T Eder1, A K Hess2, R Konschak3, C Stromberger2, K Jöhrens4, V Fleischer2, M Hummel5, P Balermpas6, J von der Grün6, A Linge7, F Lohaus7, M Krause8, M Baumann9, M Stuschke10, D Zips11, A L Grosu12, A Abdollahi13, J Debus13, C Belka14, S Pigorsch15, S E Combs15, V Budach3, I Tinhofer16. 1. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Berlin, Germany. 2. Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany. 3. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany. 4. Institute of Pathology, Charité University Hospital Berlin, Berlin, Germany. 5. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Berlin, Germany; Institute of Pathology, Charité University Hospital Berlin, Berlin, Germany. 6. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Frankfurt, Germany; Department of Radiotherapy and Oncology, Goethe-University Frankfurt, Germany. 7. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Dresden, Germany; 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; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany. 8. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Dresden, Germany; 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; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Germany. 9. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Dresden, Germany; 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; Department of Radiotherapy and Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; National Center for Tumor Diseases (NCT), Partner Site Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology - OncoRay, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. 10. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Essen, Germany; Department of Radiotherapy, Medical Faculty, University of Duisburg-Essen, Essen, Germany. 11. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Tu¨bingen Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Tu¨bingen, Eberhard Karls Universität Tu¨bingen, Germany. 12. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Freiburg, Germany; Department of Radiation Oncology, University of Freiburg, Germany. 13. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, 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), Germany. 14. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Munich, Germany; Department of Radiotherapy and Radiation Oncology, Ludwig-Maximilians-Universität, Munich, Germany. 15. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Munich, Germany; Department of Radiation Oncology, Technische Universität Mu¨nchen, Germany. 16. German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) Partner Sites, Berlin, Germany; Department of Radiooncology and Radiotherapy, Charité University Hospital, Berlin, Germany. Electronic address: ingeborg.tinhofer@charite.de.
Abstract
BACKGROUND: Tumour mutational burden (TMB) estimated from whole exome sequencing or comprehensive gene panels has previously been established as predictive factor of response to immune checkpoint inhibitors (ICIs). Its predictive value for the efficacy of concurrent chemoradiation (cCRTX), a potential combination partner of ICI, remains unknown. METHODS: The accuracy of TMB estimation by an in-house 327-gene panel was established in the Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) data set. Interference of TMB with outcome after cCRTX was determined in a multicentre cohort of patients with locally advanced HNSCC uniformly treated with cCRTX. Targeted next-generation sequencing was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumour samples. In a subset of cases (n = 40), tumour RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, human papilloma virus (HPV) status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort. RESULTS: A high accuracy of TMB estimation by the 327-gene panel was established. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB (hazard ratio for death: 1.79, 95% confidence interval: 1.02-3.14; P = 0.042) which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort. CONCLUSION: High TMB identifies HNSCC patients with poor outcome after cCRTX who might preferentially benefit from CRTX-ICI combinations.
BACKGROUND:Tumour mutational burden (TMB) estimated from whole exome sequencing or comprehensive gene panels has previously been established as predictive factor of response to immune checkpoint inhibitors (ICIs). Its predictive value for the efficacy of concurrent chemoradiation (cCRTX), a potential combination partner of ICI, remains unknown. METHODS: The accuracy of TMB estimation by an in-house 327-gene panel was established in the Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) data set. Interference of TMB with outcome after cCRTX was determined in a multicentre cohort of patients with locally advanced HNSCC uniformly treated with cCRTX. Targeted next-generation sequencing was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumour samples. In a subset of cases (n = 40), tumour RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, human papilloma virus (HPV) status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort. RESULTS: A high accuracy of TMB estimation by the 327-gene panel was established. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB (hazard ratio for death: 1.79, 95% confidence interval: 1.02-3.14; P = 0.042) which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort. CONCLUSION: High TMB identifies HNSCC patients with poor outcome after cCRTX who might preferentially benefit from CRTX-ICI combinations.
Authors: Nicole D Facompre; Pavithra Rajagopalan; Varun Sahu; Alexander T Pearson; Kathleen T Montone; Claire D James; Frederico O Gleber-Netto; Gregory S Weinstein; Jalal Jalaly; Alexander Lin; Anil K Rustgi; Hiroshi Nakagawa; Joseph A Califano; Curtis R Pickering; Elizabeth A White; Bradford E Windle; Iain M Morgan; Roger B Cohen; Phyllis A Gimotty; Devraj Basu Journal: Int J Cancer Date: 2020-07-06 Impact factor: 7.396
Authors: Carlos E De Andrea; Sandra Hervas-Stubbs; Diego Salas-Benito; Enrique Conde; Ibon Tamayo-Uria; Uxua Mancheño; Edurne Elizalde; David Garcia-Ros; Jose M Aramendia; Juan C Muruzabal; Julia Alcaide; Francisco Guillen-Grima; Jose A Minguez; Jose Amores-Tirado; Antonio Gonzalez-Martin; Pablo Sarobe; Juan J Lasarte; Mariano Ponz-Sarvise Journal: Br J Cancer Date: 2021-01-05 Impact factor: 7.640