Interference of tumour mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group

被引：40

作者：

Eder, T. ^{[1
,2
]}

Hess, A. K. ^{[10
]}

Konschak, R. ^{[1
,2
,10
]}

Stromberger, C. ^{[10
]}

Joehrens, K. ^{[11
]}

Fleischer, V ^{[10
]}

Hummel, M. ^{[1
,2
,11
]}

Balermpas, P. ^{[1
,5
,19
]}

von der Gruen, J. ^{[1
,5
,19
]}

Linge, A. ^{[1
,3
,12
,13
,14
,15
,16
]}

Lohaus, F. ^{[1
,3
,12
,13
,14
,15
,16
]}

Krause, M. ^{[1
,3
,12
,13
,14
,15
,16
,17
]}

Baumann, M. ^{[1
,3
,12
,13
,14
,15
,16
,17
]}

Stuschke, M. ^{[1
,4
,18
]}

Zips, D. ^{[1
,9
,24
,25
]}

Grosu, A. L. ^{[1
,6
,20
]}

Abdollahi, A. ^{[1
,7
,21
]}

Debus, J. ^{[1
,7
,21
]}

Belka, C. ^{[1
,8
,22
]}

Pigorsch, S. ^{[1
,8
,23
]}

Combs, E. ^{[1
,8
,23
]}

Budach, V ^{[1
,2
,10
]}

Tinhofer, I ^{[1
,2
,10
]}

机构：

[1] German Canc Res Ctr, Heidelberg, Germany

[2] German Canc Consortium DKTK Partner Sites, Berlin, Germany

[3] German Canc Consortium DKTK Partner Sites, Dresden, Germany

[4] German Canc Consortium DKTK Partner Sites, Essen, Germany

[5] German Canc Consortium DKTK Partner Sites, Frankfurt, Germany

[6] German Canc Consortium DKTK Partner Sites, Freiburg, Germany

[7] German Canc Consortium DKTK Partner Sites, Heidelberg, Germany

[8] German Canc Consortium DKTK Partner Sites, Munich, Germany

[9] German Canc Consortium DKTK Partner Sites, Tubingen, Germany

[10] Charite, Dept Radiooncol & Radiotherapy, Berlin, Germany

[11] Charite, Inst Pathol, Berlin, Germany

[12] Tech Univ Dresden, Helmholtz Zentrum Dresden Rossendorf, Fac Med, OncoRay Natl Ctr Radiat Res Oncol, Dresden, Germany

[13] Tech Univ Dresden, Helmholtz Zentrum Dresden Rossendorf, Univ Hosp Carl Gustav Carus, Dresden, Germany

[14] Tech Univ Dresden, Fac Med, Dept Radiotherapy & Radiat Oncol, Dresden, Germany

[15] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Dresden, Germany

[16] Natl Ctr Tumor Dis NCT, Partner Site Dresden, Dresden, Germany

[17] Helmholtz Zentrum Dresden Rossendorf, Inst Radiooncol OncoRay, Dresden, Germany

[18] Univ Duisburg Essen, Med Fac, Dept Radiotherapy, Essen, Germany

[19] Goethe Univ Frankfurt, Dept Radiotherapy & Oncol, Frankfurt, Germany

[20] Univ Freiburg, Dept Radiat Oncol, Freiburg, Germany

[21] Heidelberg Univ, Med Sch, HIRO, Natl Ctr Radiat Res Oncol NCRO, Heidelberg, Germany

[22] Ludwig Maximilians Univ Munchen, Dept Radiotherapy & Radiat Oncol, Munich, Germany

[23] Tech Univ Munich, Dept Radiat Oncol, Munich, Germany

[24] Eberhard Karls Univ Tubingen, Fac Med, Dept Radiat Oncol, Tubingen, Germany

[25] Eberhard Karls Univ Tubingen, Univ Hosp Tubingen, Tubingen, Germany

来源：

EUROPEAN JOURNAL OF CANCER | 2019年 / 116卷

关键词：

Tumour mutational burden; Targeted next-generation sequencing; Concurrent chemoradiation; Immune expression profile; Prognosis; Biomarker; SQUAMOUS-CELL CARCINOMA; PD-1; BLOCKADE; CTLA-4; HPV STATUS; RECURRENT; CHEMORADIOTHERAPY; LYMPHOCYTES; SUBGROUPS; NIVOLUMAB; SURVIVAL;

D O I：

10.1016/j.ejca.2019.04.015

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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. (C) 2019 Elsevier Ltd. All rights reserved.

引用

页码：67 / 76

页数：10

共 32 条

[1] Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer [J].

Ang, K. Kian ;

Harris, Jonathan ;

Wheeler, Richard ;

Weber, Randal ;

Rosenthal, David I. ;

Nguyen-Tan, Phuc Felix ;

Westra, William H. ;

Chung, Christine H. ;

Jordan, Richard C. ;

Lu, Charles ;

Kim, Harold ;

Axelrod, Rita ;

Silverman, C. Craig ;

Redmond, Kevin P. ;

Gillison, Maura L. .

NEW ENGLAND JOURNAL OF MEDICINE, 2010, 363 (01) :24-35

[2] Prognostic value of genomic alterations in head and neck squamous cell carcinoma detected by comparative genomic hybridisation [J].

Ashman, JNE ;

Patmore, HS ;

Condon, LT ;

Cawkwell, L ;

Stafford, ND ;

Greenman, J .

BRITISH JOURNAL OF CANCER, 2003, 89 (05) :864-869

[3] Tumour-infiltrating lymphocytes predict response to definitive chemoradiotherapy in head and neck cancer [J].

