scholarly journals Plasminogen Activator System and Breast Cancer: Potential Role in Therapy Decision Making and Precision Medicine

2016 ◽  
Vol 11 ◽  
pp. BMI.S33372 ◽  
Author(s):  
Adel Gouri ◽  
Aoulia Dekaken ◽  
Khalid El Bairi ◽  
Arifa Aissaoui ◽  
Nihad Laabed ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Decision Making ◽  
Precision Medicine ◽  
Plasminogen Activator ◽  
Critical Role ◽  
Multiple Cancer ◽  
Dismal Prognosis ◽  
Plasminogen Activator System ◽  
Pai 1

Shifting from the historical TNM paradigm to the determination of molecular and genetic subtypes of tumors has been a major improvement to better picture cancerous diseases. The sharper the picture is, the better will be the possibility to develop subsequent strategies, thus achieving higher efficacy and prolonged survival eventually. Recent studies suggest that urokinase-type plasminogen activator (uPA), uPA receptor (uPAR), and plasminogen activator inhibitor-1 (PAI-1) may play a critical role in cancer invasion and metastasis. Consistent with their role in cancer dissemination, high levels of uPA, PAI-1, and uPAR in multiple cancer types correlate with dismal prognosis. In this respect, upfront determination of uPA and PAI-1 as invasion markers has further opened up the possibilities for individualized therapy of breast cancer. Indeed, uPA and PAI-1 could help to classify patients on their risk for metastatic spreading and subsequent relapse, thus helping clinicians in their decision-making process to propose, or not propose, adjuvant therapy. This review covers the implications for cancer diagnosis, prognosis, and therapy of uPA and PAI-1, and therefore how they could be major actors in the development of a precision medicine in breast cancer.

Dissemination Risk Index Based on Plasminogen Activator System Components in Primary Breast Cancer

1999 ◽  
Vol 17 (10) ◽  
pp. 3048-3057 ◽  
Author(s):  
Cécile Bouchet ◽  
Kamel Hacène ◽  
Pierre-Marie Martin ◽  
Véronique Becette ◽  
Michèle Tubiana-Hulin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasminogen Activator ◽  
Correspondence Analysis ◽  
Primary Breast Cancer ◽  
Multiple Correspondence Analysis ◽  
Risk Index ◽  
Node Negative ◽  
Plasminogen Activator System ◽  
Activator System ◽  
Pai 1

PURPOSE: To study interactions between disease-free survival (DFS) and four components of the plasminogen activator system: urokinase-type plasminogen activator (uPA), its two inhibitors (PAI-1 and PAI-2), and its membrane receptor uPAR. PATIENTS AND METHODS: We conducted a retrospective study of 499 primary breast cancer patients (median follow-up, 6 years). uPA, PAI-1, and PAI-2 were determined on cytosols and uPAR on solubilized pellets, using enzyme-linked immunoadsorbent assay kits (American Diagnostica, Greenwich, CT). Classical univariate and multivariate statistical methods were used together with multiple correspondence analysis to graphically examine interactions between the variables and outcome. RESULTS: By univariate analysis, higher uPA and PAI-1 values were significantly related to shorter DFS (P = .002; P < .00002). PAI-2 was not significantly related to DFS, although patients with high and very low PAI-2 values had a longer DFS. Multiple correspondence analysis showed the parallel impact of uPA and PAI-1 on outcome, and the clearly different behavior of PAI-2 compared with PAI-1. The prognostic contribution of uPAR seemed weak by both methods. A dissemination risk index [uPA × PAI-1/(PAI-2 + 1)], taking into account the modulation of uPA proteolytic activity by the ratio of its two inhibitors, was then tested. Dissemination risk index was selected as an independent variable in the Cox model in the overall population (P < .000001) and in node-positive patients (P < .00001). It was the only variable selected in node-negative patients (P = .003). CONCLUSION: A dissemination risk index determined on primary tumor and taking into account the different effects of PAI-1 and PAI-2 on uPA can be of major help in clinical management of breast cancer, particularly in node-negative patients.

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

2000 ◽  
Vol 15 (1) ◽  
pp. 73-78 ◽  
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.

