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Abstract

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.  

Author information

Linge A1, Löck S2, Gudziol V3, Nowak A4, Lohaus F1, von Neubeck C5, Jütz M2, Abdollahi A6, Debus J7, Tinhofer I8, Budach V8, Sak A9, Stuschke M9, Balermpas P10, Rödel C10, Avlar M11, Grosu AL12, Bayer C13, Belka C14, Pigorsch S15, Combs SE15, Welz S16, Zips D16, Buchholz F17, Aust DE18, Baretton GB18, Thames HD19, Dubrovska A5, Alsner J20, Overgaard J20, Baumann M21, Krause M22; DKTK-ROG.​

1German 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.

2OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

3Department of Otorhinolaryngology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

4Department of Oral and Maxillofacial Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

5German 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.

6German 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.

7German 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.

8German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Berlin, Germany. Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany.

9German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Essen, Germany. Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany.

10German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Frankfurt, Germany. Department of Radiotherapy and Oncology, Goethe University, Frankfurt, Germany.

11German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Freiburg, Germany. Department of Radiation Oncology, Clinical Study Section, University of Freiburg, Freiburg, Germany.

12German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Freiburg, Germany. Department of Radiation Oncology, University of Freiburg, Freiburg, Germany.

13German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany.

14German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany. Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-University, Munich, Germany.

15German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany. Department of Radiation Oncology, Technische Universität München, Munich, Germany.

16German 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.

17German 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.

18German 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.

19Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.

20Department of Experimental Clinical Oncology, Aarhus University Hospital, Denmark.

21German 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.

22German 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.