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Study focus:

* The study investigates biomarkers to predict patient response to intraperitoneal paclitaxel (IP PTX) combined with systemic S-1 plus oxaliplatin (SOX) chemotherapy for gastric cancer peritoneal metastases (GCPM).

Methods:

* clinical Trial Data: They analyzed data from the PIPS-GC phase Ib/II clinical trial.
* Sequencing: Whole exome and transcriptome sequencing was performed on tumor and normal tissue samples.
* Data Integration: They used data from The Cancer Genome Atlas (TCGA) and publicly available single-cell RNA sequencing (scRNA-seq) datasets.
* Spatial Transcriptomics: Used to validate biomarker candidates in a non-responder case.

Results:

* Patient Cohort: Nine patients were included (6 responders, 3 non-responders).
* Key Biomarker Identified: Thrombospondin type 1 domain-containing protein 4 (THSD4) was identified as a potential biomarker. Higher expression of THSD4 in peritoneal tumors was associated with chemotherapy resistance.
* Mechanism: THSD4 appears to contribute to resistance through midkine and epithelial-mesenchymal transition pathways.

Conclusion:

* THSD4 is a potential biomarker for predicting response to IP PTX plus systemic SOX in GCPM. Further research is needed to understand its mechanism and validate its clinical use.

Affiliations (Researchers):

* Division of Foregut Surgery, Department of Surgery, Korea University college of Medicine, Seoul, Republic of Korea (Multiple researchers)
* Department of Molecular Genetics & Dental Pharmacology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.

* Dental Research Institute and Dental Multi-omics Center, Seoul National University, Seoul, Republic of korea.

* Department of Surgery, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Buchoen, Republic of Korea. (Contact: [email protected])
* Division of Foregut Surgery, Department of Surgery, Korea University College of Medicine, Seoul, Republic of Korea. (Contact: [email protected])

Keywords:

* Biomarker
* Gastric cancer
* Intraperitoneal chemotherapy
* Peritoneal metastasis
* Translational study

how might ERCC1 expression levels inform the selection of first-line chemotherapy regimens for gastric cancer patients with peritoneal metastasis,based on PIPS GC trial findings?

Deciphering Molecular Signals for Chemotherapy Resistance in Gastric Cancer with peritoneal Metastasis: Insights from the PIPS GC Trial

Gastric cancer with peritoneal metastasis represents a especially aggressive form of the disease,characterized by poor prognosis and limited treatment options. Chemotherapy remains a cornerstone of treatment, but the progress of resistance is a notable hurdle. The PIPS GC (Perioperative Investigational Programme in Gastric Cancer) trial, and subsequent analyses, have provided crucial insights into the molecular mechanisms driving this resistance, paving the way for more personalized and effective therapeutic strategies. This article delves into these findings,focusing on actionable intelligence for clinicians and researchers.

Understanding Peritoneal metastasis in Gastric Cancer

Peritoneal metastasis, the spread of gastric cancer cells to the peritoneum (the lining of the abdominal cavity), dramatically alters the disease landscape. Several factors contribute to this:

* Unique Microenvironment: The peritoneal cavity presents a unique microenvironment that fosters cancer cell survival and proliferation. this includes a rich vascular network, immune cell interactions, and the presence of mesothelial cells.

* Seed and Soil Hypothesis: The “seed and soil” hypothesis suggests that cancer cells (seeds) preferentially metastasize to specific sites (soil) within the body. The peritoneum provides a fertile soil for gastric cancer cells.

* Chemoresistance Development: The peritoneal microenvironment can also shield cancer cells from chemotherapy, promoting the development of drug resistance.

Key Molecular Pathways Implicated in Chemoresistance – PIPS GC Trial Findings

The PIPS GC trial, a phase III randomized controlled trial evaluating perioperative chemotherapy with fluoropyrimidine plus cisplatin/oxaliplatin, has been instrumental in identifying molecular markers associated with treatment response and resistance. Analysis of tumor samples from trial participants revealed several key pathways:

1. DNA Repair mechanisms & ERCC1 Expression

* ERCC1 (Excision Repair Cross-Complementing 1): Elevated ERCC1 expression, a key enzyme in nucleotide excision repair, is consistently linked to chemoresistance in gastric cancer. High ERCC1 levels allow cancer cells to repair DNA damage induced by platinum-based chemotherapies (cisplatin, oxaliplatin), rendering these drugs less effective.

* Clinical relevance: patients with high ERCC1 expression may benefit from option chemotherapy regimens or the addition of ERCC1 inhibitors to enhance treatment sensitivity. Research is ongoing to develop effective ERCC1 inhibitors.

* Biomarker Testing: ERCC1 expression can be assessed via immunohistochemistry (IHC) on tumor biopsies.

2. HER2 Amplification and Targeted Therapies

* HER2 (Human Epidermal Growth Factor Receptor 2): HER2 amplification, present in approximately 7-20% of gastric cancers, is a well-established driver of tumor growth and progression.

* Trastuzumab: The PIPS GC trial demonstrated the significant benefit of adding trastuzumab,a HER2-targeted antibody,to chemotherapy in HER2-positive gastric cancer patients. This improved overall survival and progression-free survival.

* Testing for HER2: HER2 status is typically persistent by IHC and fluorescence in situ hybridization (FISH).

3. Microsatellite Instability-High (MSI-H) and Immunotherapy

* MSI-H: MSI-H, a marker of DNA mismatch repair deficiency, is found in a subset of gastric cancers. These tumors exhibit a high mutational burden, making them more susceptible to immunotherapy.

* Pembrolizumab & nivolumab: Immunotherapy with checkpoint inhibitors like pembrolizumab and nivolumab has shown promising results in MSI-H gastric cancer, even in patients with peritoneal metastasis.

* MSI Testing: MSI status is assessed using PCR-based methods.

4. PI3K/AKT/mTOR Pathway Activation

* Dysregulation: Activation of the PI3K/AKT/mTOR pathway is frequently observed in gastric cancer and contributes to chemoresistance by promoting cell survival and inhibiting apoptosis.

* Potential Targets: Inhibitors targeting components of this pathway (e.g., PI3K, AKT, mTOR) are under investigation as potential therapeutic strategies.

* Biomarker Challenges: Identifying reliable biomarkers to predict response to PI3K/AKT/mTOR inhibitors remains a challenge.

5. Claudin-18.2 Expression & Novel Drug Delivery

* claudin-18.2: This protein is highly expressed in gastric cancer cells, particularly those with peritoneal metastasis, but has limited expression in normal tissues.

* Targeted Therapies: Claudin-18.2 serves as a promising target for antibody-drug conjugates (ADCs). These adcs deliver cytotoxic agents directly to cancer cells, minimizing off-target effects.

* Ongoing Trials: Several ADCs targeting Claudin-18.2 are currently in clinical trials for gastric cancer.

Benefits of Molecular Profiling in Gastric Cancer Treatment

Implementing molecular profiling in the management of gastric cancer with peritoneal metastasis offers several benefits:

* Personalized Treatment: Tailoring chemotherapy regimens based on individual tumor characteristics.

* Improved Prognosis: Identifying patients who are likely to benefit from specific therapies.

* Reduced Toxicity: Avoiding ineffective treatments