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

Eder, Theresa; Heß, Anne-Katrin; Konschak, Robert; Stromberger, Carmen; Jöhrens, Korinna; Fleischer, Vanessa; Hummel, Michael; Balermpas, Panagiotis; Grün, Jens von der; Linge, Annett; Lohaus, Fabian; Krause, Mechthild; Baumann, Michaël; Stuschke, Martin; Zips, Daniel; Grosu, Anca‐Ligia; Abdollahi, Amir; Debus, Jürgen; Belka, Claus; Pigorsch, Steffi; Combs, Stephanie E.; Budach, Volker; Tinhofer, Ingeborg; Dktk-Rog,

doi:10.1016/j.ejca.2019.04.015

Cited by 46 publications

(46 citation statements)

References 32 publications

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“…Some, such as tumor mutational burden (TMB) are prevalent in laryngeal and HPV-negative pharyngeal HNSCC (14) but require DNA sequencing data. TMB was found to be associated with poor prognosis in HPV-negative chemo-radiotherapy treated patients in our previous study (36) and more strongly so in a cohort of patients that also included oral cavity cancers and HPV-positive oropharyngeal (107). Interestingly, low immune cell infiltration or CD8+ T cell values, as assessed by gene expression, have been assigned to HNSCC high in TMB or mutational signatures related to smoking (56,107).…”

Section: Discussionmentioning

confidence: 77%

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

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Purpose: Tumor markers that are related to hypoxia, proliferation, DNA damage repair and stem cell-ness, have a prognostic value in advanced stage HNSCC patients when assessed individually. Here we aimed to evaluate and validate this in a multifactorial context and assess interrelation and the combined role of these biological factors in determining chemo-radiotherapy response in HPV-negative advanced HNSCC. Methods: RNA sequencing data of pre-treatment biopsy material from 197 HPV-negative advanced stage HNSCC patients treated with definitive chemoradiotherapy was analyzed. Biological parameter scores were assigned to patient samples using previously generated and described gene expression signatures. Locoregional control rates were used to assess the role of these biological parameters in radiation response and compared to distant metastasis data. Biological factors were ranked according to their clinical impact using bootstrapping methods and multivariate Cox regression analyses that included clinical variables. Multivariate Cox regression analyses comprising all biological variables were used to define their relative role among all factors when combined. Results: Only few biomarker scores correlate with each other, underscoring their independence. The different biological factors do not correlate or cluster, except for the two stem cell markers CD44 and SLC3A2 (r = 0.4, p < 0.001) and acute hypoxia prediction scores which correlated with T-cell infiltration score, CD8 + T cell abundance and proliferation scores (r = 0.52, 0.56, and 0.6, respectively with p < 0.001). van der Heijden et al. HNSCC Biology Impacting Chemo-Radiotherapy Outcomes Locoregional control association analyses revealed that chronic (Hazard Ratio (HR) = 3.9) and acute hypoxia (HR = 1.9), followed by stem cell-ness (CD44/SLC3A2; HR = 2.2/2.3), were the strongest and most robust determinants of radiation response. Furthermore, multivariable analysis, considering other biological and clinical factors, reveal a significant role for EGFR expression (HR = 2.9, p < 0.05) and T-cell infiltration (CD8 + T-cells: HR = 2.2, p < 0.05; CD8 + T-cells/Treg: HR = 2.6, p < 0.01) signatures in locoregional control of chemoradiotherapy-treated HNSCC. Conclusion: Tumor acute and chronic hypoxia, stem cell-ness, and CD8 + Tcell parameters are relevant and largely independent biological factors that together contribute to locoregional control. The combined analyses illustrate the additive value of multifactorial analyses and support a role for EGFR expression analysis and immune cell markers in addition to previously validated biomarkers. This external validation underscores the relevance of biological factors in determining chemoradiotherapy outcome in HNSCC.

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Section: Discussionmentioning

confidence: 77%

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

et al. 2020

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“…Recent analysis in a cohort of HNSCCs treated nonsurgically showed a marginally significant association of TMB with OS. 46 The association shown here narrows TMBs prognostic to early-stage HPV− disease, where it is also not limited to patients receiving chemoradiation. Prediction of tumor progression in both the milieu of an immunodeficient mouse and patients is therefore a novel finding that may lead to expanded utility for TMB as a biomarker.…”

Section: Lower P16 Ink4a Expression In An Atypical Hpv+ Pdx May Be mentioning

confidence: 70%

Identifying predictors of HPV‐related head and neck squamous cell carcinoma progression and survival through patient‐derived models

Facompre

Rajagopalan

Sahu

et al. 2020

Intl Journal of Cancer

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Therapeutic innovation for human papilloma virus-related (HPV+) head and neck squamous cell carcinomas (HNSCCs) is impaired by inadequate preclinical models and the absence of accurate biomarkers. Our study establishes the first well-characterized panel of patient-derived xenografts (PDXs) and organoids from HPV+ HNSCCs while determining fidelity of the models to the distinguishing genetic features of this cancer type. Despite low engraftment rates, whole exome sequencing showed that PDXs retain multiple distinguishing features of HPV+ HNSCC lost in existing cell lines, including PIK3CA mutations, TRAF3 deletion and the absence of EGFR amplifications. Engrafted HPV+ tumors frequently contained NOTCH1 mutations, thus providing new models for a negatively prognostic alteration in this disease. Genotypephenotype associations in the models were then tested for prediction of tumor progression and survival in published clinical cohorts. Observation of high tumor mutational burdens (TMBs) in the faster-growing models facilitated identification of a

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“…A multicentre retrospective study from Germany developed a 327-gene panel to define TMB and then performed TMB analysis in 101 archival tumour samples from HNSCC patients treated with definitive CRT, aiming to assess the impact of TMB on prognosis. High TMB was demonstrated to be correlated with poor survival, which suggests that it may predict patients who might potentially benefit from CRT-ICI combinations [ 67 ]. Further research is needed to determine the value of TMB in response to RT alone.…”

Section: Biomarkersmentioning

confidence: 99%

Understanding the Effects of Radiotherapy on the Tumour Immune Microenvironment to Identify Potential Prognostic and Predictive Biomarkers of Radiotherapy Response

Cheng

Cheadle

Illidge

2020

Cancers

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Radiotherapy (RT) is a highly effective anti-cancer treatment. Immunotherapy using immune checkpoint blockade (ICI) has emerged as a new and robust pillar in cancer therapy; however, the response rate to single agent ICI is low whilst toxicity remains. Radiotherapy has been shown to have local and systemic immunomodulatory effects. Therefore, combining RT and immunotherapy is a rational approach to enhance anti-tumour immune responses. However, the immunomodulatory effects of RT can be both immunostimulatory or immunosuppressive and may be different across different tumour types and patients. Therefore, there is an urgent medical need to establish biomarkers to guide clinical decision making in predicting responses or in patient selection for RT-based combination treatments. In this review, we summarize the immunological effects of RT on the tumour microenvironment and emerging biomarkers to help better understand the implications of these immunological changes, and we provide new insights into the potential for combination therapies with RT and immunotherapy.

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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

Cited by 46 publications

References 32 publications

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Biological Determinants of Chemo-Radiotherapy Response in HPV-Negative Head and Neck Cancer: A Multicentric External Validation

Identifying predictors of HPV‐related head and neck squamous cell carcinoma progression and survival through patient‐derived models

Understanding the Effects of Radiotherapy on the Tumour Immune Microenvironment to Identify Potential Prognostic and Predictive Biomarkers of Radiotherapy Response

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