The prognostic relevance of urokinase-type plasminogen activator (uPA) in the blood of patients with metastatic breast cancer

Background: In breast cancer (BC), elevated levels of urokinase-type plasminogen activator (uPA) in tumor tissue have been confirmed as a strong prognostic factor in level-of-evidence-1 studies and the biomarker has been incorporated into national and international guidelines. So far, data on the biological significance of serum uPA in BC are scarce. The aim of the present study was to evaluate the clinical relevance of uPA levels in serum of metastatic BC patients and to compare uPA with other blood-based biomarkers, most importantly circulating tumor cells (CTCs). Materials and Methods: 252 patients with metastatic breast cancer were enrolled in this prospective, multicentre study. Blood samples were collected before start of first-line or later-line treatment. Serum uPA was quantified by a commercially available ELISA. CTCs were detected using CellSearch; other biomarkers (EGFR, VEGF, HER2, RAS p21, TIMP1, CAIX) by ELISA. Results: The optimal cut-off value for serum uPA (2.52 ng/ml) was determined using the ROC analysis and the Youden index. Using this value, 26% of patients had elevated uPA levels. Patients with visceral metastasis and more than one metastatic site were significantly more likely to present with elevated uPA (p = 0.036 and p = 0.016, respectively). CTC status (p = 0.008), serum HER2 (p = 0.001), RAS p21 (p = 0.003), CAIX (p < 0.001), TIMP1 (p < 0.001) and VEGF (p = 0.001) correlated significantly with uPA levels. Elevated uPA levels predicted shorter overall and progression-free survival in the univariate analysis (median OS: 7.5 months [95%-CI 4.5 – 10.5 months] vs. not reached, p < 0.001; PFS: 4.8 [95%-CI: 3.1 – 6.5] vs. 9.1 [7.4 – 10.8] months, p < 0.001). In the multivariate analysis, elevated uPA, presence of ≥5 CTCs, elevated RAS p21, higher grading and higher line of therapy were independent predictors of shorter OS, while elevated CTC counts, higher line of therapy and negative estrogen status were independent predictors of shorter PFS. Conclusions: This is the first trial on the relevance of serum uPA in correlation to the CTC status in metastatic BC patients. Elevated uPA levels independently predict reduced overall survival and improved prognostication in patients with known CTC status. Whether high serum uPA might identify patients most likely to benefit from therapies targeting uPA, remains to be evaluated in future trials.