Abstract
Urokinase-type plasminogen activator (uPA) and its main inhibitor (PAI-1) were shown with level 1 evidence to be prognostic factors for primary breast cancer. Our preliminary retrospective study on a cohort of 1,220 consecutive patients hinted that uPA and PAI-1 could also serve as predictive factors for systemic therapy, namely that patients with high levels of the two markers benefit much more from anthracycline-based chemotherapy than patients with low levels of the two markers. The latter could equally well be treated with less toxic CMF-based chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). The retrospective study, however, suffered from severely uneven patient and tumor characteristics as the patients were treated per institutional guidelines valid at the time and were not randomized between the anthracycline and CMF arms. In the present paper, we attempted to remedy this shortcoming and recheck our previous observations on more balanced data. To this end we employed a custom-made computer algorithm that selected 180 patients out of a total of 1,220 patients such that we obtained very well balanced anthracycline and CMF arms according to patient and tumor characteristics. Moreover, the low and high uPA/PAI-1 subgroups within both arms were also completely balanced. The algorithm in a way created a similar setting to that of a randomized study at the expense of greatly reducing the number of patients included into the study. In this setting, we observed the 3-year disease-free survival (DFS) in all four subgroups (according to treatment and levels of markers: both uPA and PAI-1 low versus one or both high). We report that the 3-year DFS in the CMF arm differed significantly: 87.1% for patients with low levels of markers versus 77.0% for patients with high levels of markers (P = 0.044, HR = 2.81, 95% CI = 0.98–8.04). On the other hand, the 3-year DFS in the anthracycline arm did not differ much between the two marker level subgroups: 85.2% for patients with low levels of markers versus 81.8% for patients with high levels of markers. Our observation points out that worse prognosis correlated to high uPA and PAI-1 levels can be reversed by treatment efficacy achieved through anthracycline-based chemotherapy. Based on this observation, we hypothesize that uPA/PAI-1 combination could be predictive for response to systemic therapy.
Similar content being viewed by others
References
Early Breast Cancer Trialists Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365:1687–1717
Gennari A, Sormani MP, Pronzato P, Puntoni M, Colozza M, Pfeffer U, Bruzzi P (2008) HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: a pooled analysis of randomized trials. J Natl Cancer Inst 100(1):14–20
Pritchard KI, Messersmith H, Elavathil L, Trudeau M, O’Malley F, Dhesy-Thind B (2008) HER-2 and topoisomerase II as predictors of response to chemotherapy. J Clin Oncol 26(5):736–744
O’Malley FP, Chia S, Tu D, Shepherd LE, Levine MN, Huntsman D, Bramwell VH, Andrulis I, Pritchard KI (2006) Prognostic and predictive value of topoisomerase II alpha in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA. 5). J Clin Oncol 24:11s (suppl; abstr 533)
Andreasen PA, Kjøller L, Christensen L, Duffy MJ (1997) The urokinase-type plasminogen activator system in cancer metastasis: a review. Int J Cancer 72:1–22
Schmitt M, Harbeck N, Thomssen C, Wilhelm O, Magdolen V, Reuning U, Ulm K, Höfler H, Jänicke F, Graeff H (1997) Clinical impact of the plasminogen activation system in tumor invasion and metastases: prognostic relevance and target for therapy. Tromb Haemostasis 78:285–296
Duffy MJ, Maguire T, McDermott EW, O’Higgins N (1999) Urokinase plasminogen activator: a prognostic marker in multiple types of cancer. J Surg Oncol 71:130–135
Look MP, Foekens JA (2000) Clinical relevance of the urokinase plasminogen activator system in breast cancer. APMIS 107:150–159
Borstnar S, Vrhovec I, Cufer T (2002) Prognostic value of plasminogen activator inhibitors in breast cancer. Int J Biol Markers 17(2):96–103
Borstnar S, Vrhovec I, Svetic B, Cufer T (2002) Prognostic value of the urokinase-type plasminogen activator, and its inhibitors and receptor in breast cancer patients. Clin Breast Cancer 3(2):138–146
Cufer T, Borstnar S, Vrhovec I (2003) 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 18(2):106–115
Look MP, van Putten WL, Duffy MJ, Harbeck N, Christensen IJ, Thomssen C, Kates R, Spyratos F, Fernö M, Eppenberger-Castori S, Sweep CG, Ulm K, Peyrat JP, Martin PM, Magdelenat H, Brünner N, Duggan C, Lisboa BW, Bendahl PO, Quillien V, Daver A, Ricolleau G, Meijer-van Gelder ME, Manders P, Fiets WE, Blankenstein MA, Broët P, Romain S, Daxenbichler G, Windbichler G, Cufer T, Borstnar S, Kueng W, Beex LV, Klijn JG, O’Higgins N, Eppenberger U, Jänicke F, Schmitt M, Foekens JA (2002) Pooled analysis of prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in 8377 breast cancer patients. J Natl Cancer Inst 94(2):116–128
Jänicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Untch M, Sweep CG, Selbmann HK, Graeff H, Schmitt M, German N0 Study Group (2001) Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 93:913–920
