S-Phase Fraction and Urokinase Plasminogen Activator Are Better Markers for Distant Recurrences Than Nottingham Prognostic Index and Histologic Grade in a Prospective Study of Premenopausal Lymph Node–Negative Breast Cancer

PURPOSE: Histologic grade, Nottingham Prognostic Index (NPI), estrogen receptor (ER) and progesterone receptor (PgR) status, and tumor size have previously been shown to be important prognostic indicators for distant recurrence of breast cancer. The purpose of this study was to compare the prognostic value of these factors with flow cytometric S-phase fraction (SPF), urokinase plasminogen activator (uPA), and plasminogen activator inhibitor type 1 (PAI-1) in premenopausal patients with lymph node–negative breast cancer. PATIENTS AND METHODS: In 237 consecutive premenopausal patients with lymph node–negative breast cancer and freshly frozen tumor material available, SPF, ER and PgR status, uPA and its inhibitor PAI-1, histologic grade, and NPI were evaluated. RESULTS: SPF was univariately the most powerful prognostic factor for distant recurrence, followed by uPA, histologic grade, PgR, age, ER, NPI, and PAI-1, the latter being nonsignificant. Multivariate analysis revealed that neither NPI nor histologic grade was significant after adjustment for SPF, a fact that may be explained by the strong association between these factors. uPA was, however, an independent prognostic factor in addition to SPF, NPI, or histologic grade. CONCLUSION: In this prospective study, SPF and uPA were found to be independent prognostic factors in premenopausal women with lymph node–negative breast cancer. We suggest that SPF, if performed under standardized conditions, can replace histologic grade as a selection instrument for adjuvant medical treatment. The value of the combination of SPF and uPA needs to be confirmed in an independent prospective trial.

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Tumor-Biological Factors Upa and PAI-1 as Stratification Criteria of a Multicenter Adjuvant Chemotherapy Trial in Node-Negative Breast Cancer

The International Journal of Biological Markers ◽

10.1177/172460080001500114 ◽

2000 ◽

Vol 15 (1) ◽

pp. 73-78 ◽

Cited By ~ 16

Author(s):

A. Prechtl ◽

N. Harbeck ◽

C. Thomssen ◽

C. Meisner ◽

M. Braun ◽

...

Keyword(s):

Breast Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Plasminogen Activator ◽

Systemic Therapy ◽

Axillary Node ◽

Breast Cancer Patients ◽

Node Negative ◽

Node Negative Breast Cancer ◽

Pai 1

In axillary node-negative primary breast cancer, 70% of the patients will be cured by locoregional treatment alone. Therefore, adjuvant systemic therapy is only needed for those 30% of node-negative patients who will relapse after primary therapy and eventually die of metastases. Traditional histomorphological and clinical factors do not provide sufficient information to allow accurate risk group assessment in order to identify node-negative patients who might benefit from adjuvant systemic therapy. In the last decade various groups have reported a strong and statistically independent prognostic impact of the serine protease uPA (urokinase-type plasminogen activator) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1) in node-negative breast cancer patients. Based on these data, a prospective multicenter therapy trial in node-negative breast cancer patients was started in Germany in June 1993, supported by the German Research Association (DFG). Axillary node-negative breast cancer patients with high levels of either or both proteolytic factors in the tumor tissue were randomized to adjuvant CMF chemotherapy versus observation only. Recruitment was continued until the end of 1998, by which time 684 patients had been enrolled. Since then, patients have been followed up in order to assess the value of uPA and PAI-1 determination as an adequate selection criterion for adjuvant chemotherapy in node-negative breast cancer patients. This paper reports on the rationale and design of this prospective multicenter clinical trial, which may have an impact on future policies in prognosis-oriented treatment strategies.

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The complex between urokinase plasminogen activator (uPA) and its type-1 inhibitor (PAI-1) denotes poor disease outcome in 576 node-negative breast cancer patients

European Journal of Cancer Supplements ◽

10.1016/s1359-6349(04)91005-1 ◽

2004 ◽

Vol 2 (3) ◽

pp. 173

Author(s):

P Manders ◽

L Beex ◽

V Tjan-Heijnen ◽

P Span ◽

N Grebenchtchikow ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Plasminogen Activator ◽

Urokinase Plasminogen Activator ◽

Disease Outcome ◽

Breast Cancer Patients ◽

Node Negative ◽

Node Negative Breast Cancer ◽

Pai 1

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The Prognostic Value of Vascular Endothelial Growth Factor, Urokinase Plasminogen Activator and Plasminogen Activator Inhibitor-1 in Node-Negative Breast Cancer

The International Journal of Biological Markers ◽

10.1177/172460080401900405 ◽

2004 ◽

Vol 19 (4) ◽

pp. 282-288 ◽

Cited By ~ 12

Author(s):

