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

Abstract

Urokinase-type plasminogen activator (uPA) and its inhibitor plasminogen activator inhibitor-1 (PAI-1) are key factors in tumour invasion and metastasis. Increased levels of uPA and/or PAI-1 in primary tumour tissues correlate with tumour aggressiveness and poor patient outcome [1, 2]. In primary breast cancer, Duffy et al. [3] in 1988 were the first to show that high enzymatic activity of uPA in primary breast cancer tissues was correlated with advanced tumour stage and poor clinical outcome. In 1989, Janicke et al. [4] demonstrated that high uPA antigen levels in primary tumour tissue measured by enzyme-linked immunosorbent assay (ELISA) also predicted poor prognosis. At the same time, it also became apparent that not only antigen levels of uPA but also those of PAI-1 are of prognostic importance in node-negative and node-positive breast cancer patients [4, 5]. Subsequently, many international, mostly European, researchers validated that primary breast cancer patients, and in particular node-negative patients with high tumour tissue antigen content of uPA and/or PAI-1, have a worse probability of disease-free survival (DFS) and overall survival (OS) than patients with low levels of either or both biomarkers [6,7,8,9]. For clinical utility, the combination of uPA/PAI-1 (both low versus either or both high) is superior to either factor taken alone regarding risk group assessment [10]. uPA and PAI-1 render prognostic information independent of established prognostic factors such as tumour size, tumour grade, steroid hormone receptor status, menopausal status [10] and even HER2 status [11,12,13]. Next to their prognostic impact, uPA/PAI-1 also provide predictive information in early breast cancer. Patients with high uPA/PAI-1 have an enhanced benefit from adjuvant chemotherapy compared to those with low levels. Regarding adjuvant endocrine therapy, no such interaction between benefit and uPA/PAI-1 levels could be found [14]. A large meta-analysis conducted by the European Organisation for Research and Treatment of Cancer (EORTC) Receptor and Biomarker Group, comprising 8377 breast cancer patients from 18 independent collectives, validated the prognostic [15] and predictive impact of uPA/PAI-1 [16], thus achieving the highest level of evidence (LOE-I) for clinical utility of a cancer-associated biomarker, according to the American Society of Clinical Oncology (ASCO) tumour marker utility grading system (TMUGS) [17].