Harbeck N, Schmitt M, Meisner C, Friedel C, Untch M, Schmidt M, Lisboa B, Sweep C, Jänicke F, Thomssen C, Chemo N0 Study Group (2009) Final 10-year analysis of prospective multicenter Chemo N0 trial for validation of ASCO-recommended biomarkers uPA/PAI-1 for therapy decision making in node-negative breast cancer. J Clin Oncol 27:15s (suppl; abstr 511)
Harbeck N, Alt U, Berger U, Krüger A, Thomssen C, Jänicke F, Höfler H, Kates RE, Schmitt M (2001) Prognostic impact of proteolytic factors (uPA, PAI-1, cathepsins B, D, L) in primary breast cancer reflects effects of adjuvant systemic therapy. Clin Cancer Res 7:2757–2764
Harbeck N, Kates R, Schmitt M (2002) 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 20(4):1000–1007
Fernö M, Bendahl PO, Borg Å, Brundell J, Hirschberg L, Olsson H, Killander D (1996) Urokinase plasminogen activator in breast cancer, analysed in steroid receptors cytosols with a luminometric immunoassay. Eur J Cancer 32A:793–801
Manders P, Tjan-Heijnen VCG, Span PN, Grebenchtchikov N, Geurts-Moespot A, van Tienoven DT, Beex LV, Sweep FC (2004) Predictive impact of urokinase-type plasminogen activator: plasminogen activator inhibitor type-1 complex on the efficacy of adjuvant systemic therapy in primary breast cancer. Cancer Res 64:659–664
Hamilton A, Piccart M (2000) The contribution of molecular markers to the prediction of response in the treatment of breast cancer: a review of the literature on HER-2, p53 and BCL-2. Ann Oncol 11:647–663
Harbeck N, Kates RE, Look MP, Meijer-Van Gelder ME, Klijn JG, Krüger A, Kiechle M, Jänicke F, Schmitt M, Foekens JA (2002) Enhanced benefit from adjuvant systemic chemotherapy in breast cancer patients classified high-risk according to urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1). Cancer Res 62:4617–4622
Borstnar S, Vrhovec I, Cufer T (2004) High levels of uPA and PAI-1 predicts a good response to antracyclines (abstract). Breast Cancer Res Treat 88(suppl. 1):54–55
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics (2005) Reporting recommendations for tumor marker prognostic studies. J Clin Oncol 23(36):9067–9072
Elston CW (1987) Grading of invasive carcinoma of the breast. In: Page DL, Anderson TJ (eds) Diagnostic histopathology of the breast. Churchill Livingstone, Edinburgh, pp 300–311
Sweep CG, Geurts-Moespot J, Grebenschikov N, de Witte JH, Heuvel JJ, Schmitt M, Duffy MJ, Jänicke F, Kramer MD, Foekens JA, Brünner N, Brugal G, Pedersen AN, Benraad TJ (1998) External quality assessment of trans-European multicentre antigen determinations (enzyme-linked immunoabsorbent assay) of urokinase-type plasminogen activator (Upa) and its type 1 inhibitor (PAI-1) in human breast cancer tissue extracts. Br J Cancer 78:1434–1441
Gu XS, Rosenbaum PR (1993) Comparison of multivariate matching methods: structures, distances, and algorithms. J Comput Graph Stat 2(4):405–420
Annecke K, Schmitt M, Euler U, Zerm M, Paepke D, Paepke S, von Minckwitz G, Thomssen C, Harbeck N (2008) uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial. Adv Clin Chem 45:31–45
Knoop AS, Knudsen H, Balslev E, Rasmussen BB, Overgaard J, Nielsen KV, Schonau A, Gunnarsdóttir K, Olsen KE, Mouridsen H, Ejlertsen B, Danish Breast Cancer Cooperative Group (2006) Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin, and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 24(6):1015
Ravnik M, Takac I, Arko D, Gorisek B, Cas-Sikosek N, Lampelj M, Ravnik J, Cufer T (2007) Correlation between invasive markers (uPA/PAI-1) and HER-2 status in early breast cancer. In: Samija M (ed). 5th Central European oncology congress, Opatija, Croatia, June 20–23. Final program & abstract book: Croatian Oncological Society, p 81
Bouchet C, Ferrero-Poüs M, Hacene K, Becette V, Spyratos F (2003) Limited prognostic value of c-erbB-2 compared to uPA and PAI-1 in primary breast carcinoma. Int J Biol Markers 18(3):207–217
Urban P, Vuaroqueaux V, Labuhn M, Delorenzi M, Wirapati P, Wight E, Senn HJ, Benz C, Eppenberger U, Eppenberger-Castori S (2006) Increased expression of urokinase-type plasminogen activator mRNA determines adverse prognosis in ErbB2-positive primary breast cancer. J Clin Oncol 24(26):4245–4253
Harbeck N, Ross J, Yurdseven S, Dettmar P, Pölcher M, Kuhn W, Ulm K, Graeff H, Schmitt M (1999) HER-2/neu gene amplification determined by in-situ hybridization (FISH) allows risk group assessment in node-negative breast cancer. Int J Oncol 14:663–671
Konecny G, Untch M, Arboleda J, Wilson C, Kahlert S, Boettcher B, Felber M, Beryt M, Lude S, Hepp H, Slamon D, Pegram M (2001) HER-2/neu and urokinase-type plasminogen activator and its inhibitor in breast cancer. Clin Cancer Res 7:2448–2457
Zemzoum I, Kates RE, Ross JS, Dettmar P, Dutta M, Henrichs C, Yurdseven S, Höfler H, Kiechle M, Schmitt M, Harbeck N (2003) Invasion factors uPA/PAI-1 and HER2 status provide independent and complementary information on patients outcome in node-negative breast cancer. J Clin Oncol 21(6):1022–1028
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Borstnar, S., Sadikov, A., Mozina, B. et al. High levels of uPA and PAI-1 predict a good response to anthracyclines. Breast Cancer Res Treat 121, 615–624 (2010). https://doi.org/10.1007/s10549-009-0691-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10549-009-0691-8