A Novel 2-Metagene Signature to Identify High-Risk HNSCC Patients amongst Those Who Are Clinically at Intermediate Risk and Are Treated with PORT
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Shivaprasad Patil
1,9,10,†, 
Annett Linge
1,9,11,12,†,
Hannah Hiepe
9,11,
Marianne Grosser
13,
Fabian Lohaus
1,9,11,12,
Volker Gudziol
14,15,
Max Kemper
12,14,
Alexander Nowak
12,16,
Dominik Haim
12,16,
Inge Tinhofer
2,17,
Volker Budach
2,17,
Maja Guberina
3,18,
Martin Stuschke
3,18, 
Panagiotis Balermpas
4,19,
Jens von der Grün
4,19,
Henning Schäfer
5,20,
Anca-Ligia Grosu
5,20,
Amir Abdollahi
6,21,22,23,24,
Jürgen Debus
6,21,22,23,25,
Ute Ganswindt
7,26,
Claus Belka
7,26,27,
Steffi Pigorsch
7,28,
Stephanie E. Combs
7,28,29,
Simon Boeke
8,30,
Daniel Zips
8,30,
Korinna Jöhrens
1,12,13,
Gustavo B. Baretton
1,12,13,31,
Michael Baumann
9,11,32,
Mechthild Krause
1,9,10,11,12,
Steffen Löck
1,9,11,12,* and add
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1
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany and German Cancer Consortium (DKTK), partner site Dresden, 01307 Dresden, Germany
2
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Berlin, 10117 Berlin, Germany
3
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen, 45147 Essen, Germany
4
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Frankfurt, 60590 Frankfurt, Germany
5
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Freiburg, 79106 Freiburg, Germany
6
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Heidelberg, 69120 Heidelberg, Germany
7
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Munich, 80336 Munich, Germany
8
German Cancer Research Center (DKFZ), 60120 Heidelberg, Germany and German Cancer Consortium (DKTK), partner site Tübingen, 72076 Tübingen, Germany
9
OncoRay—National Center for Radiation Research in Oncology, Faculty of Medicine and UniversityHospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden—Rossendorf, 01307 Dresden, Germany
10
Helmholtz-Zentrum Dresden—Rossendorf, 01307 Dresden, Germany
11
Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
12
National 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, 01307 Dresden, Germany; Helmholtz Association/Helmholtz-Zentrum Dresden—Rossendorf (HZDR), 01307 Dresden, Germany
13
Institute of Pathology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
14
Department of Otorhinolaryngology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
15
Department of Otorhinolaryngology, Head and Neck Surgery, Municipal Hospital Dresden, 01067 Dresden, Germany
16
Department of Oral and Maxillofacial Surgery, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
17
Department of Radiooncology and Radiotherapy, Charité University Medicine Berlin, 10117 Berlin, Germany
18
Department of Radiation Therapy, University Hospital, Medical Faculty, University of Duisburg-Essen, 45147 Essen, Germany
19
Department of Radiotherapy and Oncology, Goethe-University Frankfurt, 60590 Frankfurt, Germany
20
Department of Radiation Oncology, Medical Center, Medical Faculty, University of Freiburg, 79106 Freiburg, Germany
21
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), 69120 Heidelberg, Germany
22
Heidelberg Ion Therapy Center (HIT), Department of Radiation Oncology, University of Heidelberg Medical School, 69120 Heidelberg, Germany
23
National Center for Tumor Diseases (NCT), University of Heidelberg Medical School and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
24
Translational Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
25
Clinical Cooperation Unit Radiation Oncology, University of Heidelberg Medical School and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
26
Department of Radiotherapy and Radiation Oncology, University Hospital, Ludwig-Maximilians-Universität, 81377 Munich, Germany
27
Clinical Cooperation Group Personalized Radiotherapy in Head and Neck Cancer, Helmholtz Zentrum Munich, 85764 Neuherberg, Germany
28
Department of Radiation Oncology, Technische Universität München, 81675 Munich, Germany
29
Department of Radiation Sciences (DRS), Institut für Innovative Radiotherapie (iRT), Helmholtz Zentrum Munich, 85764 Neuherberg, Germany
30
Department of Radiation Oncology, Faculty of Medicine and University Hospital Tübingen, Eberhard Karls Universität Tübingen, 72076 Tübingen, Germany
31
Tumor- and Normal Tissue Bank, University Cancer Centre (UCC), University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
32
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
‡
The authors of this manuscript are part of the DKTK-ROG.
Cancers 2022, 14(12), 3031; https://doi.org/10.3390/cancers14123031
Submission received: 3 May 2022
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Revised: 13 June 2022
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Accepted: 15 June 2022
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Published: 20 June 2022
(This article belongs to the Special Issue Molecular Signatures in Head and Neck Cancer)
Simple Summary
The aim of this matched-pair study including patients with locally advanced head and neck squamous cell carcinoma (HNSCC) was to identify patients who are biologically at high risk for the development of loco–regional recurrences after surgery and postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors, with the help of a novel predictive gene signature. These patients may benefit from treatment with postoperative radiochemotherapy (PORT-C). Based on 108 matched patient pairs treated with PORT and PORT-C, we identified a gene signature consisting of two metagenes. A significant association of the interaction between the risk classification by this signature and the type of treatment was observed for the endpoint loco–regional control (LRC), i.e., the 2-metagene signature was indicative for the type of treatment. The developed signature may thus help to identify high-risk patients currently treated with PORT, who may benefit from additional concurrent chemotherapy.
Abstract
(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.
