Biomarker Analysis of Anti-PD-1 Antibody Combined With Chemotherapy for Neoadjuvant Treatment of G/GEJ Adenocarcinoma

Study Overview
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Brief Summary
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G/GEJ adenocarcinoma is one of the most common malignant tumors in China, ranking the fifth highest incidence and third highest mortality worldwide. Currently, surgical resection is the preferred treatment for G/GEJ adenocarcinoma, while the 5-year survival rate of patients is lower than 25%. Compared with surgical resection, immunotherapy is proved to be able to effectively prolong the survival time of patients. On one hand, with the continuous promotion of immunotherapy drugs, the exploration of neoadjuvant application of immunotherapy in G/GEJ adenocarcinoma has become a hotspot in recent years. It's also on their way that clinical trials of programmed death receptor-1 (PD-1), programmed death ligand-1 (PD-L1) and other immune checkpoints are carried out. On the other hand, the research found that although the curative effect of immune therapy seems better, the present G/GEJ adenocarcinoma immunotherapy marker researches mainly focused on the late stage of the cancer, with few studies of immune markers of neoadjuvant therapy for G/GEJ adenocarcinoma. Additionally, it's not quite feasible for single biomarkers to predict the immune treatment effect precisely. Therefore, combined with clinicopathology and therapeutic effects, this study is aimed to construct the efficacy prediction model of anti-PD-1 antibody together with chemotherapy for G/GEJ adenocarcinoma, by detecting patients' DNA mutation and RNA expression. Furthermore, this study will perform drug sensitivity test and bio-molecular test on patient derived organoid model to validate the biomarkers found from biological specimens.

Official Title
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Predictive Biomarker Analysis and Model Construction of PD-1 Monoclonal Antibody Combined With Chemotherapy for Neoadjuvant Treatment of G/GEJ Adenocarcinoma: A Single-center, Observational Study

Conditions
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Locally Advanced Gastric Adenocarcinoma, PD-1

Intervention / Treatment
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* Other: DNA panel and RNA Sequencing


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-80 (including 18 and 80); G/GEJ adenocarcinoma confirmed by basic ultrasound gastroscopy, enhanced CT (PET/CT), MRI or diagnostic laparoscopy; Biopsy histologically confirmed adenocarcinoma As assessed by the investigator, patients who are qualified for receiving PD-1 mab combined with chemotherapy neoadjuvant therapy; Patients who volunteer to participate in this study and sign the informed consent, with good compliance and cooperation in the acquisition of biological specimens. Exclusion Criteria: Patients whose biological specimens do not meet the detection standards; In the judgment of the investigator, the patients with factors that might have caused the study to be terminated.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| PD-1 group<br>Patients who are qualified for receiving anti-PD-1 antibody combined with chemotherapy neoadjuvant therapy | Other: DNA panel and RNA Sequencing<br>* Interventions include collecting samples, DNA panel test and full transcriptome sequencing. Before collecting samples, obtaining written informed consent from patient in advance. Blood cell samples; Paraffin sample of residual tumor tissue of biopsy; Paraffin sample of residual tumor tissue and paracancer tissue after gastrectomy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relative DNA biomarkers | At the DNA level, to identify the biomarkers related to the efficacy of neoadjuvant therapy with PD-1 mab combined with chemotherapy in locally advanced gastric cancer. | From the initiation date of patients recruited into groups to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Relative RNA biomarkers | At the RNA level, to identify the biomarkers related to the efficacy of neoadjuvant therapy with PD-1 mab combined with chemotherapy in locally advanced gastric cancer. | From the initiation date of patients recruited into groups to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Prediction model for efficacy | A prediction model for the efficacy of PD-1 mab combined with chemotherapy, constructed on the basis of clinical pathology, gene variation, gene expression and other factors. | From the date of completing collecting data, to the date of death from any cause or the end date of the whole trail, whichever came first, assessed up to 2 years | 
| Response of organoids to the same neoadjuvant drugs as the corresponding patients | The investigators will establish the G/GEJ adenocarcinoma organoid and tumor infiltration immune cell co-cultural model. The model will be treated with the same PD-1 mab combined with chemotherapy drugs as the corresponding patients. The viability of the organoids will be observed and quantified after treatment. The correlation of 3D organoid sensitivity and the patient response will be analyzed. And RNA expression detection of organoids before and after treatment will be performed to further validate the biomarkers from biological specimens. | From the initiation date of patients recruited into groups to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Conditions of immune microenvironment | To monitor the changes of immune microenvironment before and after neoadjuvant treatment with PD-1 mab combined with chemotherapy for locally advanced gastric cancer. To evaluate whether the tumor infiltration immune cell and organoid co-cultural system can rebuild the tumor immune micro-environment, the immune cell subpopulations will be detected by single-cell sequencing, immunofluorescence staining and flow-cytometry. | From the initiation date of patients recruited into groups to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years | 
| Drug resistance mechanism | To explore the drug resistance mechanism of locally advanced gastric cancer after neoadjuvant therapy with PD-1 mab combined with chemotherapy. | From the initiation date of patients recruited into groups to the date of first documented progression or date of death from any cause, whichever came first, assessed up to 2 years |