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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)

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

PROVIDER: PRJNA988031 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25043610_1.fastq.gz	Fastqsanger.gz
	SRR25043610_2.fastq.gz	Fastqsanger.gz
	SRR25043611_1.fastq.gz	Fastqsanger.gz
	SRR25043611_2.fastq.gz	Fastqsanger.gz
	SRR25043612_1.fastq.gz	Fastqsanger.gz

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

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Window of Opportunity Study in Colorectal Cancer

Project description:This is a window of opportunity translational study investigating the use of pre-operative pembrolizumab and chemotherapy or chemoradiotherapy in non-metastatic colorectal cancer.

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

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.

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Project description:Head and neck squamous cell carcinoma (HNSCC) has a large global burden of disease and poor survival outcomes. Recent targeted therapies and immunotherapies have been explored in HNSCC, but there has been limited translation to clinical practice outside of recurrent or metastatic cases. Window of opportunity settings, where novel agents are administered between cancer diagnosis and planned definitive therapy, have begun to be employed in HNSCC. Tumor tissue biopsies are obtained at diagnosis and after the investigation treatment, along with other biospecimens and radiographic exams. Thus, this study design can characterize the safety profiles, pharmacodynamics, and initial tumor responses to novel therapies in a treatment-naïve subject. Early window studies have also identified potential biomarkers to predict sensitivity or resistance to treatments. However, these early investigations have revealed multiple challenges associated with this trial design. In this review, we discuss recent window of opportunity trials in HNSCC and how they inform design considerations for future studies.

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Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial.

Project description:ObjectiveThe tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors.Study designWindow of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. Fifty patients were enrolled, and 39 completed a full-treatment course. Metformin was titrated to standard diabetic dose (2,000 mg/day) for a course of 9 or more days prior to surgery.MethodsImmunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB), and monocarboxylate transporter 4 (MCT4), as well as the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay and Ki-67 IHC, were performed in pre- and postmetformin specimens. Exploratory mass spectroscopy imaging (MSI) to assess lactate levels also was performed in three subjects.ResultsMetformin was well tolerated. The average treatment course was 13.6 days. Posttreatment specimens showed a significant increase in stromal CAV1 (P < 0.001) and GALB (P < 0.005), as well as tumor cell apoptosis by TUNEL assay (P < 0.001). There was no significant change in stromal MCT4 expression or proliferation measured by Ki67. Lactate levels in carcinoma cells were increased 2.4-fold postmetformin (P < 0.05), as measured by MSI.ConclusionMetformin increases markers of reduced catabolism and increases senescence in stromal cells as well as carcinoma cell apoptosis. This study demonstrates that metformin modulates metabolism in the HNSCC microenvironment.Level of evidence4. Laryngoscope, 127:1808-1815, 2017.

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