Pooled analysis of prognostic impact of uPA and PAI-1 in breast cancer patients

Summary

In this report we present an extension of the pooled analysis of the prognostic impact of urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 in breast cancer patients. We analyzed a different endpoint, metastasis-free survival (MFS). We checked the consistency of the estimates for uPA and PAI-1 for relapse-free survival (RFS) and MFS exploring possible sources of heterogeneity. Nodal status, the most important prognostic factor for breast cancer, introduced heterogeneity in the uPA/PAI-1 survival analyses, reflecting the interaction between nodal status and uPA/PAI-1. The estimates for uPA and PAI-1 were found to be consistent, even when a different transformation of their values was used. The heterogeneity of the separate data sets decreased if the levels of uPA and PAI-1 were ranked, data sets were pooled, and the analyses corrected for the base model that included all traditional prognostic factors, and stratified by data set. We conclude that uPA and PAI-1 are ready to be used in the clinic to help classify breast cancer patients into high and low risk groups.

Part of this paper was originally presented at the joint meetings of the 16th International Congress of the International Society of Fibrinolysis and Proteolysis (ISFP) and the 17th International Fibrinogen Workshop of the International Fibrinogen Research Society (IFRS) held in Munich, Germany, September, 2002.

Keywords

Pooled-analysis - uPA - PAI-1 - breast cancer - prognosis

• References

• 1 Early Breast Cancer Trialists’ Collaborative Group. Effect of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: an overview of 61 randomised trials among 28,896 women. N Engl J Med 1988; 319: 1681-92.
• 2 Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Lancet 1992; 339: 1-15. (Part I) and 71-85 (Part II)
• 3 Andreasen PA, Kjøller L, Christensen L. et al. The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 1997; 72: 1-22.
• 4 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: 285-96.
• 5 Look MP, Foekens JA. Clinical relevance of the urokinase plasminogen activator system in breast cancer. APMIS 1999; 107: 150-9.
• 6 Harbeck N, Kates RE, Look MP. et al. Enhanced benefit from adjuvant chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type I (n = 3424). Cancer Res 2002; 62: 4617-22.
• 7 Jänicke F, Prechtl A, Thomssen C. et al. for the German Chemo No Study Group. Randomized adjuvant therapy trial in high-risk lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator inhibitor type I. J Natl Cancer Inst 2001; 93: 913-20.
• 8 Look MP, van Putten WLJ, Duffy MJ. et al. Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 2002; 94: 116-28.
• 9 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: 1456-66.
• 10 Olkin I. Diagnostic statistical procedures in medical meta-analyses. Stat Med 1999; 18: 2331-41.
• 11 Sweep CGJ, Geurts-Moespot J, Grebenschikov N. et al. External quality assessment of trans-European multicentre antigen determinations (enzyme-linked immunosorbent assay) of urokinase-type plasminogen activator (uPA) and its type 1 inhibitor (PAI-1) in human breast cancer tissue extracts. Br J Cancer 1998; 78: 1434-41.
• 12 Harrell Jr FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996; 15: 361-87.
• 13 Sharp S, Sterne J.. sbe 16: Meta-analysis Stata. Technican Bulletin 1997; 38: 9-14.
• 14 Galbraith RF. A note on graphical presentation of estimated odds ratios from several clinical trials. Stat Med 1988; 7: 889-94.
• 15 Tobias A. sbe 20: Assessing heterogeneity in meta-analysis: the Galbraith plot. Stata Technical Bulletin 1998; 41: 15-7.
• 16 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-81.
• 17 Schmitt M, Thomssen C, Ulm K. et al. Time-varying prognostic impact of tumour biological factors urokinase (uPA), PAI-1 and steroid hormone receptor status in primary breast cancer. Br J Cancer 1997; 76: 306-11.
• 18 van 't Veer LJ, Dai H, van de Vijver MJ. et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature 2002; 31: 530-6.
• 19 van de Vijver MJ, He YD, van ’t Veer LJ. et al. A gene-expression signature as a predictor of survival in breast cancer. NEJM 2002; 347 (25) 1999-2009.