Abstract
Urokinase plasminogen activator (uPA) is an extracellular matrix-degrading protease involved in cancer invasion and metastasis, interacting with plasminogen activator inhibitor-1 (PAI-1), which was originally identified as a blood-derived endogenous fast-acting inhibitor of uPA. At concentrations found in tumor tissue, however, both PAI-1 and uPA promote tumor progression and metastasis. Consistent with the causative role of uPA and PAI-1 in cancer dissemination, several retrospective and prospective studies have shown that elevated levels of uPA and PAI-1 in breast tumor tissue are statistically independent and potent predictors of poor patient outcome, including adverse outcome in the subset of breast cancer patients with lymph node-negative disease. In addition to being prognostic, high levels of uPA and PAI-1 have been shown to predict benefit from adjuvant chemotherapy in patients with early breast cancer. The unique clinical utility of uPA/PAI-1 as prognostic biomarkers in lymph node-negative breast cancer has been confirmed in two independent level-of-evidence-1 studies (that is, in a randomized prospective clinical trial in which the biomarker evaluation was the primary purpose of the trial and in a pooled analysis of individual data from retrospective and prospective studies). Thus, uPA and PAI-1 are among the best validated prognostic biomarkers currently available for lymph node-negative breast cancer, their main utility being the identification of lymph node-negative patients who have HER-2-negative tumors and who can be safely spared the toxicity and costs of adjuvant chemotherapy. Recently, a phase II clinical trial using the low-molecular-weight uPA inhibitor WX-671 reported activity in metastatic breast cancer.
Highlights
The ideal cancer biomarker should possess all or most of the following properties [1,2]: have an analytically validated assay for its measurement, have undergone validation for addressing a specific clinical problem, have been shown to have clinical utility such as improving patient outcome, enhancing quality of life, or reducing cost of care, have a cost-effective assay, and be a target for therapy.In breast cancer, the biomarkers that best meet these criteria are the estrogen receptor (ER) [3] and the oncoprotein human epidermal growth factor receptor 2 (HER-2) [4]
Though not that widely used in the clinic at present, two other biomarkers - the serine protease urokinase plasminogen activator and its inhibitor plasminogen activator inhibitor-1 (PAI-1) - meet most of the above criteria
In the group of patients who had received prior adjuvant chemotherapy, progression-free survival (PFS) increased from 4.3 months in those treated with capecitabine alone to 8.3 months in the group receiving upamostat and capecitabine
Summary
The ideal cancer biomarker should possess all or most of the following properties [1,2]: have an analytically validated assay for its measurement, have undergone validation for addressing a specific clinical problem, have been shown to have clinical utility such as improving patient outcome, enhancing quality of life, or reducing cost of care, have a cost-effective assay, and be a target for therapy. Direct evidence that uPA/PAI-1 measurement is costeffective and cost-saving was recently shown in a prospective multicenter study involving 93 lymph nodenegative and ER-positive breast cancer patients [83] In this economic analysis, measurement of uPA/PAI-1 was found to decrease the use of adjuvant chemotherapy in 35 (37.6%) of the 93 patients investigated. ASCO uPA/PAI-1 measured by ELISAs may be used for the determination of prognosis in patients with newly diagnosed, node-negative [86] breast cancer Low levels of both markers are associated with a sufficiently low risk of disease recurrence, especially in steroid hormone receptor-positive women who will receive adjuvant endocrine therapy and who will receive only minimal additional benefit from chemotherapy. We recommend that, where possible, further trials with anti-uPA treatments involve prior measurement of uPA protein expression levels
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