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.

Abstract

Abstract Background:ASCO Tumor Marker Guidelines 2007 recommended clinical routine use of the invasion markers uPA and PAI-1 for risk assessment in N0 breast cancer patients (Harris et al. JCO 2007; 25:5287). We conducted the prospective NNBC 3-Europe trial addressing the direct comparison between risk-assessment by uPA/PAI-1 and clinico-pathological factors, and optimization of adjuvant chemotherapy for high-risk N0 pts: FEC*3-Doc*3 vs. standard FE100C*6.Study Design:Risk assessment was based on grade, and in G2 tumors either by uPA/PAI-1 status (UP) or by a St. Gallen adapted algorithm (CP). Type of assessment was decided by each centre prior to study participation. High-risk patients received adjuvant chemotherapy according to randomisation. Adjuvant endocrine therapy is given according to guidelines. Use of fresh tissue sampling was necessary for determination of uPA/PAI-1 by ELISA. All laboratories took part on the central quality assurance program. HER2 overexpression was confirmed centrally.Results:From Dec 2002 to Jan 2009, 153 centres recruited 4,150 pts (4,145 evaluable). In 2,497 pts., risk was assessed by UP, and in 1,648 by CP. By UP, 38.7% were assigned to the low-risk group, whilst 61.3% of the patients still had to receive adjuvant chemotherapy; by CP-assessment (n=1,648) the risk groups comprised 31.3%, and 68.7 %.Tab.1. Tumor characteristics.risk groupUP lowUP highCP lowCP hightotaln9671,5305161,1324,145age (median)54 (31-70)53 (21-70)57 (34-70)53 (21-70)54 (21-70)pT2178 (18.4%)544 (35.6%)24 (4.7%)603 (53.3%)1,349 (33%)Steroid hormone receptor status pos.951 (98.3%)1,116 (72.9%)513 (99.4%)739 (65.3%)3,331 (80.4%)HER2 overexpression45 (4.7%)284 (18.6%)6 (1.2%)247 (21.8%)582 (14.0%)triple negative (TNBC)15 (1.6%)319 (20.8%)2 (0.4%)295 (26.1%)631 (15.2%)Grading 1417 (43.1%)-164 (32.0%)15 (1.3%)596 (14.4%)Grading 2550 (56.9%)750 (48.9%)345 (67.4%)464 (40.7%)2,115 (51.0%)Grading 3-780 (50.9%)7 (1.4%)639 (56.1%)1,424 (34.4%)uPA value [ng/mg] median1.33.8--2.4PAI-1 value [ng/mg]median9.121.5--15.4 More pT2 tumors were listed as low risk by the UP method. Typical high risk groups (e.g. TNBC, HER2) were identified by UP. A substantial number of HER2 overexpressing tumors (4.7%) in UP were assigned to the low risk group, suggesting an independent effect of UP and HER2. In the QA programm, mean coefficients of variations were 12% for uPA and PAI-1 determination. In total 1,335 pts. were randomised to receive FEC-Doc, and 1.327 to receive FEC. The chemotherapy was well tolerated. However, we observed four therapy related deaths.Conclusions:Determination of uPA and PAI-1 in frozen tissue is feasible and reliable. Using UP for additional prognostic information may prevent chemotherapy from many patients. The effect of the taxane containing regimen will be evaluated with longer follow-up.Cooperation: EORTC Patho-Biology Group, AGO Breast Group, GBG, Unrestricted grants by Sanofi-Aventis, Pfizer, American Diagnostica, Martin-Luther-University Halle-Wittenberg. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4040.