Abstract
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. 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. 252 patients were enrolled in this prospective, multicentre study. Blood samples were collected before begin of first-line or later-line systemic treatment. Serum uPA was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch; other biomarkers (EGFR, VEGF, HER2, RAS p21, TIMP1, CAIX) by ELISA. Using the ROC analysis, the optimal cut-off value (determined by the Youden index) of serum uPA was 2.52 ng/ml. 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 levels. CTC status, serum HER2, RAS p21, CAIX, TIMP1 and VEGF correlated significantly with uPA levels. Elevated uPA levels predicted shorter overall and progression-free survival in 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 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 receptor status were independent predictors of shorter PFS. In conclusion, 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.
| Original language | English |
|---|---|
| Article number | 2318 |
| Journal | Scientific Reports |
| Volume | 9 |
| Issue number | 1 |
| ISSN | 2045-2322 |
| DOIs | |
| Publication status | Published - 01.12.2019 |
Funding
Competing Interests: Wolfgang Janni received a research grant from Roche. Bahriye Aktas has served as a consultant/advisor for Roche, Pfizer, Novartis. Klaus Pantel has served as a consultant/advisor for Agena Bioscience. Sabine Kasimir-Bauer has served as a consultant/advisor for Qiagen. Peter A. Fasching has served as a consultant/advisor for Amgen, Novartis, Roche, Pfizer, Teva, Puma Celgene and received a research grant from Novartis. Brigitte Rack has received honoraria or research grants from Novartis, Roche, Pfizer, Janssen Diagnostics, Astra Zeneca, Novartis, Lilly, Chugai and Sanofi. Malgorzata Banys-Paluchowski has received lecture honoraria from Roche, Novartis and Pfizer. Isabell Witzel, Sabine Riethdorf, Andreas Hartkopf, Gerhard Schön, Erich-Franz Solomayer, Tanja Fehm and Volkmar Müller declare that they have no conflicts of interest. No other conflicts of interest were reported. The authors wish to thank Walter Carney, Ph.D., for his help with the methodology chapter. The DETECT study was supported by a research grant from Roche Pharma AG, Germany and by Adnagen AG, Germany. ELISA kits were provided at no cost by Oncogene Science, a former part of Siemens Medical Solutions Diagnostics and now part of Wilex. The funding agencies had no role in study design or collection, analysis, and interpretation of data nor in the writing of the manuscript.
Research Areas and Centers
- Research Area: Luebeck Integrated Oncology Network (LION)
- Centers: University Cancer Center Schleswig-Holstein (UCCSH)
