Annett Linge1, Fabian Lohaus1, Steffen Löck2, Alexander Nowak3, Volker Gudziol4, Chiara Valentini5, Cläre von Neubeck6, Martin Jütz7, Inge Tinhofer8, Volker Budach8, Ali Sak9, Martin Stuschke9, Panagiotis Balermpas10, Claus Rödel10, Anca-Ligia Grosu11, Amir Abdollahi12, Jürgen Debus13, Ute Ganswindt14, Claus Belka15, Steffi Pigorsch16, Stephanie E Combs17, David Mönnich18, Daniel Zips18, Frank Buchholz19, Daniela E Aust20, Gustavo B Baretton20, Howard D Thames21, Anna Dubrovska22, Jan Alsner23, Jens Overgaard23, Mechthild Krause24, Michael Baumann25. 1. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden - Rossendorf, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany. 2. OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden - Rossendorf, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany. 3. National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; Department of Oral and Maxillofacial Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. 4. National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; Department of Otorhinolaryngology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. 5. Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden - Rossendorf, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany. 6. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden - Rossendorf, Germany. 7. OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden - Rossendorf, Germany. 8. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany. 9. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Essen, Germany; Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Germany. 10. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Frankfurt, Germany; Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Germany. 11. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Freiburg, Germany; Department of Radiation Oncology, University of Freiburg, Germany. 12. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany; Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, Germany; National Center for Tumor Diseases (NCT), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany; Translational Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany. 13. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Heidelberg, Germany; Heidelberg Institute of Radiation Oncology (HIRO), National Center for Radiation Research in Oncology (NCRO), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany; Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, Germany; National Center for Tumor Diseases (NCT), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany; Clinical Cooperation Unit Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany. 14. Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, Germany; Department of Radiation Oncology, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperation Group, Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum, Munich, Germany. 15. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany; Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, Germany; Department of Radiation Oncology, Ludwig-Maximilians-Universität, Munich, Germany; Clinical Cooperation Group, Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum, Munich, Germany. 16. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany; Department of Radiation Oncology, Technische Universität München, Germany. 17. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany; Department of Radiation Oncology, Technische Universität München, Germany; Institute of Innovative Radiotherapy (iRT), Helmholtz Zentrum München, Oberschleißheim, Germany. 18. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Tübingen, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Tübingen, Eberhard Karls Universität Tübingen, Germany. 19. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; Medical Systems Biology, University Cancer Center (UCC), University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. 20. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Tumour- and Normal Tissue Bank, University Cancer Center (UCC), University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany. 21. Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA. 22. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden - Rossendorf, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Germany. 23. Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark. 24. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden - Rossendorf, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Germany. 25. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden - Rossendorf, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Germany. Electronic address: Michael.Baumann@dkfz.de.
Abstract
OBJECTIVE: To investigate the impact of the tumour volume, HPV status, cancer stem cell (CSC) marker expression and hypoxia gene signatures, as potential markers of radiobiological mechanisms of radioresistance, in a contemporary cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received primary radiochemotherapy (RCTx). MATERIALS AND METHODS: For 158 patients with locally advanced HNSCC of the oral cavity, oropharynx or hypopharynx who were treated at six DKTK partner sites, the impact of tumour volume, HPV DNA, p16 overexpression, p53 expression, CSC marker expression and hypoxia-associated gene signatures on outcome of primary RCTx was retrospectively analyzed. The primary endpoint of this study was loco-regional control (LRC). RESULTS: Univariate Cox regression revealed a significant impact of tumour volume, p16 overexpression, and SLC3A2 and CD44 protein expression on LRC. The tumour hypoxia classification showed a significant impact only for small tumours. In multivariate analyses an independent correlation of tumour volume, SLC3A2 expression, and the 15-gene hypoxia signature with LRC was identified (CD44 protein n/a because of no event in the CD44-negative group). Logistic modelling showed that inclusion of CD44 protein expression and p16 overexpression significantly improved the performance to predict LRC at 2years compared to the model with tumour volume alone. CONCLUSIONS: Tumour volume, HPV status, CSC marker expression and hypoxia gene signatures are potential prognostic biomarkers for patients with locally advanced HNSCC, who were treated by primary RCTx. The study also supports that the individual tumour volumes should generally be included in biomarker studies and that panels of biomarkers are superior to individual parameters.
OBJECTIVE: To investigate the impact of the tumour volume, HPV status, cancer stem cell (CSC) marker expression and hypoxia gene signatures, as potential markers of radiobiological mechanisms of radioresistance, in a contemporary cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received primary radiochemotherapy (RCTx). MATERIALS AND METHODS: For 158 patients with locally advanced HNSCC of the oral cavity, oropharynx or hypopharynx who were treated at six DKTK partner sites, the impact of tumour volume, HPV DNA, p16 overexpression, p53 expression, CSC marker expression and hypoxia-associated gene signatures on outcome of primary RCTx was retrospectively analyzed. The primary endpoint of this study was loco-regional control (LRC). RESULTS: Univariate Cox regression revealed a significant impact of tumour volume, p16 overexpression, and SLC3A2 and CD44 protein expression on LRC. The tumour hypoxia classification showed a significant impact only for small tumours. In multivariate analyses an independent correlation of tumour volume, SLC3A2 expression, and the 15-gene hypoxia signature with LRC was identified (CD44 protein n/a because of no event in the CD44-negative group). Logistic modelling showed that inclusion of CD44 protein expression and p16 overexpression significantly improved the performance to predict LRC at 2years compared to the model with tumour volume alone. CONCLUSIONS:Tumour volume, HPV status, CSC marker expression and hypoxia gene signatures are potential prognostic biomarkers for patients with locally advanced HNSCC, who were treated by primary RCTx. The study also supports that the individual tumour volumes should generally be included in biomarker studies and that panels of biomarkers are superior to individual parameters.
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Authors: Apostolos Menegakis; Rob Klompmaker; Claire Vennin; Aina Arbusà; Maartje Damen; Bram van den Broek; Daniel Zips; Jacco van Rheenen; Lenno Krenning; René H Medema Journal: Cells Date: 2021-03-10 Impact factor: 6.600