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Invasion marker PAI‐1 remains a strong prognostic factor after long‐term follow‐up both for primary breast cancer and following first relapse

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Abstract

In 1991, our group was the first to report the prognostic strength of plasminogen activator inhibitor type 1 (PAI‐1) in primary breast cancer. The prognostic impact of invasion markers PAI‐1 and urokinase‐type plasminogen activator (uPA) on disease‐free survival (DFS) and overall survival (OS) in breast cancer has since been independently confirmed. We now report on the prognostic impact of PAI‐1 and uPA after long‐term median follow‐up of 77 months for our cohort (n=316).

Levels of uPA, PAI‐1, and cathepsin D were determined in tumor tissue extracts by immunoenzymatic methods. S‐phase fraction (SPF) was measured flowcytometrically in paraffin sections. Using log‐rank statistics, optimized cutoffs were found for PAI‐1 (14 ng/mg), uPA (3 ng/mg), cathepsin D (41 pmol/mg), and SPF (6%). In all patients, various factors (PAI‐1, uPA, nodal status, SPF, cathepsin D, grading, tumor size, hormone receptor status) showed significant univariate impact on DFS. In Cox analysis, only nodal status (p < 0.001, RR: 3.1) and PAI‐1 (p < 0.001, RR: 2.7) remained significant. In node‐negative patients (n = 147), PAI‐1, uPA, and SPF had significant univariate impact on DFS, whereas in Cox analysis, only PAI‐1 was significant. PAI‐1 was also significant for DFS within subgroups defined by established factors. In CART analysis, uPA enhanced the prognostic value of PAI‐1 and nodal status for determination of a very‐low‐risk subgroup. For OS, only lymph node status and PAI‐1 were significant in multivariate analysis. PAI‐1 levels in the primary tumor were also a significant prognostic marker for survival after first relapse in both univariate and multivariate analysis.

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References

  1. Early Breast Cancer Trialists' Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 339: 1–15, 71–85, 1992

    Google Scholar 

  2. McGuire W, Clark GM: Prognostic factors and treatment decisions in axillary node-negative breast cancer. N Engl J Med 326: 1756–1761, 1992

    Google Scholar 

  3. Clark G: Prognostic and predictive factors. In: Harris JR, Lippman ME, Morrow M, Hellmann S (eds). Diseases of the Breast. Lippincott-Raven, Philadelphia, 1996, pp 461–485

    Google Scholar 

  4. Duffy MJ, O'Grady P, Devaney D, O'Siorain L, Fennelly JJ, Lijnen HJ: Urokinase-plasminogen activator, a marker for aggressive breast cancers. Cancer 62: 531–533, 1988

    Google Scholar 

  5. Jänicke F, Schmitt M, Hafter R, Hollrieder A, Babic R, Ulm K, Gössner W, Graeff H: Urokinase-type plasminogen activator (uPA) antigen is a predictor of early relapse in breast cancer. Fibrinolysis 4: 69–78, 1990

    Google Scholar 

  6. Jänicke F, Schmitt M, Graeff H: Clinical relevance of the urokinase-type and tissue type plasminogen activators and of their type 1 inhibitor in breast cancer. Sem Thromb Hemostasis 17: 303–312, 1991

    Google Scholar 

  7. Jänicke F, Schmitt M, Pache L, Ulm K, Harbeck N, H¨ofler H, Graeff H: Urokinase (uPA) and its inhibitor PAI-1 are strong, independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 24: 195–208, 1993

    Google Scholar 

  8. Andreasen PA, Kj¨oller L, Christensen L, Duffy MJ: The urokinase-type plasminogen activator system in cancer metastasis: A review. Int J Cancer 72: 1–22, 1997

    Google Scholar 

  9. Lauffenburger D: Making connections count. Nature 383: 390–391, 1996

    Google Scholar 

  10. Grøhndahl-Hansen J, Christensen IJ, Rosenquist C, Brünner N, Mouridsen HT, Danø K, Blichert-Toft M: High levels of urokinase-type plasminogen activator and its inhibitor PAI-1 in cytosolic extracts of breast carcinomas are associated with poor prognosis. Cancer Res 53: 2513–252, 1993

