This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zemzoum, I. Articles by Harbeck, N. Search for Related Content PubMed PubMed Citation Articles by Zemzoum, I. Articles by Harbeck, N. Social Bookmarking                            What's this?

Invasion Factors uPA/PAI-1 and HER2 Status Provide Independent and Complementary Information on Patient Outcome in Node-Negative Breast Cancer

Iris Zemzoum, Ronald E. Kates, Jeffrey S. Ross, Peer Dettmar, Moshumi Dutta, Cordula Henrichs, Suna Yurdseven, Heinz Höfler, Marion Kiechle, Manfred Schmitt, Nadia Harbeck

From the Frauenklinik and Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität, and Gemeinschaftspraxis Lachnerstrasse 2 für Pathologie und Zytologie, München, Germany; and Department of Pathology and Laboratory Medicine, Albany Medical College, Albany, NY.

Address reprint requests to Nadia Harbeck, MD, Frauenklinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, D-81675 Munich, Germany; email: nadia.harbeck{at}lrz.tum.de.

Purpose: The independent clinical relevance of invasion factors urokinase-type plasminogen activator (uPA)/PAI-1 and HER2 status was evaluated in lymph node-negative breast cancer patients (N = 118) without adjuvant systemic therapy after long-term follow-up of more than 10 years (median, 126 months).

Patients and Methods: Levels of uPA and its inhibitor PAI-1 were prospectively measured by enzyme-linked immunosorbent assay in primary tumor tissue extracts. HER2 gene amplification (HER2_AMP) was evaluated by fluorescence in situ hybridization (FISH; Ventana Medical Systems HER-2/neu probe; Tucson, AZ), and HER2 protein overexpression (HER2_EXP) was evaluated by immunohistochemistry (IHC; Oncogene Science antibody Ab-3; Cambridge, MA) on parallel-cut formalin-fixed paraffin-embedded tissue sections.

Results: uPA/PAI-1 was high (either one or both factors were high) in 44% of the tumors. HER2_AMP was detected by FISH in 33% of the patients, and HER2_EXP was found by IHC in 44% of the patients. In a multivariate analysis of established and tumor-biologic prognostic factors, uPA/PAI-1 was the only independent prognostic factor for disease-free survival ([DFS]; P < .001; relative risk [RR], 8.3; 95% confidence interval [CI], 3.4 to 20.4). Although HER2_AMP and HER2_EXP did not reach significance for DFS, they were significant for overall survival (OS), even in multivariate analysis (HER2_AMP: P = .004; RR, 3.7; 95% CI, 1.5 to 9.2; HER2_EXP: P = .009; RR, 3.4; 95% CI, 1.4 to 8.7).

Conclusion: After long-term follow-up, uPA/PAI-1 levels in primary tumor tissue reliably and strongly indicate an aggressive course of disease in lymph node-negative breast cancer independent of HER2 status. The particular prognostic effect of HER2 status on OS may reflect its ability to predict resistance to systemic therapy.

Supported in part by a grant to N.H. by the State of Bavaria (KKF Project no. 8756159), the Wilhelm-Sander Stiftung (2000.017.1), and Ventana Medical Systems, Inc, Gaithersburg, MD.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				P. DE CREMOUX, L. GRANDIN, V. DIERAS, A. SAVIGNONI, A. DEGEORGES, R. SALMON, M. A. BOLLET, F. REYAL, B. SIGAL-ZAFRANI, A. VINCENT-SALOMON, et al. Urokinase-type Plasminogen Activator and Plasminogen-activator-inhibitor Type 1 Predict Metastases in Good Prognosis Breast Cancer Patients Anticancer Res, May 1, 2009; 29(5): 1475 - 1482. [Abstract] [Full Text] [PDF]

				L. Harris, H. Fritsche, R. Mennel, L. Norton, P. Ravdin, S. Taube, M. R. Somerfield, D. F. Hayes, and R. C. Bast Jr American Society of Clinical Oncology 2007 Update of Recommendations for the Use of Tumor Markers in Breast Cancer J. Clin. Oncol., November 20, 2007; 25(33): 5287 - 5312. [Abstract] [Full Text] [PDF]

				M. D. Sternlicht, A. M. Dunning, D. H. Moore, P. D.P. Pharoah, D. G. Ginzinger, K. Chin, J. W. Gray, F. M. Waldman, B. A.J. Ponder, and Z. Werb Prognostic Value of PAI1 in Invasive Breast Cancer: Evidence That Tumor-Specific Factors Are More Important Than Genetic Variation in Regulating PAI1 Expression. Cancer Epidemiol. Biomarkers Prev., November 1, 2006; 15(11): 2107 - 2114. [Abstract] [Full Text] [PDF]

				P. Urban, V. Vuaroqueaux, M. Labuhn, M. Delorenzi, P. Wirapati, E. Wight, H.-J. Senn, C. Benz, U. Eppenberger, and S. Eppenberger-Castori Increased Expression of Urokinase-Type Plasminogen Activator mRNA Determines Adverse Prognosis in ErbB2-Positive Primary Breast Cancer J. Clin. Oncol., September 10, 2006; 24(26): 4245 - 4253. [Abstract] [Full Text] [PDF]

				F. Andre, A. Khalil, K. Slimane, C. Massard, M. C. Mathieu, S. Vignot, H. Assi, S. Delaloge, and M. Spielmann Mitotic Index and Benefit of Adjuvant Anthracycline-Based Chemotherapy in Patients With Early Breast Cancer J. Clin. Oncol., May 1, 2005; 23(13): 2996 - 3000. [Abstract] [Full Text] [PDF]

				M. Cicek, R. Fukuyama, D. R. Welch, N. Sizemore, and G. Casey Breast Cancer Metastasis Suppressor 1 Inhibits Gene Expression by Targeting Nuclear Factor-{kappa}B Activity Cancer Res., May 1, 2005; 65(9): 3586 - 3595. [Abstract] [Full Text] [PDF]

				J. S. Ross, J. A. Fletcher, K. J. Bloom, G. P. Linette, J. Stec, W. F. Symmans, L. Pusztai, and G. N. Hortobagyi Targeted Therapy in Breast Cancer: The HER-2/neu Gene and Protein Mol. Cell. Proteomics, April 1, 2004; 3(4): 379 - 398. [Abstract] [Full Text] [PDF]

				B. V. Offersen, B. S. Nielsen, G. Hoyer-Hansen, F. Rank, S. Hamilton-Dutoit, J. Overgaard, and P. A. Andreasen The Myofibroblast Is the Predominant Plasminogen Activator Inhibitor-1-Expressing Cell Type in Human Breast Carcinomas Am. J. Pathol., November 1, 2003; 163(5): 1887 - 1899. [Abstract] [Full Text] [PDF]