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  • [Clin Cancer Res] Development and Validation of a Gene Signature for Patients with Head and Neck Carcinomas Treated by Postoperative Radio(chemo)therapy

    Technische Universitat Dresden / Mechthild Krause*

  • 출처
    Clin Cancer Res
  • 등재일
    2018 Mar 15
  • 저널이슈번호
    24(6):1364-1374.
  • 내용

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    Abstract

    Purpose: The aim of this study was to identify and independently validate a novel gene signature predicting locoregional tumor control (LRC) for treatment individualization of patients with locally advanced HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio(chemo)therapy (PORT-C).

    Experimental Design: Gene expression analyses were performed using NanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed of genes with a previously reported association with radio(chemo)sensitivity or resistance to radio(chemo)therapy. Gene selection and model building were performed comparing several machine-learning algorithms.

    Results: We identified a 7-genesignature consisting of the three individual genes HILPDA, CD24, TCF3, and one metagene combining the highly correlated genes SERPINE1, INHBA, P4HA2, and ACTN1 The 7-gene signature was used, in combination with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci = 0.82), which was successfully validated (ci = 0.71). The signature showed improved performance compared with clinical parameters alone (ci = 0.66) and with a previously published model including hypoxia-associated genes and cancer stem cell markers (ci = 0.65). It was used to stratify patients into groups with low and high risk of recurrence, leading to significant differences in LRC in training and validation (P < 0.001).

     

    Figure 4.Patient stratification by the 7-gene signature and clinical parameters for locoregional tumor control. Kaplan–Meier estimates of locoregional tumor control (LRC) are shown for the training cohort (A) and the validation cohort (B). Patients were stratified into a low-risk group (LR) or a high-risk group (HR) by the linear predictor of the multivariable Cox model which included the 7-gene signature and the clinical parameters ECE status and tumor localization. The cut-off risk score (0.37) was determined on the training cohort and applied to the validation cohort. C, Heatmap of the 7-gene signature as well as ECE status (0, light; 1, dark), localization (oral cavity, dark; others, light), risk group (LR, light; HR, dark), and LRC during follow-up (yes, light; no, dark) for the training cohort.

    Conclusions: We have identified and validated the first hypothesis-based genesignature for HPV-negative HNSCC treated by PORT-C including genes related to several radiobiological aspects. A prospective validation is planned in an ongoing prospective clinical trial before potential application in clinical trials for patient stratification. 

     


    Author information

    Schmidt S#1,2,3, Linge A#1,4,5,6, Zwanenburg A1,3,6,7, Leger S1,4, Lohaus F1,4,5,6, Krenn C4, Appold S5,6, Gudziol V6,8, Nowak A6,9, von Neubeck C1,4, Tinhofer I10,11, Budach V10,11, Sak A12,13, Stuschke M12,13, Balermpas P14,15, Rödel C14,15, Bunea H16,17, Grosu AL16,17, Abdollahi A18,19,20,21,22, Debus J18,19,20,21,23, Ganswindt U24,25,26, Belka C24,25,26, Pigorsch S24,27, Combs SE24,27,28, Mönnich D29,30, Zips D29,30, Baretton GB1,6,31,32, Buchholz F1,33, Baumann M1,2,4,5,6,7, Krause M34,2,4,5,6, Löck S1,3,5; DKTK-ROG.

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

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