Autor:innen:
Theresa Eder | Charité - Universitätsmedizin Berlin | Germany
AK Hess | Charité University Hospital, Berlin, Germany | Germany
R Konschak | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Berlin | Germany
C Stromberger | Charité University Hospital, Berlin, Germany | Germany
K Jöhrens | Charité University Hospital Berlin, Berlin, Germany | Germany
V Fleischer | Charité University Hospital, Berlin, Germany | Germany
Prof. Dr. Michael Hummel | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Berlin | Germany
P Balermpas | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Frankfurt | Germany
J von der Grün | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Frankfurt | Germany
A Linge | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Dresden | Germany
FA Lohaus | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Dresden | Germany
M Krause | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Dresden | Germany
Michael Baumann | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Dresden | Germany
M Stuschke | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Essen | Germany
D Zips | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Tübingen | Germany
AL Grosu | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Freiburg | Germany
A Abdollahi | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Heidelberg | Germany
Prof Dr Jürgen Debus | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Heidelberg | Germany
C Belka | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Munich | Germany
S Pigorsch | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Munich | Germany
Stephanie Combs | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Munich | Germany
V Budach | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Berlin | Germany
I Tinhofer | German Cancer Research Center (DKFZ), Heidelberg and German Cancer Consortium (DKTK) partner site Berlin | Germany
Background: Tumor mutational burden (TMB) estimated from whole exome sequencing (WES) or comprehensive gene panels has previously been established as predictive factor of response to immune checkpoint inhibitors (ICI). 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 TCGA HNSCC dataset. Interference of TMB with outcome after cCRTX was determined in a multicenter cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) uniformly treated with cCRTX. tNGS was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumor samples. In a subset of cases (n=40), tumor RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, 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.