    Google Scholar 

  11. Bouchet C, Spyratos F, Martin PM, Hacène K, Gentile A, Oglobine J: Prognostic value of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitors PAI-1 and PAI-2 in breast carcinomas. Br J Cancer 69: 398–405, 1994

    Google Scholar 

  12. Foekens JA, Schmitt M, van Putten WLJ, Peters HA, Kramer MD, Jänicke F, Klijn JGM: Plasminogen activator inhibitor-1 and prognosis in primary breast cancer. J Clin Oncol 12: 1648–1658, 1994

    Google Scholar 

  13. Grøhndahl-Hansen J, Hilsenbeck SG, Christensen IJ, Clark GM, Osborne CK, Brünner N: Prognostic significance of PAI-1 and uPA in cytosolic extracts obtained from nodepositive breast cancer patients. Breast Cancer Res Treat 43: 153–163, 1997

    Google Scholar 

  14. Schmitt M, Harbeck N, Thomssen C,Wilhelm O, Magdolen V, Reuning U, Ulm K, H¨ofler H, Jänicke F, Graeff H: Clinical impact of the plasminogen activation system in tumor invasion and metastasis: Prognostic relevance and target for therapy. Thromb Haemostasis 78: 285–296, 1997

    Google Scholar 

  15. Schmitt M, Thomssen C, Ulm K, Seiderer A, Harbeck N, H¨ofler H, Jänicke F, Graeff H: Time-varying prognostic impact of tumor-biological factors urokinase (uPA), PAI-1, and steroid hormone receptor status in primary breast cancer. Br J Cancer 76: 306–311, 1997

    Google Scholar 

  16. Jänicke F, Pache L, Schmitt M, Ulm K, Thomssen C, Prechtl A, Graeff H: Both the cytosols and detergent extracts of breast cancer tissues are suited to evaluate the prognostic impact of the urokinase-type plasminogen activator and its inhibitor, plasminogen activator inhibitor type 1. Cancer Res 54: 2527–2530, 1994

    Google Scholar 

  17. Harbeck N, Yamamoto N, Moniwa N, Schüren E, Ziffer P, Dettmar P, Höfler H, Schmitt M, Graeff H: Flow cytometric DNA analysis in primary breast cancer: Technical pitfalls and clinical applications. In: Schmitt M, Graeff H, Jänicke F (eds) Prospects in Diagnosis and Treatment of Cancer: Elsevier Science, Netherlands, 1994, pp 63–74

    Google Scholar 

  18. Dettmar P, Harbeck N, Thomssen C, Pache L, Ziffer P, Fizi K, Jänicke F, Nathrath W, Schmitt M, Graeff H, Höfler H: Prognostic impact of the proliferation associated factors Ki-67 and S-phase in node-negative breast cancer using MIB1 immunostaining and flowcytofluorometric S-phase determination. Br J Cancer 75: 1525–1533, 1997

    Google Scholar 

  19. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53: 457–481, 1958

    Google Scholar 

  20. Cox DR: Regression models and life-tables. J R Stat Soc (B) 34: 187–200, 1972

    Google Scholar 

  21. Breiman I, Friedman J, Olshen R, Stone C: Classification and Regression Trees. Chapman and Hall, New York, 1984

    Google Scholar 

  22. Danø K, Andreasen PA, Grøhndahl-Hansen J, Kristensen P, Nielsen L, Skriver L: Plasminogen activators, tissue degradation and cancer.Adv Cancer Res 44: 139–266, 1985

    Google Scholar 

  23. Schmitt M, J¨anicke F, Graeff H: Tumor-associated proteases. Fibrinolysis 6: 3–26, 1992

    Google Scholar 

  24. Cubellis MV, Wun TC, Blasi F: Receptor-mediated internalization and degradation of urokinase is caused by its specific inhibitor PAI-1. EMBO J 9: 1079–1085, 1990

    Google Scholar 

  25. Stefansson S, Lawrence DA: The serpin PAI-1 inhibits cell migration by blocking integrin αvβ3 binding to vitronectin. Nature 383: 441–443, 1996

    Google Scholar 

  26. Wei Y, Lukashev M, Simon DI, Bodary SC, Rosenberg S, Doyle MV, Chapman HA: Regulation of integrin function by the urokinase receptor. Science 273: 1551–1555, 1996

