Molecular risk estimation and adjuvant chemotherapy in node-negative breast cancer patients—A status report of the prospective clinical trial NNBC 3-Europe

Abstract

10503 Background: Feasibility of risk assessment in node negative breast cancer using the invasion markers urokinase-type plasminogen activator uPA and its inhibitor PAI-1 has been demonstrated in several prospective and retrospective studies and in a large meta analysis. Patients with low uPA and/or PAI-1 concentrations in tumor tissue levels have an excellent 5-year overall survival (>95%) even without any adjuvant therapy. Use of these molecular markers may spare adjuvant chemotherapy in approximately one half of node-negative breast cancer patients. Particulary, patients with an intermediate grade tumor can easily be differentiated in low and high risk. In addition, patients with high uPA and/or PAI-1 level seem to benefit from adjuvant chemotherapy. The NNBC-3-Europe trial seeks to answer two questions: 1. Is risk assessment by molecular markers uPA/PAI-1 superior to that by clinico-pathological factors regarding identification of low-risk patients? 2. Is adjuvant chemotherapy with anthracycline-taxane sequence (FEC-Docetaxel) superior to standard FEC in high-risk patients? Methods: In the NNBC-3-Europe trial, participating centres opt to either perform risk estimation by clinico-pathological factors or by the uPA and PAI-1 concentration in tumor tissue biopsies. Low-risk patients will be observed without adjuvant chemotherapy. High-risk patients are randomised based on the kind of adjuvant chemotherapy. Patients with steroid hormone receptor positive tumors receive adequate endocrine therapy. Results: Of the first 506 patients in the study arm with molecular risk assessment, 62 had a grade 1 tumors, and 184 had grade 3 tumors. Among grade 2 tumors (n = 260), 87 had low uPA/PAI-1. 173 patients presented with high levels. About 30% of the patients were allocated to the low-risk group using uPA/PAI-1. Conclusions: An adjuvant chemotherapy trial based on uPA/PAI-1 determination in the primary tumor is feasible in a multicentre setting. Applying these molecular markers for risk assessment, at this stage of the study, adjuvant chemotherapy could be spared in almost one third of N0 patients. It is performed in association with the EORTC PathoBiology Group Receptor und the German AGO Breast Group. [Table: see text]

Components of the plasminogen activator system and their complexes in renal cell and bladder cancer: comparison between normal and matched cancerous tissues

“…Thereby, uPA and PAI‐1 have achieved a ‘level of evidence I’ as a tumour biomarker [28]. Indeed, uPA and PAI‐1 levels (as assessed by ELISA) are being used to prospectively assign patients with breast cancer to a high‐risk or low‐risk group, after which adjuvant treatment is scheduled accordingly in a multicentre European trial [29]. By contrast, high tPA levels in breast tumour cytosols are significantly associated with prolonged survival, but when complexed with PAI‐1 denote a poor prognosis [14].…”