
        • Foekens JA
        • Look MP
        • Peters HA
        • et al.
        Urokinase-type plasminogen activator and its inhibitor PAI-1: predictors of poor response to tamoxifen therapy in recurrent breast cancer.
        J Natl Cancer Inst. 1995; 87: 751-756
        • Pierga JY
        • Laine-Bidron C
        • Beuzeboc P
        • et al.
        Plasminogen activator inhibitor-1 (PAI-1) is not related to response to neoadjuvant chemotherapy in breast cancer.
        Br J Cancer. 1997; 76: 537-540
        • Harbeck N
        • Kates RE
        • Look MP
        • et al.
        Enhanced benefit from adjuvant systemic chemotherapy in breast cancer patients classified high-risk according to uPA and PAI-1 (n=3,424).
        Cancer Res. 2002; 62: 4617-4622
        • Cufer T
        • Borstnar S
        • Vrhovec I
        Prognostic and predictive value of the urokinase-type plasminogen activator (uPA) and its inhibitors PAI-1 and PAI-2 in operable breast cancer.
        Int J Biol Markers. 2003; 18: 106-115
        • Hayes DF
        • Bast RC
        • Desch CE
        • et al.
        Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers.
        J Natl Cancer Inst. 1996; 88: 1456-1466
        • van't Veer LJ
        • Dai H
        • van de Vijver MJ
        • et al.
        Gene expression profiling predicts clinical outcome of breast cancer.
        Nature. 2002; 415: 530-536
        • van de Vijver MJ
        • He YD
        • van't Veer LJ
        • et al.
        A gene-expression signature as a predictor of survival in breast cancer.
        N Engl J Med. 2002; 347: 1999-2009
        • Paik S
        • Shak S
        • Tang G
        • et al.
        Multi-gene RT-PCR assay for predicting recurrence in node negative breast cancer patients: NSABP studies B-20 and B-14.
        Breast Cancer Res Treat. 2003; 82 (Abstract #16).: S10
        • Schmitt M
        • Wilhelm OG
        • Reuning U
        • et al.
        The plasminogen activation system as a novel target for therapeutic strategies.
        Fibrinolysis. 2000; 14: 114-132
        • Muehlenweg B
        • Sperl S
        • Magdolen V
        • et al.
        Interference with the urokinase plasminogen activator system: a promising therapy concept for solid tumors.
        Exp Opin Biol Ther. 2001; 1: 683-691
      1. Wilex Reports Positive Phase Ia Clinical Data on its Anti-Metastatic Urokinase Inhibitor WX-UK1.
        (Accessed January 10, 2004)
      2. Fox Chase Cancer Center and Wilex Awarded First Biotechnology Clinical Partnership Grant from Department of Defense Breast Cancer Research Program.
        (Accessed January 12, 2004)