    Google Scholar 

  27. Graeff H, Harbeck N, Pache L, Wilhelm O, Jänicke F, Schmitt M: Prognostic impact and clinical relevance of tumor-associated proteases in breast cancer. Fibrinolysis 6: 45–53, 1992

    Google Scholar 

  28. Grøhndahl-Hansen J, Christensen IJ, Briand P, Pappot H, Mouridsen HT, Blichert-Toft M, Danø K, Brünner N: Plasminogen activator inhibitor type PAI-1 in cytosolic tumor extracts predicts prognosis in low-risk breast cancer patients. Clin Cancer Res 3: 233–239, 1997

    Google Scholar 

  29. Thorpe SM, Rochefort H, Garcia M, Freiss G, Christensen IJ, Khalaf S, Paolucci F, Pau B, Rasmussen BB, Rose C: Association between high concentrations of Mr 52,000 Impact of PAI-1 in breast cancer 157 cathepsin D and poor prognosis in primary human breast cancer. Cancer Res 49: 6008–6014, 1989

    Google Scholar 

  30. Clark GM: Do we really need prognostic factors for breast cancer? Breast Cancer Res Treat 30: 117–126, 1994

    Google Scholar 

  31. Wenger CR, Beardslee S, Owens MA, Pounds G, Oldaker T, Vendely P, Pandian MR, Harrington D, Clark GM, McGuire W:DNAploidy, S-phase, and steroid receptors in more than 127,000 breast cancer patients. Breast Cancer Res Treat 28:9–20, 1993

    Google Scholar 

  32. Jänicke F, Thomssen C, Pache L, Schmitt M, Graeff H: 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 (eds) Prospects in Diagnosis and Treatment of Cancer: Elsevier Science, Netherlands, 1994, pp 207–218

    Google Scholar 

  33. Foekens JA, Look MP, Peters HA, van Putten WLJ, Portengen H, Klijn JGM: Urokinase-type plasminogen activator and its inhibitor PAI-1: Predictors of poor response to tamoxifen therapy in recurrent breast cancer. J Natl Cancer Inst 87: 751–756, 1995

    Google Scholar 

  34. Pierga JY, Laine-Bidron C, Beuzeboc P, De Cremoux P, Pouillart P, Magdelenat H: Plasminogen activator inhibitor-1 (PAI-1) is not related to response to neoadjuvant chemotherapy in breast cancer. Br J Cancer 76: 537–540, 1997

    Google Scholar 

  35. Benraad TJ, Geurts-Moespot J, Grøndahl-Hansen J, Schmitt M, Heuvel JJTM, deWitte JH, Foekens JA, Leake RE, Brünner N, Sweep CGJ: Immunoassays (ELISA) of urokinase-type plasminogen activator (uPA): Report of an EORTC/BIOMED-1 workshop. Eur J Cancer 32A: 1371–1381, 1996

    Google Scholar 

  36. Sweep CGJ, Geurts-Moespot J, Grebenschikov N, deWitte JH, Heuvel JJTM, Schmitt M, Duffy MJ, Jänicke F, Kramer MD, Foekens JA, Brünner N, Brugal G, Pedersen AN, Benraad TJ: External quality assessment of trans-European multicentre antigen determinations (ELISA) of urokinasetype plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) in human breast cancer tissue extracts. Br J Cancer 78: 1434–1441, 1998

    Google Scholar 

  37. Graeff H, Wilmanns W, J¨anicke F, Sauer H, Classen S: Prognostische und therapierelevante Faktoren beim Mammakarzinom. Ergebnisse einer Konsensuskonferenz. Onkologe 3: 409–412, 1997

    Google Scholar 

  38. Blankenstein MA: Biochemical assessment of tissue prognostic factors in breast cancer. Breast 6: 31–37, 1997

    Google Scholar 

  39. McGuire W: Breast cancer prognostic factors: Evaluation guidelines. J Natl Cancer Inst 83: 154–155, 1991

    Google Scholar 

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Harbeck, N., Thomssen, C., Berger, U. et al. Invasion marker PAI‐1 remains a strong prognostic factor after long‐term follow‐up both for primary breast cancer and following first relapse. Breast Cancer Res Treat 54, 147–157 (1999). https://doi.org/10.1023/A:1006118828278

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