ESTRO 2022

Session Item

Saturday

May 07

16:55 - 17:55

Room D4

Personalised radiation therapy

Co-Chair: Sebastian Christ, Switzerland;

Chair: , The Netherlands

Session Type: Proffered Papers

Track: Interdisciplinary

Journey:

17:05 - 17:15

Biomarker development from joint analyses of HNSCC xenografts and patients treated by PORT-C

Annett Linge, Germany

Presentation Number: OC-0256

Abstract

Abstract Title:

Biomarker development from joint analyses of HNSCC xenografts and patients treated by PORT-C

Authors:

Annett Linge^1,2,3,4, Shivaprasad Patil^5,6, Kristin Gurtner^6,1,7, Marianne Grosser⁸, Fabian Lohaus^5,6,1,7, Volker Gudziol⁹, Alexander Nowak¹⁰, Inge Tinhofer^11,12, Volker Budach^11,12, Maja Guberina^13,14, Martin Stuschke^15,14, Panangiotis Balermpas¹⁶, Panagiotis Balermpas¹⁷, Claus Rödel^16,17, Henning Schäfer^18,19, Anca-Ligia Grosu^18,19, Amir Abdollahi^{20,21,22,23,24}, Jürgen Debus^{20,21,22,23,25}, Claus Belka^26,27,28, Steffi Pigorsch^26,29, Stephanie E. Combs^26,29,30, Simon Boeke^31,32, Daniel Zips^31,32, Michael Baumann^33,6,1, Steffen Löck^5,6,1,7, Mechthild Krause^34,6,1,7,35

¹Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; ²German Cancer Research Center (DKFZ), Heidelberg, German Cancer Consortium (DKTK), partner site Dresden, Dresden, Germany; ³OncoRay - Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany; ⁴National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany , Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; ⁵German Cancer Research Center (DKFZ),Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Dresden, Dresden, Germany; ⁶OncoRay - Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Dresden, Germany; ⁷National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany: German Cancer Research Center (DKFZ), Heidelberg, Germany, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany, and Helmholtz Association / Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; ⁸Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; ⁹Department of Otorhinolaryngology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; ¹⁰Department of Oral and Maxillofacial Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; ¹¹German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Berlin, Berlin, Germany; ¹²Charité University Medicine Berlin, Department of Radiooncology and Radiotherapy, Berlin, Germany; ¹³German Cancer Research Center (DKFZ), Heidelberg, Germany, , German Cancer Consortium (DKTK), partner site Essen, Essen, Germany; ¹⁴Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany; ¹⁵German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Essen, Essen, Germany; ¹⁶German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Frankfurt, Frankfurt, Germany; ¹⁷Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Frankfurt, Germany; ¹⁸German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Freiburg, Freiburg, Germany; ¹⁹Department of Radiation Oncology, Medical Center, Medical Faculty, University of Freiburg, Freiburg, Germany; ²⁰German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Heidelberg, Heidelberg, Germany; ²¹Heidelberg 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; ²²Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, Heidelberg, Germany; ²³National Center for Tumor Diseases (NCT), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Heidelberg, Germany; ²⁴Translational Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Heidelberg, Germany; ²⁵Clinical Cooperation Unit Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), Heidelberg, Germany; ²⁶German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Munich, Munich, Germany; ²⁷Department of Radiotherapy and Radiation Oncology, University Hospital, Ludwig-Maximilians-Universität, Munich, Germany; ²⁸Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum Munich, Neuherberg, Munich, Germany; ²⁹Department of RadioOncology, Technische Universität München, Munich, Germany; ³⁰Department of Radiation Sciences (DRS), Institut für Innovative Radiotherapie (iRT), Helmholtz Zentrum Munich, Neuherberg, Munich, Germany; ³¹German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Tübingen, Tübingen, Germany; ³²Department of Radiation Oncology, Faculty of Medicine and University Hospital Tübingen, Eberhard Karls Universität Tübingen, Tübingen, Germany; ³³German Cancer Research Center (DKFZ), Heidelberg, Heidelberg, Germany; ³⁴German Cancer Research Center (DKFZ), Heidelberg, Germany, German Cancer Consortium (DKTK), partner site Dresden, Dresden, Germany; ³⁵Institute of Radiooncology – OncoRay, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany

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Purpose or Objective

The aim of the study was (i) to analyse whether previously identified prognostic gene signatures and a molecular-subtype classification¹ from patients with head and neck squamous cell carcinoma (HNSCC) can be applied to HNSCC xenograft models and (ii) to develop and validate a novel gene signature based on a combination of xenograft data and data from patients with HPV-negative locally advanced HNSCC who received postoperative radio(chemo)therapy (PORT-C).

Material and Methods

Gene expression analysis was performed using GeneChip Human Transcriptome Array 2.0 on a cohort of 59 mice bearing xenografts of ten established human HNSCC cell lines and on a multicentre retrospective development cohort of 128 patients and an independent validation cohort of 114 patients of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG) treated with PORT-C. (i) Xenografts were stratified based on molecular subtypes and gene classifiers. The dose to control 50% of tumours (TCD50) was compared between the groups by Kruskal-Wallis or Mann-Whitney-U tests, respectively. (ii) A novel gene signature was developed based on xenograft and patient data using differential gene expression analysis. The Kaplan-Meier method was applied to estimate loco-regional control (LRC), overall survival (OS) and freedom from distant metastases (DM), which were compared using log-rank tests.

Results

(i) The tumour xenografts were classified into the four subtypes basal, mesenchymal, atypical and classical. Mesenchymal tumours showed significantly higher TCD50 compared to other subtypes (p<0.001). In addition, gene signatures related to hypoxia² and radiosensitivity³ were significantly associated with TCD50. (ii) Based on the joint xenograft and patient data, we identified a 2-gene signature consisting of FN1 and SERPINE1. This signature was prognostic for the TCD50 in pre-clinical models (p<0.001) and for LRC (p=0.007), OS (p<0.001), and DM (p=0.001) in the independent PORT-C patient cohort.

Conclusion

The transferability of the molecular subtype classification and gene signatures related to hypoxia² and radiosensitivity³to pre-clinical HNSCC tumour models not only underlines their robustness but also the value of xenograft models. The developed 2-gene signature was prognostic for both, xenografts and patients, and may represent an additional promising biomarker for future individualized treatment approaches.

References

[1] Walter, V. et al. PLOS One 8: e56823 (2013).

[2] Toustrup, K. et al. Cancer Res 7: 5923 (2011).

[3] Kim, H. S. et al. BMC Genomics 13: 348 (2012).