Prospective Biomarker Trials Chemo N0 and NNBC-3 Europe Validate the Clinical Utility of Invasion Markers uPA and PAI-1 in Node-Negative Breast Cancer.

The Chemo N0 trial is a prospective randomised multicentre breast cancer therapy trial in which 689 node-negative primary breast cancer patients were enrolled in 14 study centres in Germany and Slovenia between 1993 and 1998 [18]. Principal investigator was Prof. Dr. Fritz Jänicke, formerly at the Technical University of Munich, who is now at the University of Hamburg. In this trial (fig. 1), uPA and PAI-1 antigen levels were determined in primary tumour tissue extracts by commercially available ELISA kits (American Diagnostica Inc., Stamford, CT, USA) and used for patient stratification: Patients with low uPA and PAI-1 levels were only observed; patients with high uPA and/or PAI-1 were randomised to either adjuvant chemo therapy with 6 cycles of cyclophosphamide/methotrexate/5-fluorouracil (CMF) or observation only. The prognostic impact of uPA/PAI-1 was then evaluated prospectively by comparing the two observation arms (low versus high uPA/PAI-1), whereas comparison of the two randomised arms allowed prospective evaluation of the predictive benefit of uPA/PAI-1 regarding benefit of adjuvant chemotherapy (fig. 1). The first scheduled interim analysis of the Chemo N0 trial after a median follow-up time of 32 months (n = 556) vali dated prospectively the statistically independent prognostic impact of uPA/PAI-1 regarding DFS [18]. In addition, previously optimised cut-off values for uPA and PAI-1 to discriminate between low and high uPA/PAI-1 were confirmed. The second analysis after a median follow-up time of 50 months comprising 647 patients substantiated the prognostic impact of uPA/PAI-1 regarding DFS as well as OS. Of the 647 patients, 283 had low uPA/PAI-1 and 364 had high uPA and/or PAI-1. The actuarial 3-year recurrence rate for patients with low uPA/PAI-1 was 6.3%, but was 14.2% (p = 0.009) for those with high uPA/PAI-1 in the observation group. Thus, this second interim analysis revealed that node-negative breast cancer patients with low uPA/PAI-1 have an esIntroduction