SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy

Chiara De-Colle; David Mönnich; Stefan Welz; Simon Boeke; Bence Sipos; Falko Fend; Paul-Stefan Mauz; Inge Tinhofer; Volker Budach; Jehad Abu Jawad; Martin Stuschke; Panagiotis Balermpas; Claus Rödel; Anca-Ligia Grosu; Amir Abdollahi; Jürgen Debus; Christine Bayer; Claus Belka; Steffi Pigorsch; Stephanie E Combs; Fabian Lohaus; Annett Linge; Mechthild Krause; Michael Baumann; Daniel Zips; Apostolos Menegakis

doi:10.1016/j.ctro.2017.06.004

SDF-1/CXCR4 expression in head and neck cancer and outcome after postoperative radiochemotherapy

Clin Transl Radiat Oncol. 2017 Jul 14:5:28-36. doi: 10.1016/j.ctro.2017.06.004. eCollection 2017 Aug.

Authors

Chiara De-Colle¹, David Mönnich^{1

2}, Stefan Welz¹, Simon Boeke¹, Bence Sipos³, Falko Fend³, Paul-Stefan Mauz⁴, Inge Tinhofer^{5

6}, Volker Budach^{5

6}, Jehad Abu Jawad^{7

8}, Martin Stuschke^{7

8}, Panagiotis Balermpas^{9

10}, Claus Rödel^{9

10}, Anca-Ligia Grosu^{11

12}, Amir Abdollahi^{13

14

15

16

17}, Jürgen Debus^{13

14

15

16

18}, Christine Bayer¹⁹, Claus Belka^{19

20}, Steffi Pigorsch^{19

21}, Stephanie E Combs^{19

21}, Fabian Lohaus^{22

23

24

25}, Annett Linge^{22

23

24

25}, Mechthild Krause^{22

23

24

25

26}, Michael Baumann^{22

23

24

25

26

27}, Daniel Zips^{1

2}, Apostolos Menegakis¹

Affiliations

¹ Radiation Oncology, Medical Faculty and University Hospital, Eberhard Karls University Tübingen, Tübingen, Germany.
² German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Tübingen, Germany.
³ Department of Pathology, Medical Faculty and University Hospital, Eberhard Karls University Tübingen, Tübingen, Germany.
⁴ Department of Otorhinolaryngology, Head and Neck Surgery, Medical Faculty and University Hospital, Eberhard Karls University Tübingen, Tübingen, Germany.
⁵ German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Berlin, Germany.
⁶ Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany.
⁷ German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Essen, Germany.
⁸ Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany.
⁹ German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Frankfurt, Germany.
¹⁰ Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Germany.
¹¹ German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Freiburg, Germany.
¹² Department of Radiation Oncology, University of Freiburg, Germany.
¹³ German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Heidelberg, Germany.
¹⁴ 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.
¹⁵ Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, Germany.
¹⁶ National Center for Tumor Diseases (NCT), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany.
¹⁷ Translational Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany.
¹⁸ Clinical Cooperation Unit Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Germany.
¹⁹ German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Munich, Germany.
²⁰ Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität, Munich, Germany.
²¹ Department of Radiation Oncology, Technische Universität München, Institute for Innovative Radiation Therapy in Helmholtz-Zentrum München, Germany.
²² German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK), Dresden, Germany.
²³ Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
²⁴ OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf, Germany.
²⁵ National Center for Tumor Diseases (NCT), Dresden, Germany.
²⁶ Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology - OncoRay, Germany.
²⁷ German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

Introduction: Outcome after postoperative radiochemotherapy (RT-CT) for patients with advanced head and neck squamous cell carcinomas (HNSCC) remains unsatisfactory, especially among those with HPV negative tumours. Therefore, new biomarkers are needed to further define subgroups for individualised therapeutic approaches. Preclinical and first clinical observations showed that the chemokine receptor CXCR4 and its ligand SDF-1 (CXCL12) play an important role in tumour cell proliferation, survival, cancer progression, metastasis and treatment resistance. However, the data on the prognostic value of SDF-1/CXCR4 expression for HNSCC are conflicting. The aim of our hypothesis-generating study was to retrospectively explore the prognostic potential of SDF-1/CXCR4 in a well-defined cohort of HNSCC patients collected within the multicenter biomarker study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG).

Material and methods: Patients with stage III and IVA HNSCC of the oral cavity, oropharynx and hypopharynx were treated with resection and adjuvant radiotherapy (RT) with ≥60 Gy and concurrent cisplatin-based chemotherapy (CT). Tissue micro-arrays (TMAs) from a total of 221 patients were generated from surgical specimens, 201 evaluated for the SDF-1 and CXCR4 expression by immunofluorescence and correlated with clinico-pathological and outcome data.

Results: In univariate and multivariate analyses intracellular SDF-1 expression was associated with lower loco-regional control (LRC) in the entire patient group as well as in the HPV16 DNA negative subgroup. CXCR4 expression showed a trend for lower LRC in the univariate analysis which was not confirmed in the multivariate analysis. Neither for SDF-1 nor CXCR4 expression associations with distant metastasis free or overall survival were found.

Conclusions: Our exploratory data support the hypothesis that overexpression of intracellular SDF-1 is an independent negative prognostic biomarker for LRC after postoperative RT-CT in high-risk HNSCC. Prospective validation is warranted and further exploration of SDF-1/CXCR4 as a potential therapeutic target to overcome treatment resistance in HNSCC appears promising.

Keywords: Biomarker; CXCR4; Head and neck cancer; Postoperative radiochemotherapy; Prognostic; SDF-1.