Gene expression-based prediction of pazopanib efficacy in sarcoma

Christoph E Heilig; Andreas Laßmann; Sadaf S Mughal; Andreas Mock; Sebastian Pirmann; Veronica Teleanu; Marcus Renner; Carolin Andresen; Bruno C Köhler; Bogac Aybey; Sebastian Bauer; Jens T Siveke; Rainer Hamacher; Gunnar Folprecht; Stephan Richter; Evelin Schröck; Christian H Brandts; Marit Ahrens; Peter Hohenberger; Gerlinde Egerer; Thomas Kindler; Melanie Boerries; Anna L Illert; Nikolas von Bubnoff; Leonidas Apostolidis; Philipp J Jost; C Benedikt Westphalen; Wilko Weichert; Ulrich Keilholz; Frederick Klauschen; Katja Beck; Ulrike Winter; Daniela Richter; Lino Möhrmann; Michael Bitzer; Klaus Schulze-Osthoff; Benedikt Brors; Gunhild Mechtersheimer; Simon Kreutzfeldt; Christoph Heining; Daniel B Lipka; Albrecht Stenzinger; Richard F Schlenk; Peter Horak; Hanno Glimm; Daniel Hübschmann; Stefan Fröhling

doi:10.1016/j.ejca.2022.05.025

Gene expression-based prediction of pazopanib efficacy in sarcoma

Eur J Cancer. 2022 Sep:172:107-118. doi: 10.1016/j.ejca.2022.05.025. Epub 2022 Jun 25.

Authors

Christoph E Heilig¹, Andreas Laßmann², Sadaf S Mughal³, Andreas Mock⁴, Sebastian Pirmann⁵, Veronica Teleanu⁶, Marcus Renner⁷, Carolin Andresen⁸, Bruno C Köhler⁹, Bogac Aybey¹⁰, Sebastian Bauer¹¹, Jens T Siveke¹², Rainer Hamacher¹³, Gunnar Folprecht¹⁴, Stephan Richter¹⁴, Evelin Schröck¹⁵, Christian H Brandts¹⁶, Marit Ahrens¹⁷, Peter Hohenberger¹⁸, Gerlinde Egerer¹⁹, Thomas Kindler²⁰, Melanie Boerries²¹, Anna L Illert²², Nikolas von Bubnoff²³, Leonidas Apostolidis²⁴, Philipp J Jost²⁵, C Benedikt Westphalen²⁶, Wilko Weichert²⁷, Ulrich Keilholz²⁸, Frederick Klauschen²⁹, Katja Beck³⁰, Ulrike Winter³⁰, Daniela Richter³¹, Lino Möhrmann³¹, Michael Bitzer³², Klaus Schulze-Osthoff³³, Benedikt Brors³⁴, Gunhild Mechtersheimer³⁵, Simon Kreutzfeldt³⁰, Christoph Heining³⁶, Daniel B Lipka³⁷, Albrecht Stenzinger³⁸, Richard F Schlenk³⁹, Peter Horak⁴⁰, Hanno Glimm³¹, Daniel Hübschmann⁴¹, Stefan Fröhling⁴²