S. Meo ◽

R. Dittadi ◽

L. Peloso ◽

M. Gion

Keyword(s):

Breast Cancer ◽

Plasminogen Activator ◽

Plasminogen Activator Inhibitor ◽

Vascular Endothelial ◽

Plasminogen Activator Inhibitor 1 ◽

Node Negative ◽

Node Negative Breast Cancer ◽

Endothelial Growth Factor ◽

The Relationship ◽

Pai 1

The vascular endothelial growth factor (VEGF) and the plasminogen activator system play an essential role in solid tumor angiogenesis and in tumor invasion and metastasis. In the present study we investigated the relationship between patient outcome and levels of VEGF, urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor cytosols of 196 node-negative primary invasive breast cancer patients who did not receive any adjuvant therapy. The median follow-up was 65 months. VEGF, uPA and PAI-1 were measured by commercially available enzyme-linked immunosorbent assays. Cox's univariate analysis showed that pT (p=0.0007), uPA (p=0.0156) and PAI-1 (p=0.0015) had a significant impact on relapse-free survival, whereas VEGF did not have any prognostic value (p=0.18). Bivariate analysis showed significant interactions between uPA and PAI-1 (p=0.0035) and between VEGF and PAI-1 (p=0.006). Our study confirms that uPA and PAI-1 cytosol levels can be considered as prognostic factors for relapse-free survival in node-negative breast cancer. Moreover, the interaction between VEGF and PAI-1 warrants further investigation into the relationship between the biomarkers of angiogenesis and those of the protease cascade.

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Risk Assessment in Node-Negative Breast Cancer by the Invasion Factors (Urokinase-Type Plasminogen Activator) and Its Inhibitor PAI-1. Correlation to the Tumor Characteristics in the Prospective NNBC 3-Europe Trial. On Behalf of the NNBC-3 Trial Group.

10.1158/0008-5472.sabcs-09-4040 ◽

2009 ◽

Author(s):

M. Vetter ◽

C. Thomssen ◽

E. Kantelhardt ◽

F. Sweep ◽

C. Meisner ◽

...

Keyword(s):

Breast Cancer ◽

Risk Assessment ◽

Plasminogen Activator ◽

Trial Group ◽

Tumor Characteristics ◽

Node Negative ◽

Node Negative Breast Cancer ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

Pai 1

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Contribution of vascular endothelial growth factor to the Nottingham prognostic index in node-negative breast cancer

British Journal of Cancer ◽

10.1054/bjoc.2001.2019 ◽

2001 ◽

Vol 85 (6) ◽

pp. 795-797 ◽

Cited By ~ 23

Author(s):

D Coradini ◽

P Boracchi ◽

M Grazia Daidone ◽

C Pellizzaro ◽

P Miodini ◽

...

Keyword(s):

Breast Cancer ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Prognostic Index ◽

Nottingham Prognostic Index ◽

Vascular Endothelial ◽

Node Negative ◽

Node Negative Breast Cancer ◽

Endothelial Growth Factor

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Urokinase Plasminogen Activator and Its Inhibitor, PAI-1, as Prognostic Markers in Breast Cancer: From Pilot to Level 1 Evidence Studies

Clinical Chemistry ◽

10.1093/clinchem/48.8.1194 ◽

2002 ◽

Vol 48 (8) ◽

pp. 1194-1197 ◽

Cited By ~ 137

Author(s):

Michael J Duffy

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Plasminogen Activator ◽

Poor Prognosis ◽

Axillary Node ◽

Breast Cancer Patients ◽

Node Negative ◽

Node Negative Breast Cancer ◽

Level 1 ◽

Pai 1

Abstract Background: For optimum management of patients with cancer, accurate assessment of prognosis is essential. The primary determinant of outcome in malignancy is the formation of distant metastases. Urokinase plasminogen activator (uPA) is a serine protease causally involved in invasion and metastasis. Content: Data from model systems show that uPA is unequivocally involved in cancer dissemination. Consistent with its role in metastasis, multiple independent groups have shown that high uPA concentrations in primary breast cancers correlate with poor prognosis. For determining outcome, the prognostic impact of uPA was both independent of traditionally used factors and prognostic in patients with axillary node-negative disease. Paradoxically, high concentrations of plasminogen activator inhibitor (PAI-1), an endogenous inhibitor of uPA, also correlate with poor prognosis in patients with breast cancer, including the subgroup with node-negative disease. The prognostic value of uPA/PAI-1 in axillary node-negative breast cancer patients was recently confirmed in both a prospective randomized trial and a pooled analysis, i.e., two different level 1 evidence (LOE-1) studies. Conclusions: uPA and PAI-1 are among the first biological prognostic factors to have their clinical value validated using LOE-1 evidence studies. Determination of these analytes may help identify low-risk node-negative breast cancer patients for whom adjuvant chemotherapy is unnecessary.

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