title: Low Cancer Stem Cell Marker Expression and Low Hypoxia Identify Good Prognosis Subgroups in HPV(-) HNSCC after Postoperative Radiochemotherapy: A Multicenter Study of the DKTK-ROG.
abstract: To investigate the impact of hypoxia-induced gene expression and cancer stem cell (CSC) marker expression on outcome of postoperative cisplatin-based radiochemotherapy (PORT-C) in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).
  
  
  
  Expression of the CSC markers CD44, MET, and SLC3A2, and hypoxia gene signatures were analyzed in the resected primary tumors using RT-PCR and nanoString technology in a multicenter retrospective cohort of 195 patients. CD44 protein expression was further analyzed in tissue microarrays. Primary endpoint was locoregional tumor control.
  
  
  
  Univariate analysis showed that hypoxia-induced gene expression was significantly associated with a high risk of locoregional recurrence using the 15-gene signature (P = 0.010) or the 26-gene signature (P = 0.002). In multivariate analyses, in patients with HPV16 DNA-negative but not with HPV16 DNA-positive tumors the effect of hypoxia-induced genes on locoregional control was apparent (15-gene signature: HR 4.54, P = 0.006; 26-gene signature: HR 10.27, P = 0.024). Furthermore, MET, SLC3A2, CD44, and CD44 protein showed an association with locoregional tumor control in multivariate analyses (MET: HR 3.71, P = 0.016; SLC3A2: HR 8.54, P = 0.037; CD44: HR 3.36, P = 0.054; CD44 protein n/a because of no event in the CD44-negative group) in the HPV16 DNA-negative subgroup.
  
  
  
  We have shown for the first time that high hypoxia-induced gene expression and high CSC marker expression levels correlate with tumor recurrence after PORT-C in patients with HPV16 DNA-negative HNSCC. After validation in a currently ongoing prospective trial, these parameters may help to further stratify patients for individualized treatment de-escalation or intensification strategies. Clin Cancer Res; 22(11); 2639-49. ©2016 AACR.
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, Dresden, Germany. OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Linge
authors.affiliation: OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Löck
authors.affiliation: Department of Otorhinolaryngology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Gudziol
authors.affiliation: Department of Oral and Maxillofacial Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Nowak
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, Dresden, Germany. OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Lohaus
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, Dresden, 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, Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Jütz
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), Heidelberg, Germany. Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg, Germany. National Center for Tumor Diseases (NCT), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Heidelberg, Germany. Translational Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Heidelberg, 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), Heidelberg, Germany. Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg, Germany. National Center for Tumor Diseases (NCT), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Heidelberg, Germany. Clinical Cooperation Unit Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
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, 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, 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, Clinical Study Section, University of Freiburg, Freiburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Avlar
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Freiburg, Germany. Department of Radiation Oncology, University of Freiburg, 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), Munich, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Bayer
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany. Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, 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, Munich, 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, Munich, 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: Stefan
authors.initials: S
authors.lastname: Welz
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. University Cancer Center (UCC), Medical Systems Biology, University Hospital Carl Gustav Carus, Technische Universität Dresden, 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. Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Tumor- and Normal Tissue Bank, University Cancer Center (UCC), University Hospital Carl Gustav Carus, Technische Universität Dresden, 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. Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Tumor- and Normal Tissue Bank, University Cancer Center (UCC), University Hospital Carl Gustav Carus, Technische Universität Dresden, 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, Texas.
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, Dresden, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Dubrovska
authors.affiliation: Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.
authors.forename: Jan
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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, Dresden, Germany. OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Dresden, Germany. National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
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, Dresden, Germany. OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Dresden, Germany. National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Mechthild.Krause@uniklinikum-dresden.de.
authors.forename: Mechthild
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mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015687:Cell Hypoxia; D059248:Chemoradiotherapy; D002945:Cisplatin / Q000627:therapeutic use; D027282:Fusion Regulatory Protein 1, Heavy Chain / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D009062:Mouth Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D015999:Multivariate Analysis; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D030361:Papillomavirus Infections / Q000175:diagnosis; D011379:Prognosis; D011446:Prospective Studies; D059467:Transcriptome; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D027282:Fusion Regulatory Protein 1, Heavy Chain; D018960:Hyaluronan Receptors; C545989:SLC3A2 protein, human; D002945:Cisplatin