Affiliations

¹ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: https://twitter.com/ChrisHeiligMD.
² Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.
³ Division of Applied Bioinformatics, DKFZ, Heidelberg, Germany.
⁴ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany. Electronic address: https://twitter.com/am0ck.
⁵ Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg and DKFZ, Heidelberg, Germany.
⁶ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
⁷ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
⁸ Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.
⁹ Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany. Electronic address: https://twitter.com/koehlerlab.
¹⁰ Division of Applied Bioinformatics, DKFZ, Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg, Germany.
¹¹ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK, Essen, Germany. Electronic address: https://twitter.com/seppobauer.
¹² Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK, Essen, Germany; Division of Solid Tumor Translational Oncology, DKTK, Essen, and DKFZ, Heidelberg, Germany; Bridge Institute of Experimental Tumor Therapy, West German Cancer Center, University Hospital Essen, Essen, Germany.
¹³ Department of Medical Oncology, West German Cancer Center, University Hospital Essen, Essen, Germany; DKTK, Essen, Germany.
¹⁴ Department of Medicine I, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany.
¹⁵ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, Dresden, Germany; Center for Personalized Oncology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany; DKTK, Dresden, Germany.
¹⁶ University Cancer Center (UCT) Frankfurt, University Hospital Frankfurt, Goethe University, Frankfurt, Germany; Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany; Frankfurt Cancer Institute, Frankfurt, Germany; DKTK, Frankfurt, Germany.
¹⁷ Department of Medicine, Hematology/Oncology, University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
¹⁸ Department of Surgery, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany; Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Heidelberg University, Mannheim, Germany.
¹⁹ Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany.
²⁰ UCT Mainz, Johannes Gutenberg University Mainz, Mainz, Germany; Department of Hematology, Medical Oncology and Pneumology, University Medical Center, Mainz, Germany; DKTK, Mainz, Germany.
²¹ Institute of Medical Bioinformatics and Systems Medicine, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Comprehensive Cancer Center Freiburg, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; DKTK, Freiburg, Germany.
²² Comprehensive Cancer Center Freiburg, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; DKTK, Freiburg, Germany; Department of Internal Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
²³ Department of Internal Medicine I, University of Freiburg Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Hematology and Oncology, University Hospital of Schleswig-Holstein, Lübeck, Germany.
²⁴ Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.
²⁵ Department of Hematology and Oncology, Klinikum Rechts der Isar, Technical University Munich, Munich, Germany; Division of Clinical Oncology, Department of Medicine, Medical University of Graz, Graz, Austria; DKTK, Munich, Germany.
²⁶ DKTK, Munich, Germany; Comprehensive Cancer Center, University Hospital, Ludwig Maximilians University Munich, Munich, Germany; Department of Medicine III, University Hospital, Ludwig Maximilians University Munich, Munich, Germany.
²⁷ DKTK, Munich, Germany; Institute of Pathology, Technical University Munich, Munich, Germany.
²⁸ Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany; DKTK, Berlin, Germany.
²⁹ DKTK, Berlin, Germany; Institute of Pathology, Charité - Universitätsmedizin Berlin, And Berlin Institute of Health, Berlin, Germany; Institute of Pathology, Ludwig Maximilians University Munich, Munich, Germany.
³⁰ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany.
³¹ Center for Personalized Oncology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany; DKTK, Dresden, Germany; Department of Translational Medical Oncology, NCT Dresden and DKFZ, Dresden, Germany.
³² Department of Internal Medicine I, University Hospital, Eberhard-Karls University, Tübingen, Germany; DKTK, Tübingen, Germany.
³³ DKTK, Tübingen, Germany; Department of Molecular Medicine, Interfaculty Institute for Biochemistry, University of Tübingen, Tübingen, Germany.
³⁴ German Cancer Consortium (DKTK), Heidelberg, Germany; Division of Applied Bioinformatics, DKFZ, Heidelberg, Germany.
³⁵ Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
³⁶ Center for Personalized Oncology, University Hospital Carl Gustav Carus, Technical University Dresden, Dresden, Germany; DKTK, Dresden, Germany; Department of Translational Medical Oncology, NCT Dresden and DKFZ, Dresden, Germany. Electronic address: https://twitter.com/ChrisHeining.
³⁷ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: https://twitter.com/dblipka1.
³⁸ German Cancer Consortium (DKTK), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
³⁹ German Cancer Consortium (DKTK), Heidelberg, Germany; Department of Medical Oncology, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany; Department of Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany; NCT Trial Center, NCT Heidelberg and DKFZ, Heidelberg, Germany.
⁴⁰ Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: https://twitter.com/PeterHorak_MD.
⁴¹ German Cancer Consortium (DKTK), Heidelberg, Germany; Computational Oncology Group, Molecular Precision Oncology Program, NCT Heidelberg and DKFZ, Heidelberg, Germany; Pattern Recognition and Digital Medicine Group, Heidelberg Institute for Stem Cell Technology and Experimental Medicine, Heidelberg, Germany.
⁴² Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany. Electronic address: [email protected].

PMID: 35763870
DOI: 10.1016/j.ejca.2022.05.025

Abstract

Background: The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.

Patients and methods: We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers.

Results: Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p < 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib.

Conclusion: A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.

Keywords: Multi-omics; Pazopanib; Precision oncology; Predictor; Sarcoma.

Publication types

Observational Study
Research Support, Non-U.S. Gov't

MeSH terms

Gene Expression
Humans
Indazoles / therapeutic use
Prospective Studies
Pyrimidines
Sarcoma* / drug therapy
Sarcoma* / genetics
Soft Tissue Neoplasms* / drug therapy
Sulfonamides
Young Adult

Substances

Indazoles
Pyrimidines
Sulfonamides
pazopanib