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Article

Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study)

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Department of Urology and Pediatric Urology, Saarland University, Kirrberger Street, 66421 Homburg/Saar, Germany
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Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Universitätsplatz 10, 06108 Halle (Saale), Germany
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Center for Biomedical Education and Research (ZBAF), Faculty of Health, Institute of Pharmacology and Toxicology, School of Medicine, Witten/Herdecke University, Stockumer Straße 10, 58453 Witten, Germany
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Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, University Hospital, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany
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Clinic for Internal Medicine (Tumor Research) and Clinic for Urology, West German Cancer Center, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany
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Department of Medical Oncology, University Hospital Essen, Hufelandstrasse 55, 45147 Essen, Germany
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Department of Medical Oncology & Hematology, Evang. Kliniken Essen-Mitte, Evang. Huyssens-Stiftung Essen-Huttrop, Henricistrasse 92, 45136 Essen, Germany
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Department of Urology, University Hospital Tuebingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany
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Department of Urology, University Hospital Jena, Am Klinikum 1, 07747 Jena, Germany
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Department of Urology and Pediatric Urology, University Hospital Giessen and Marburg GmbH, Philipps-University Marburg, Baldingerstrasse, 35033 Marburg, Germany
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Ambulatory Uro-Oncological Therapy Unit Erlangen (AURONTE), Department of Urology and Clinic for Haematology and Internistic Oncology, University Hospital Erlangen, Krankenhausstrasse 12, 91054 Erlangen, Germany
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Department of Hematology and Oncology, Paracelsus Medical University, Prof.-Ernst-Nathan-Strasse 1, 90419 Nürnberg, Germany
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Department of Urology and Paediatric Urology, University Medical Center Mainz, Langenbeckstraße 1, 55131 Mainz, Germany
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Department of Urology, University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany
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Medical Department, iOMEDICO, Ellen-Gottlieb-Strasse 19, 70106 Freiburg im Breisgau, Germany
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Interdisciplinary Center of Renal Tumors, Department of Urology, Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377 Munich, Germany
*
Author to whom correspondence should be addressed.
Present address: Ingenieurbüro für Gesundheitswesen GmbH, Mozartstraße 3, 04107 Leizpig, Germany.
Academic Editor: Anja Rabien
Cancers 2021, 13(11), 2594; https://doi.org/10.3390/cancers13112594
Received: 9 April 2021 / Revised: 20 May 2021 / Accepted: 20 May 2021 / Published: 25 May 2021
(This article belongs to the Special Issue Metastatic Renal Cell Carcinoma – from Diagnosis to Therapy)
Treatment of metastatic renal cell carcinoma (mRCC) remains a challenge due to the lack of biomarkers indicating the optimal drug for each patient. This study analyzed blood samples of patients with predominant clear cell mRCC who were treated with the mTOR inhibitor everolimus after failure of one prior tumor therapy. In an exploratory approach, predictive blood biomarkers were searched. We found lower levels of the protein thrombospondin-2 (TSP-2) at the start of the therapy and higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation to be associated with therapy response. Of note, these blood biomarkers had a higher predictive value than baseline patient parameters or risk classifications. Polymorphisms in the mTOR gene appeared to be associated with therapy response, but were not significant. To conclude, it seems feasible to identify patients showing longtime responses to everolimus and possible to increase tumor therapy response rates based on biomarkers for individual therapy selection.
There is an unmet need for predictive biomarkers in metastatic renal cell carcinoma (mRCC) therapy. The phase IV MARC-2 trial searched for predictive blood biomarkers in patients with predominant clear cell mRCC who benefit from second-line treatment with everolimus. In an exploratory approach, potential biomarkers were assessed employing proteomics, ELISA, and polymorphism analyses. Lower levels of angiogenesis-related protein thrombospondin-2 (TSP-2) at baseline (≤665 parts per billion, ppb) identified therapy responders with longer median progression-free survival (PFS; ≤665 ppb at baseline: 6.9 months vs. 1.8, p = 0.005). Responders had higher lactate dehydrogenase (LDH) levels in serum two weeks after therapy initiation (>27.14 nmol/L), associated with a longer median PFS (3.8 months vs. 2.2, p = 0.013) and improved overall survival (OS; 31.0 months vs. 14.0 months, p < 0.001). Baseline TSP-2 levels had a stronger relation to PFS (HR 0.36, p = 0.008) than baseline patient parameters, including IMDC score. Increased serum LDH levels two weeks after therapy initiation were the best predictor for OS (HR 0.21, p < 0.001). mTOR polymorphisms appeared to be associated with therapy response but were not significant. Hence, we identified TSP-2 and LDH as promising predictive biomarkers for therapy response on everolimus after failure of one VEGF-targeted therapy in patients with clear cell mRCC. View Full-Text
Keywords: biomarker; everolimus; metastatic renal cell carcinoma; second-line; phase IV biomarker; everolimus; metastatic renal cell carcinoma; second-line; phase IV
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Figure 1

MDPI and ACS Style

Zeuschner, P.; Hölters, S.; Stöckle, M.; Seliger, B.; Mueller, A.; Bachmann, H.S.; Grünwald, V.; Christoph, D.C.; Stenzl, A.; Grimm, M.-O.; Brüning, F.; Goebell, P.J.; Augustin, M.; Roos, F.; Harde, J.; Benz-Rüd, I.; Staehler, M.; Junker, K. Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study). Cancers 2021, 13, 2594. https://doi.org/10.3390/cancers13112594

AMA Style

Zeuschner P, Hölters S, Stöckle M, Seliger B, Mueller A, Bachmann HS, Grünwald V, Christoph DC, Stenzl A, Grimm M-O, Brüning F, Goebell PJ, Augustin M, Roos F, Harde J, Benz-Rüd I, Staehler M, Junker K. Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study). Cancers. 2021; 13(11):2594. https://doi.org/10.3390/cancers13112594

Chicago/Turabian Style

Zeuschner, Philip, Sebastian Hölters, Michael Stöckle, Barbara Seliger, Anja Mueller, Hagen S. Bachmann, Viktor Grünwald, Daniel C. Christoph, Arnulf Stenzl, Marc-Oliver Grimm, Fabian Brüning, Peter J. Goebell, Marinela Augustin, Frederik Roos, Johanna Harde, Iris Benz-Rüd, Michael Staehler, and Kerstin Junker. 2021. "Thrombospondin-2 and LDH Are Putative Predictive Biomarkers for Treatment with Everolimus in Second-Line Metastatic Clear Cell Renal Cell Carcinoma (MARC-2 Study)" Cancers 13, no. 11: 2594. https://doi.org/10.3390/cancers13112594

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