Balermpas, P. ;

Michel, Y. ;

Wagenblast, J. ;

Seitz, O. ;

Weiss, C. ;

Roedel, F. ;

Roedel, C. ;

Fokas, E. .

BRITISH JOURNAL OF CANCER, 2014, 110 (02) :501-509

[4] CD8+tumour-infiltrating lymphocytes in relation to HPV status and clinical outcome in patients with head and neck cancer after postoperative chemoradiotherapy: A multicentre study of the German cancer consortium radiation oncology group (DKTK-ROG) [J].

Balermpas, Panagiotis ;

Roedel, Franz ;

Roedel, Claus ;

Krause, Mechthild ;

Linge, Annett ;

Lohaus, Fabian ;

Baumann, Michael ;

Tinhofer, Inge ;

Budach, Volker ;

Gkika, Eleni ;

Stuschke, Martin ;

Avlar, Melanie ;

Grosu, Anca-Lidia ;

Abdollahi, Amir ;

Debus, Juergen ;

Bayer, Christine ;

Stangl, Stefan ;

Belka, Claus ;

Pigorsch, Steffi ;

Multhoff, Gabriele ;

Combs, Stephanie E. ;

Moennich, David ;

Zips, Daniel ;

Fokas, Emmanouil .

INTERNATIONAL JOURNAL OF CANCER, 2016, 138 (01) :171-181

[5] Chromosomal changes characterize head and neck cancer with poor prognosis [J].

Bauer, Verena L. ;

Braselmann, Herbert ;

Henke, Michael ;

Mattern, Dominik ;

Walch, Axel ;

Unger, Kristian ;

Baudis, Michael ;

Lassmann, Silke ;

Huber, Reinhard ;

Wienberg, Johannes ;

Werner, Martin ;

Zitzelsberger, Horst F. .

JOURNAL OF MOLECULAR MEDICINE-JMM, 2008, 86 (12) :1353-1365

[6] Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice [J].

Campesato, Luis Felipe ;

Barroso-Sousa, Romualdo ;

Jimenez, Leandro ;

Correa, Bruna R. ;

Sabbaga, Jorge ;

Hoff, Paulo M. ;

Reis, Luiz F. L. ;

Galante, Pedro Alexandre F. ;

Camargo, Anamaria A. .

ONCOTARGET, 2015, 6 (33) :34221-34227

[7] Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden [J].

Chalmers, Zachary R. ;

Connelly, Caitlin F. ;

Fabrizio, David ;

Gay, Laurie ;

Ali, Siraj M. ;

Ennis, Riley ;

Schrock, Alexa ;

Campbell, Brittany ;

Shlien, Adam ;

Chmielecki, Juliann ;

Huang, Franklin ;

He, Yuting ;

Sun, James ;

Tabori, Uri ;

Kennedy, Mark ;

Lieber, Daniel S. ;

Roels, Steven ;

White, Jared ;

Otto, Geoffrey A. ;

Ross, Jeffrey S. ;

Garraway, Levi ;

Miller, Vincent A. ;

Stephens, Phillip J. ;

Frampton, Garrett M. .

GENOME MEDICINE, 2017, 9

[8] Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy [J].

Cristescu, Razvan ;

Mogg, Robin ;

Ayers, Mark ;

Albright, Andrew ;

Murphy, Erin ;

Yearley, Jennifer ;

Sher, Xinwei ;

Liu, Xiao Qiao ;

Lu, Hongchao ;

Nebozhyn, Michael ;

Zhang, Chunsheng ;

Lunceford, Jared ;

Joe, Andrew ;

Cheng, Jonathan ;

Webber, Andrea L. ;

Ibrahim, Nageatte ;

Plimack, Elizabeth R. ;

Ott, Patrick A. ;

Seiwert, Tanguy ;

Ribas, Antoni ;

McClanahan, Terrill K. ;

Tomassini, Joanne E. ;

Loboda, Andrey ;

Kaufman, David .

SCIENCE, 2018, 362 (6411) :197-+

[9] Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck [J].

Ferris, R. L. ;

Blumenschein, G., Jr. ;

Fayette, J. ;

Guigay, J. ;

Colevas, A. D. ;

Licitra, L. ;

Harrington, K. ;

Kasper, S. ;

Vokes, E. E. ;

Even, C. ;

Worden, F. ;

Saba, N. F. ;

Iglesias Docampo, L. C. ;

Haddad, R. ;

Rordorf, T. ;

Kiyota, N. ;

Tahara, M. ;

Monga, M. ;

Lynch, M. ;

Geese, W. J. ;

Kopit, J. ;

Shaw, J. W. ;

Gillison, M. L. .

NEW ENGLAND JOURNAL OF MEDICINE, 2016, 375 (19) :1856-1867

[10] Nivolumab vs investigator's choice in recurrent or metastatic squamous cell carcinoma of the head and neck: 2-year long-term survival update of CheckMate 141 with analyses by tumor PD-L1 expression [J].

Ferris, Robert L. ;

Blumenschein, George, Jr. ;

Fayette, Jerome ;

Guigay, Joel ;

Colevas, A. Dimitrios ;

Licitra, Lisa ;

Harrington, Kevin J. ;

Kasper, Stefan ;

Vokes, Everett E. ;

Even, Caroline ;

Worden, Francis ;

Saba, Nabil F. ;

Iglesias Docampo, Lara Carmen ;

Haddad, Robert ;

Rordorf, Tamara ;

Kiyota, Naomi ;

Tahara, Makoto ;

Lynch, Mark ;

Jayaprakash, Vijayvel ;

Li, Li ;

Gillison, Maura L. .

ORAL ONCOLOGY, 2018, 81 :45-51

← 1 2 3 4 →