OPPOSITE: Outcome Prediction Of Systemic Treatment in Esophagogastric Carcinoma

Study Overview
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Brief Summary
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Patients with locally advanced, resectable gastric or esophagogastric junction adenocarcinoma will receive a biopsy of the primary tumor, followed by standard-of care neoadjuvant systemic treatment; after neoadjuvant therapy tumor biopsies will be taken from different sites of the resection specimen. Aim 1: Organoid cultures of pre-treatment tumor biopsies will be established and exposed to the same chemotherapy as the corresponding patient; in vitro response to treatment will be correlated with the in vivo response of patients. Aim 2: Whole genome, methylome and RNA sequencing of tumors biopsies and organoids will be performed prior to as well as after systemic treatment. Histological and clinical outcome will be correlated with molecular subtypes.

Official Title
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Molecular Outcome Prediction of Neoadjuvant Systemic Treatment in Esophagogastric Carcinoma

Conditions
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Gastric Neoplasm, Gastroesophageal Junction Adenocarcinoma, Esophageal Adenocarcinoma, Gastric Adenocarcinoma, Esophageal Neoplasms

Intervention / Treatment
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* Procedure: Biopsy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed, resectable adenocarcinoma of the GEJ (type I-III) or the stomach (cT2, cT3,cT4, any cN category, M0), or any cT cN+ M0 with the following specifications: ECOG-Score ≤ 2 Patient is fit to undergo surgery (either subtotal or total gastrectomy, transhiatal or abdominothoracic esophagectomy) No preceding cytotoxic or targeted therapy No prior partial or complete tumor resection Exclusion of distant metastasis by CT or MRI of thorax and abdomen, and optionally bone scan (if osseous lesions are suspected due to clinical signs) Exclusion Criteria: Patients with distant metastasis Known hypersensitivity against components of the neoadjuvant systemic treatment Documented history of congestive heart failure NYHA ≥III, myocardial infarction within the past 3 months before the start of neoadjuvant treatment Uncontrollable high-risk cardiac arrhythmia, e.g. significant ventricular arrhythmia Past or current history of other malignancies not curatively treated and without evidence of disease for more than 5 years, except for curatively treated early stage cancers such as basal cell carcinoma of the skin and in situ carcinoma of the cervix or the bladder.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Interventional Arm<br>Patients with locally advanced, resectable gastric or esophagogastric junction adenocarcinoma will receive a biopsy of the primary tumor, followed by standard-of care neoadjuvant systemic treatment; after neoadjuvant therapy tumor biopsies will be taken from different sites of the resection specimen. Organoid cultures of pre-treatment tumor biopsies will be established and exposed to the same chemotherapy as the corresponding patient; in vitro response to treatment will be correlated with the in vivo response of patients. Whole genome, methylome and RNA sequencing of tumors biopsies and organoids will be performed prior to as well as after systemic treatment. | Procedure: Biopsy<br>* Patients with locally advanced, resectable gastric or esophagogastric junction adenocarcinoma will receive a biopsy of the primary tumor, followed by standard-of care neoadjuvant systemic treatment; after neoadjuvant therapy tumor biopsies will be taken from different sites of the resection specimen.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aim 1: Correlation of in-vitro response in the organoid model with histological regression in the resected tumor | Correlation of in-vitro response to cytotoxic chemotherapy in the patient-derived organoid model with histological regression in the resected specimen and analysis of reliability of this organoid model in predicting patients' response to neoadjuvant chemotherapy. | 1 year | 
| Aim 2: Correlation of molecular subtypes with histological response after neoadjuvant therapy in patients | Prognostic impact of the molecular subtypes on histological response to neoadjuvant chemotherapy in patients will be modeled using the logistic regression. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aim 1: Correlation of in-vitro response in the organoid model with relapse-free survival | The possible prognostic impact of in-vitro response in the organoid model on relapse-free survival will be investigated using the Cox proportional hazards models. | maximum 5 years | 
| Aim 2: Correlation of molecular subtypes with relapse-free survival | The possible prognostic impact of molecular subtypes on relapse-free survival will be investigated using the Cox proportional hazards models. | maximum 5 years |