title: HPV status, cancer stem cell marker expression, hypoxia gene signatures and tumour volume identify good prognosis subgroups in patients with HNSCC after primary radiochemotherapy: A multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).
abstract: 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).
  
  
  
  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).
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Annett
authors.initials: A
authors.lastname: Linge
authors.affiliation: 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.
authors.forename: Fabian
authors.initials: F
authors.lastname: Lohaus
authors.affiliation: 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.
authors.forename: Steffen
authors.initials: S
authors.lastname: Löck
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nowak
authors.affiliation: 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.
authors.forename: Volker
authors.initials: V
authors.lastname: Gudziol
authors.affiliation: 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.
authors.forename: Chiara
authors.initials: C
authors.lastname: Valentini
authors.affiliation: 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.
authors.forename: Cläre
authors.initials: C
authors.lastname: von Neubeck
authors.affiliation: 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.
authors.forename: Martin
authors.initials: M
authors.lastname: Jütz
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany.
authors.forename: Inge
authors.initials: I
authors.lastname: Tinhofer
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Budach
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Essen, Germany; Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Sak
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Essen, Germany; Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stuschke
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Frankfurt, Germany; Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Germany.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Balermpas
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Frankfurt, Germany; Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Rödel
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Freiburg, Germany; Department of Radiation Oncology, University of Freiburg, Germany.
authors.forename: Anca-Ligia
authors.initials: AL
authors.lastname: Grosu
authors.affiliation: 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.
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.affiliation: 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.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: 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.
authors.forename: Ute
authors.initials: U
authors.lastname: Ganswindt
authors.affiliation: 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.
authors.forename: Claus
authors.initials: C
authors.lastname: Belka
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany; Department of Radiation Oncology, Technische Universität München, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Pigorsch
authors.affiliation: 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.
authors.forename: Stephanie E
authors.initials: SE
authors.lastname: Combs
authors.affiliation: 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.
authors.forename: David
authors.initials: D
authors.lastname: Mönnich
authors.affiliation: 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.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.affiliation: 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.
authors.forename: Frank
authors.initials: F
authors.lastname: Buchholz
authors.affiliation: 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.
authors.forename: Daniela E
authors.initials: DE
authors.lastname: Aust
authors.affiliation: 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.
authors.forename: Gustavo B
authors.initials: GB
authors.lastname: Baretton
authors.affiliation: Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: Howard D
authors.initials: HD
authors.lastname: Thames
authors.affiliation: 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.
authors.forename: Anna
authors.initials: A
authors.lastname: Dubrovska
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
authors.forename: Jan
authors.initials: J
authors.lastname: Alsner
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
authors.forename: Jens
authors.initials: J
authors.lastname: Overgaard
authors.affiliation: 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.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.affiliation: 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.
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D015687:Cell Hypoxia / Q000235:genetics; D059248:Chemoradiotherapy; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy* / Q000821:virology; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D027383:Papillomaviridae / Q000302:isolation & purification*; D011379:Prognosis; D011836:Radiation Tolerance / Q000235:genetics; D012189:Retrospective Studies; D000077195:Squamous Cell Carcinoma of Head and Neck; D047368:Tumor Burden
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors
keywords: Biomarkers for radiotherapy; Cancer stem cells; HNSCC; HPV; Hypoxia; Primary radiochemotherapy