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

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 (FE(100)C*6 versus FE(100)C*3 followed by Docetaxel(100)*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 FE(100)C-Docetaxel(100), and 1,327 received French FE(100)C. 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.

Figure 1

Design of the NNBC 3-Europe trial. Stratification and randomization schedule: C1 = stratification by type of risk assessment based on choice of the centre (type of risk assessment); C2 = stratification by risk status; S = Stratification by HER-2/neu-FISH result; R = randomisation (FE100C: 5-Fluorouracil 500 mg/m², Epirubicin 100 mg/m², Cyclophosphamide 500 mg/m², q3 wks; Doc: Docetaxel 100 mg/m², q3 wks.). += fresh tumour tissue for patients within the "biological UP pathway", additionally in all patients paraffin blocks for central review.

Figure 2

Risk assessment using the clinical and pathological algorithm (CP) adopted from St. Gallen and NPI. - all patients G1 or G2 <2 cm were assessed as low-risk if no additional risk factors were present. Patients showing an additional risk factor or G2tumors ≥2 cm or G3 were assessed high-risk.

Figure 3

Risk assessment using the uPA/PAI-1 algorithm (UP) - all patients with G1 tumors were assessed low-risk, all patients with G3 tumors or ≤35 years were assessed high-risk. Patients with G2 tumors were assessed high-risk if uPA and/or PAI-1 were elevated above the validated cut-off levels.