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Open Access Study protocol

Prospective evaluation of prognostic factors uPA/PAI-1 in node-negative breast cancer: Phase III NNBC3-Europe trial (AGO, GBG, EORTC-PBG) comparing 6 × FEC versus 3 × FEC/3 × Docetaxel

Eva J Kantelhardt1*, Martina Vetter1, Marcus Schmidt2, Corinne Veyret3, Doris Augustin4, Volker Hanf5, Christoph Meisner6, Daniela Paepke7, Manfred Schmitt7, Fred Sweep8, Gunter von Minckwitz9, Pierre-Marie Martin10, Fritz Jaenicke11, Christoph Thomssen1 and Nadia Harbeck12

Author Affiliations

1 Klinik und Poliklinik für Gynäkologie, Martin-Luther Universität, Halle Saale, Germany

2 Klinik für Gynäkologie, Johannes Gutenberg-Universität, Mainz, Germany

3 Centre Henri Becquerel, OB-GYN, Rouen, France

4 Klinik für Gynäkologie, Klinikum Deggendorf, Deggendorf, Germany

5 Klinik für Gynäkologie, Klinikum Fürth, Fürth, Germany

6 Eberhard Karls Universität, IMB, Tübingen, Germany

7 Frauenklinik, Technische Universität, München, Germany

8 Department of Laboratory Medicine Radboud University Nijmegen Medical Cente, Nijmegen, the Netherlands

9 German Breast Group GmbH, GBG, Neu-Isenburg, Germany

10 Laboratoire de Transfer en Oncologie Biologieque, l'AP-HM, Marseille, France

11 Klinik und Poliklinik für Gynäkologie. Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

12 Brustzentrum, Frauenklinik, Universität zu Köln, Cologne, Germany

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BMC Cancer 2011, 11:140  doi:10.1186/1471-2407-11-140

Published: 16 April 2011

Abstract

Background

Today, more than 70% of patients with primary node-negative breast cancer are cured by local therapy alone. Many patients receive overtreatment by adjuvant chemotherapy due to inadequate risk assessment. So far, few clinical trials have prospectively evaluated tumor biology based prognostic factors. Risk assessment by a biological algorithm including invasion factors urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor type 1 (PAI-1) will assess up to 35-55% of node-negative patients as low-risk and thus avoid chemotherapy. In contrast, a clinical-pathological algorithm will only classify 20-40% of patients as low-risk. High-risk node-negative patients should receive chemotherapy. Anthracycline-based regimens are accepted as a standard, the additional benefit of taxanes remains an open question.

Methods/Design

The international NNBC3 ("Node Negative Breast Cancer 3-Europe") trial compares biological risk assessment (UP) using invasion factors uPA/PAI-1 with a clinical-pathological algorithm (CP). In this trial, the type of risk assessment (CP or UP) was chosen upfront by each center for its patients. Fresh frozen tissue was obtained to determine uPA/PAI-1 using an enzyme-linked immunosorbent assay (ELISA). Patients assessed as high-risk were stratified by human epidermal growth factor receptor 2 (HER2) status and then randomised to receive anthracycline-containing chemotherapy 5-Fluorouracil (F)/Epirubicin (E)/Cyclophosphymide (C) or an anthracycline-taxane sequence (FE100C*6 versus FE100C*3 followed by Docetaxel100*3).

Discussion

In this trial, 4,149 node-negative patients with operable breast cancer from 153 centers in Germany and France were included since 2002. Measurement of uPA/PAI-1 by ELISA was performed with standardised central quality assurance for 2,497 patients (60%) from 56 "UP"-centers. The NNBC 3-Europe trial showed that inclusion of patients into a clinical phase III trial is feasible based on biological testing of fresh frozen tumor material. In addition, 2,661 patients were classified as high-risk and thus received chemotherapy. As adjuvant chemotherapy, 1,334 high-risk patients received FE100C-Docetaxel100, and 1,327 received French FE100C. No unexpected toxicities were observed. Chemotherapy efficacy and comparison of UP with CP will be evaluated after longer follow-up.

Trial Registration

clinical Trials.gov NCT01222052.