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Spatial Transcriptomic Analysis of Surgical Resection Specimens of Primary Head and Neck Squamous Cell Carcinoma Treated with Afatinib in a Window-of-Opportunity Study (EORTC90111-24111)

ABSTRACT: Spatial Transcriptomic Analysis of Surgical Resection Specimens of Primary Head and Neck Squamous Cell Carcinoma Treated with Afatinib in a Window-of-Opportunity Study (EORTC90111-24111)

PROVIDER: PRJNA1225286 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR32388073_1.fastq.gz	Fastqsanger.gz
	SRR32388073_2.fastq.gz	Fastqsanger.gz
	SRR32388074_1.fastq.gz	Fastqsanger.gz
	SRR32388074_2.fastq.gz	Fastqsanger.gz
	SRR32388075_1.fastq.gz	Fastqsanger.gz

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Spatial Transcriptomic Analysis of Surgical Resection Specimens of Primary Head and Neck Squamous Cell Carcinoma Treated with Afatinib in a Window-of-Opportunity Study (EORTC90111-24111)

Project description:Afatinib-induced tumor and microenvironment modifications in head and neck squamous cell carcinoma were evaluated by spatial transcriptomics in surgical specimens and RNA-sequencing in tumor biopsies of patients included in the EORTC-90111-24111 window-of-opportunity study. The aim was to explore tumor evolution and composition under anti-HER therapy. Based on our previous investigations by RNA-seq on tumor biopsies, surgical slides of ID08 & ID15 from the epithelial-to-mesenchymal (EMT)-cluster and ID30 from the non-EMT cluster were investigated with spatial transcriptomics. Dimension reduction in ID30 revealed 14 clusters, with clusters overlapping three tumor nodules and the stroma. Differential expression analysis between tumor nodules showed enrichment of the hallmark EMT genelist, with 123 genes in common between the analyses. These genes were involved in PDGF and MET signaling pathways. By comparing gene expression in paired tumor biopsies and the 123 genes from differential analyses obtained in ID30, a list of 13 genes involved in cancer pathways and EMT emerged which were also highly expressed in ID08 and ID15. These results show a progressive apparition of genes implicated in EMT, MET and PDGF pathways in tumors after afatinib. Notably, a list of 13 genes emerged which may contain targets to prevent tumor evolution after anti-HER therapy.

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Gene expression profiling in EORTC 90111 study, a window of opportunity trial with afatinib in HNSCC

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Tumor microenvironment modifications induced by afatinib in squamous cell carcinoma of the head and neck - a window-of-opportunity study (EORTC90111-24111)

Project description:The EORTC-90111-24111 window study included treatment-naïve patients with primary HNSCC receiving afatinib versus no preoperative treatment. We found that treated patients had an increase in tumor CD3+ density and CD3+ and CD8+ T-cell infiltration compared to control patients. Afatinib- exposed tumor had upregulation of gene expression signatures predictive of response to PD-1 blockade. Also, we observed two clusters among treated patients. Cluster 1 showed a higher expression of markers and gene sets implicated in epithelial-to-mesenchymal transition and cancer-associated fibroblasts activation after afatinib compared to cluster 2 and controls. These results open perspectives to overcome resistance mechanisms to anti-HER therapy and to potentiate the activity of immune checkpoint inhibitors.

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Activity of afatinib in a window pre-operative EORTC study in patients with squamous cell carcinoma of the head and neck (HNSCC)

Project description:Afatinib is a pan-HER inhibitor that improved progression-free-survival (PFS) in recurrent HNSCC versus methotrexate: median PFS 2.6 versus 1.7 months (LUX H&N 1 trial). This study is a translational research linked to EORTC 90111 afatinib trial, an open-label, randomized, multicenter, phase II window of opportunity trial. Treatment-naïve HNSCC patients selected for primary curative surgery were randomized (5:1 ratio) to receive Afatinib during 14 days (day -15 until day -1) before surgery (day 0) or no treatment. Tumour biopsies, FDG/PET, and MRI were performed at diagnosis and at surgery. The primary end point was metabolic FDG-PET/CT response, defined according to EORTC guidelines.

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Spatial Transcriptomic Analysis of Surgical Resection Specimens of Primary Head and Neck Squamous Cell Carcinoma Treated with Afatinib in a Window-of-Opportunity Study (EORTC90111-24111).

Project description:Afatinib-induced tumor and microenvironment modifications in head and neck squamous cell carcinoma were evaluated by spatial transcriptomics in surgical specimens and RNA-sequencing in tumor biopsies of patients included in the EORTC-90111-24111 window-of-opportunity study. The aim was to explore tumor evolution and composition under anti-HER therapy. Based on our previous investigations by RNA-seq on tumor biopsies, surgical slides of ID08 and ID15 from the epithelial-to-mesenchymal (EMT) cluster and ID30 from the non-EMT cluster were investigated with spatial transcriptomics. Dimension reduction in ID30 revealed 14 clusters, with clusters overlapping three tumor nodules and the stroma. Differential expression analysis between tumor nodules showed enrichment of the hallmark EMT genelist, with 123 genes in common between the analyses. These genes were involved in PDGF and MET signaling pathways. By comparing gene expression in paired tumor biopsies and the 123 genes from differential analyses obtained in ID30, a list of 13 genes involved in cancer pathways and EMT emerged, which were also highly expressed in ID08 and ID15. These results show a progressive apparition of genes implicated in EMT, MET, and PDGF pathways in tumors after afatinib. Notably, a list of 13 genes emerged which may contain targets to prevent tumor evolution after anti-HER therapy.

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Project description:In the EORTC 90111, open-label, randomised, multicentre, phase II trial, patients were treated with afatinib for 14 days (day 15 until day 1) before surgery (day 0). Tumour biopsies, 2-[fluorine-18]-fluoro-2-deoxy-d-glucose positron emission tomography (18-FDG PET) and magnetic resonance imaging (MRI) were performed at diagnosis and just before surgery. The main aim of the study was to identify predictive biomarkers among treatment-naive patients in this curative setting.

2023-12-21 | GSE192464 | GEO

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