Prognostic Value of Plasminogen Activator Inhibitors in Breast Cancer

2002 ◽  
Vol 17 (2) ◽  
pp. 96-103 ◽  
Author(s):  
S. Borstnar ◽  
I. Vrhovec ◽  
T. Cufer
Keyword(s):  
Breast Cancer ◽  
Plasminogen Activator ◽  
Prognostic Value ◽  
Cox Model ◽  
Univariate Analysis ◽  
Lymph Node Status ◽  
Enzyme Linked Immunosorbent Assay ◽  
Plasminogen Activator Inhibitors ◽  
Increased Risk ◽  
Pai 1

The prognosis of cancer is primarily dependent on its potential to invade and metastasize. Data from both pre-clinical and clinical studies strongly suggest that serine proteases, as well as their inhibitors and receptor, play a central role in the processes leading to metastasis. We therefore investigated the prognostic value of plasminogen activator inhibitors type 1 (PAI-1) and type 2 (PAI-2) and the combination of both inhibitors in 332 patients with operable breast cancer. PAI-1 and PAI-2 content was measured in the primary tumor cytosols using an enzyme-linked immunosorbent assay. For PAI-1 the median value (3.9 ng/mg protein) was used as cutoff, while the optimized cutoff for PAI-2 (6.5 ng/mg protein) was obtained using the log-rank statistic. After a median follow-up of 46 months 96 (29%) patients relapsed. In univariate analysis patients with a high PAI-1 or a low PAI-2 content had an increased risk of relapse. The difference was statistically significant for PAI-1 (p<0.0001) and almost statistically significant for PAI-2 (p=0.057). Stage, tumor size, differentiation grade, lymph node status and hormone receptor status also showed significant univariate impact on disease-free survival (DFS). In multivariate analysis (Cox model) PAI-1 (p<0.0001, RR=2.78), PAI-2 (p=0.0075, RR=2.17), UICC stage (p=0.0014, RR=2.2), differentiation grade (p=0.0097, RR=1.91) and nodal status (p<0.0001, RR=2.9) retained their significance. When both inhibitors were combined the worst prognosis was observed in patients with simultaneous high PAI-1 and low PAI-2 levels, whereas low PAI-1 in combination with high PAI-2 values indicated a very favorable prognosis. In conclusion, our study showed that both PAI-1 and PAI-2 had independent prognostic value in breast cancer. Combination of both inhibitors further improved the differentiation of patients with respect to prognosis.

scholarly journals Determination of the Complex between Urokinase and Its Type-1 Inhibitor in Plasma from Healthy Donors and Breast Cancer Patients

1999 ◽  
Vol 45 (8) ◽  
pp. 1206-1213 ◽  
Author(s):  
Anders N Pedersen ◽  
Nils Brünner ◽  
Gunilla Høyer-Hansen ◽  
Peter Hamer ◽  
David Jarosz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Detection Limit ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Healthy Donors ◽  
Pai 1 ◽  
Healthy Females ◽  
Assay Detection

Abstract Background: The complex between urokinase (uPA) and its type-1 inhibitor (PAI-1) is formed exclusively from the active forms of these components; thus, the complex concentration in a biological sample may reflect the ongoing degree of plasminogen activation. Our aim was to establish an ELISA for specific quantification of the uPA:PAI-1 complex in plasma of healthy donors and breast cancer patients. Methods: A kinetic sandwich format immunoassay was developed, validated, and applied to plasma from 19 advanced-stage breast cancer patients, 39 age-matched healthy women, and 31 men. Results: The assay detection limit was &lt;2 ng/L, and the detection of complex in plasma was validated using immunoabsorption, competition, and recovery tests. Eighteen cancer patients had a measurable complex concentration (median, 68 ng/L; range, &lt;16 to 8700 ng/L), whereas for healthy females and males the median signal values were below the detection limit (median, &lt;16 ng/L; range, &lt;16 to 200 ng/L; P &lt;0.0001). For patient plasma, a comparison with total uPA and PAI-1 showed that the complex represented a variable, minor fraction of the uPA and PAI-1 concentrations of each sample. Conclusion: The reported ELISA enables detection of the uPA:PAI-1 complex in blood and, therefore, the evaluation of the complex as a prognostic marker in cancer.

scholarly journals Prognostic value of tissue-type plasminogen activator (tPA) and its complex with the type-1 inhibitor (PAI-1) in breast cancer

1999 ◽  
Vol 80 (1-2) ◽  
pp. 286-294 ◽  
Author(s):  
J H de Witte ◽  
C G J Sweep ◽  
J G M Klijn ◽  
N Grebenschikov ◽  
H A Peters ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Plasminogen Activator ◽  
Prognostic Value ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Pai 1
Sign in / Sign up

Export Citation Format

Share Document