Multiple studies have demonstrated that urokinase plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) have clinical utility as breast cancer biomarkers. uPA is an extracellular matrix-degrading protease involved in cancer invasion and metastasis. PAI-1 is thought to enhance angiogenesis and block apoptosis. Although PAI-1 inhibits the activity of uPA, very high levels of these two proteins in tumour tissue promote tumour progression and metastasis.

Dr. Michael Duffy1 and his colleagues published a review summarizing the evidence validating the use of uPA and PAI-1 as prognostic or predictive biomarkers in breast cancer and the potential of uPA as a therapeutic target. They also explain why the most recent American Society of Clinical Oncologists’ guidelines did not recommend these biomarkers in clinical practice. In their review they summarize characteristics of good biomarkers, including analytic validity, clinical utility and clinical validation and describe how uPA and PAI-1 fulfill most of the criteria.

The uPA/PAI-1  Biomarkers are Prognostic

Duffy reviewed a number of retrospective and prospective studies, which have shown that elevated levels of these two proteins in breast tumor tissue predict poor patient outcomes in a subset of patients with lymph node-negative breast cancer.

The uPA/PAI-1 Biomarkers are Predictive

High levels of these biomarkers in patients with early breast cancer predict those who are likely to benefit from adjuvant chemotherapy. Low levels of these two proteins help identify the lymph node-negative women with HER-2 negative tumors who can be spared from such therapy.

The prognostic and predictive value of the uPA and PAI-1 biomarkers were clinically validated in two independent “level of evidence I” studies. One study was a randomized prospective clinical trial in which the biomarker validation was the primary purpose of the trial rather than an “add on” or retrospective analysis. In this trial, low concentrations of the biomarkers were significantly associated with a lower cancer recurrence rate when compared with high concentrations of one or both biomarkers. The second study–a pooled analysis of individual data from retrospective and prospective studies—supported these findings.

uPA/PAI-1 Analysis is Cost Effective

This assay has a return on investment ratio of 8.4:1 as the upfront knowledge of uPA/PAI-1 levels has the potential to reduce the use of unnecessary adjuvant chemotherapy in a subset of patients with lymph node-negative breast cancer.

uPA is a Potential Therapeutic Target

Ideal biomarkers are also therapeutic targets. Pre-clinical studies have shown that selective inhibitors and antibodies can inhibit uPA. One of these inhibitors, upamostat, has demonstrated activity against metastatic breast cancer in phase I and II clinical trials. Additional studies with this agent are ongoing.

Are Current Assays Clinically Practical?

So why are uPA and PAI-1 not recommended as a part of routine biomarker screening for breast cancer despite the strong evidence supporting their use? The problem lies in practical assay issues. Currently, uPA and PAI-1 proteins are measured with analytically validated ELISAs, which are reproducible and have adequate sensitivity. Unfortunately, existing assays require relatively large amounts of fresh or frozen tissue, which is not practical for clinical use.  The amount of tissue obtained from needle biopsy samples is insufficient and surgical biopsy samples are usually preserved in formalin and/or paraffin after extraction. uPA and PAI-1 biomarkers have the potential to personalize treatment for women with breast cancer. However, these biomarkers won’t be used in a clinical setting until we develop assays that require only small volumes of tissue or are able to measure the proteins in formalin-fixed and paraffin-embedded tissues.

  1. Duffy, MJ, McGowan PM, Harbeck N, et al. uPA and PAI-1 as biomarkers in breast cancer: validated for clinical use in level-of-evidence-1 studies. Breast Cancer Res. 2014 Aug 22;16(4):428. doi: 10.1186/s13058-014-0428-4.