ESTRO 2020 Abstract book

S182 ESTRO 2020

HIF1α and CAIX expression were both associated with a deferred decrease in hypoxia between weeks 2 and 5 (r=0.35; p<0.05 for HIF1α; r=-0.39; p<0.05). Locoregional recurrence rates after radiotherapy were significantly higher in patients with high CAIX expression (hazard ratio 2.80 [1.08 – 7.31]; p<0.05) and also increased for high levels of Ku80 as a biomarker for radiation-induced DNA double strand breaks, although this correlation did not reach statistical significance. HPV status did not correlate with any of the tested hypoxia biomarkers, and HPV- positive patients showed lower loco-regional recurrence rates (hazard ratio 0.13 [0.02 – 0.99]; p<0.01) and progression-free survival (hazard ratio 0.232 [0.055– 0.983]; p=0.047) independent of their hypoxia dynamics and expression of hypoxia-associated tissue biomarkers. Conclusion In this exploratory trial, high expression of the tissue- based hypoxia biomarkers HIF1α and CAIX correlated with adverse hypoxia dynamics in HNSCCs during radiochemotherapy as assessed by PET imaging, and high CAIX levels were associated with increased loco-regional recurrence rates. Hence, hypoxia biomarkers warrant further investigations as potential predictors of hypoxia dynamics and hypoxia-associated radiation resistance. OC-0321 Transcriptional subtypes in primary and recurrent head and neck squamous cell carcinomas H. Zitzelsberger 1,2,3 , P. Weber 1,3 , A. Kuenstner 4 , J. Hess 1,2,3 , S. Marschner 2,3 , C. Idel 5 , J. Ribbat-Idel 6 , C. Walz 7 , A.K. Walch 8 , S. Perner 9 , K. Unger 1,2,3 , H. Busch 4 , B. Wollenberg 5 , C. Belka 2,3 1 Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Research Unit Radiation Cytogenetics, Munich, Germany ; 2 University Hospital LMU Munich, Department of Radiation Oncology, Munich, Germany ; 3 Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer", Munich, Germany ; 4 University of Luebeck, Luebeck Institute of Experimental Dermatology and Institute for Cardiogenetics, Luebeck, Germany ; 5 University Hospital Schleswig Holstein Campus Luebeck, Clinic for Otorhinolaryngology - Head and Neck Surgery, Luebeck, Germany ; 6 University Hospital Schleswig- Holstein Campus Luebeck, Institute of Pathology, Luebeck, Germany ; 7 Ludwig-Maximilians University, Institute for Pathology, Munich, Germany ; 8 Helmholtz Zentrum Muenchen - German Research Center for Environmental Health, Research Unit Analytical Pathology, Munich, Germany ; 9 University Hospital Schleswig Holstein Campus Luebeck, Institute of Pathology, Luebeck, Germany Purpose or Objective Patients suffering from advanced head and neck squamous cell carcinomas (HNSCC) are at high risk for developing local and loco-regional recurrences after radiochemotherapy. To elucidate molecular processes associated with tumor recurrences we investigated pairs of primary and relapsed tumors in HPV-negative patients after radiochemotherapy treatment at genome and Tissue samples of 34 pairs of retrospectively collected primary and recurrent tumors of locally advanced HNSCC patients were subjected to whole RNA, exome sequencing and PD-L1 expression profiling. The primary tumors of a retrospectively collected cohort of HNSCC (n=74) was subjected to whole RNA sequencing and PD-L1 profiling. transcriptome levels. Material and Methods

Single cells of three primary cultures from locally advanced HNSCC were profiled by single-cell RNA sequencing. Results While HNSCC-specific alterations were identified, the mutational and genomic copy number patterns of primary and recurrent tumors were mostly discordant and showed only a low relationship between pairs of primary and relapsed tumors. This heterogeneity between tumor pairs was also reflected by the transcriptional distance. Transcriptional subtypes according to Keck et al. (2015) comprising classical (CL), basal (BA) and inflamed- mesenchymal (IM) subtypes were assigned to all tumor samples. 15 out of the 34 tumor pairs exhibited a change in transcriptional subtype between primary and recurrent tumor and eight of these subtype switchers changed the molecular subtype from IM to either CL or BA. To explore the clinical impact of subtype changes between tumor pairs, all samples were investigated for established prognosis parameters (hypoxia, radiation resistance, pEMT, survival-score) and the expression of representative gene signatures in primary/relapsed tumors. Change of transcriptional subtypes between tumor pairs was associated with significantly improved outcome (‘locoregional relapse/recurrence’; p-value=0.0238, HR=0.43, 95%-CI=0.21-0.91). PD-L1 expression was frequently different between primary and relapsed tumors. Remarkably, the CL subtype showed almost no PD- L1 expression. This is also true for all relapsed tumors of the larger cohort with a CL subtype (p-value=0.0008). Single-cell RNA sequencing analysis of primary cultures revealed co-presence of different transcriptional subtypes in primary tumors suggesting a selection and enrichment of cells of a certain subtype in the course of radiochemotherapy. Conclusion Molecular heterogeneity was observed between matched primary and recurrent tumor tissues, which revealed the existence of transcriptional subtype switching within some patients. Our results point towards a selection of specific subtypes in relapses that exhibit unfavorable tumor properties and have possible effects on therapy innovations. This study suggests to tailor therapy also to the above mentioned specifics of the recurrent tumor.

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