TY  - JOUR
A1  - Zeuschner, Philip Alexander
A1  - Hölters, Sebastian
A1  - Stöckle, Michael
A1  - Seliger, Barbara
A1  - Müller, Anja
A1  - Bachmann, Hagen Sjard
A1  - Grünwald, Viktor
A1  - Christoph, Daniel C.
A1  - Stenzl, Arnulf
A1  - Grimm, Marc-Oliver
A1  - Brüning, Fabian
A1  - Goebell, Peter Jürgen
A1  - Augustin, Marinela
A1  - Roos, Frederik
A1  - Harde, Johanna
A1  - Benz-Rüd, Iris
A1  - Staehler, Michael
A1  - Junker, Kerstin
T1  - Thrombospondin-2 and LDH are putative predictive biomarkers for treatment with everolimus in second-line metastatic clear Ccll renal cell carcinoma (MARC-2 study)
T2  - Cancers
N2  - Simple Summary: 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.

Abstract: 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.
KW  - biomarker
KW  - everolimus
KW  - metastatic renal cell carcinoma
KW  - second-line
KW  - phase IV
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62109
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-621096
SN  - 2072-6694
VL  - 13
IS  - 11, art. 2594
SP  - 1
EP  - 15
PB  - MDPI
CY  - Basel
ER  -