Biomarker-Driven Strategies and Multidisciplinary Care in Modern Gastric Cancer Treatment

Modern management of gastric cancer has transitioned toward a highly individualized approach. By thoroughly evaluating the tumor’s biological and molecular profile, its stage, and the patient’s unique clinical characteristics, healthcare providers can select from a diverse array of treatment modalities. These include surgical intervention, conventional chemotherapy, radiation therapy, and advanced systemic options such as targeted agents and immunotherapies.

As the therapeutic landscape for gastric cancer continues to expand, clinicians must navigate increasingly complex treatment decisions. Balancing robust clinical evidence, patient-specific variables, potential treatment toxicities, and overall therapeutic goals remains a central challenge in delivering optimal care.

The Shift Toward Biomarker-Driven Treatment Paradigms

The assessment of molecular and biomarker characteristics is now integral to managing advanced gastric cancer. Key biomarkers, including HER2 expression, PD-L1 expression, microsatellite instability (MSI) or mismatch repair (MMR) deficiency, and Claudin 18.2 (CLDN18.2) expression, are critical in guiding therapeutic decisions for advanced disease.

According to the European Society for Medical Oncology (ESMO) guidelines for gastrointestinal cancers, advanced or metastatic gastric and gastroesophageal junction (GEJ) adenocarcinomas are stratified into biomarker-defined treatment pathways. Under these consensus frameworks, patients are assigned to specific therapeutic subgroups based on HER2 status, PD-L1 expression, MSI status, and CLDN18.2 expression.

While biomarker data provides a framework for systemic treatment in advanced or metastatic gastric and GEJ adenocarcinomas, its application must be tailored to clinical reality. Treatment decisions should integrate current evidence with local and international regulatory approvals, institutional capabilities, and individual patient clinical factors.

Advancing HER2-Directed Therapeutic Strategies

Trastuzumab has been established as a standard therapeutic option for HER2-positive gastric cancer, both as a monotherapy and in combination with various chemotherapy regimens. Its application spans multiple clinical scenarios, depending on patient tolerance and disease characteristics.

The combination of pembrolizumab, trastuzumab, and fluoropyrimidine- and platinum-based chemotherapy is indicated for patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma. To be eligible for this regimen, tumors must express PD-L1 with a Combined Positive Score (CPS) of 1 or greater.

Clinical assessment of HER2 and PD-L1 expression is typically conducted as independent parameters to guide decision-making. Treatment choices are often based on individual biomarker findings, sometimes in isolation from other clinical data, highlighting the need for integrated interpretation.

Integrating CLDN18.2 Expression into Clinical Practice

For adults with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma expressing CLDN18.2, the combination of zolbetuximab-clzb with fluoropyrimidine- and platinum-based chemotherapy is an approved therapeutic option. An approved companion diagnostic is available to identify eligible patients based on CLDN18.2 expression testing.

Establishing clear expression thresholds and utilizing validated testing methodologies are essential for accurately identifying gastric cancer patients who are candidates for CLDN18.2-directed therapies.

Immunotherapy and the Role of MSI Status

Immune checkpoint inhibitors have become a cornerstone in the management of advanced gastric cancer. Patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors are prime candidates for immunotherapy, with PD-L1 expression serving as a key decision-making criterion.

For other patients, PD-L1 expression is evaluated using standardized scoring systems and thresholds, such as the Combined Positive Score (CPS) recommended in ESMO guidelines for advanced gastric and GEJ adenocarcinomas. Because biomarker expression varies widely among tumors and is often present only in a subset of cases, a multidisciplinary approach is highly recommended to interpret these complex profiles and guide optimal treatment selection.

Reevaluating Treatment Sequencing and Strategies

In potentially curable cases, multidisciplinary evaluation is essential when planning surgical and perioperative strategies. For advanced disease, systemic therapy selection is increasingly driven by biomarker-defined subgroups. Clinicians should dynamically reassess treatment plans as new pathology, imaging, molecular, or clinical data emerges, rather than relying solely on initial decisions.

Primary treatment options for potentially curable gastric cancer include surgery—often incorporating neoadjuvant therapy—and/or adjuvant systemic treatment. For advanced disease, systemic therapy is tailored based on disease characteristics, prior treatments, and the patient’s overall condition and organ function.

Consequently, at every clinical follow-up, the treatment plan must be revisited in light of the latest pathology reports, imaging studies, molecular findings, and clinical updates.

Managing Toxicity and Patient-Specific Factors

Treatment planning for older patients or those with poor performance status must carefully account for prior therapies, patient preferences, organ function, comorbidities, and age.

When managing treatment-related toxicities, clinicians must evaluate potential adverse effects, drug interactions, treatment duration, and the patient’s personal resources. Comprehensive supportive care, including nutritional assessment, symptom management, and clear communication with patients and their families, is vital throughout all treatment phases to ensure adherence and maintain quality of life.

The Critical Role of Multidisciplinary Teams

Multidisciplinary team meetings involving medical oncologists, surgeons, radiation oncologists, pathologists, radiologists, dietitians, and specialist nurses are essential for navigating the increasing complexity of gastric cancer treatment.

Coordinating pathology and molecular testing with therapeutic decisions is a crucial aspect of gastric cancer management. In gastric cancer treatment, discussions within multidisciplinary meetings (MDMs) can enable clinicians to consider the key factors in treatment decision-making. These factors are the disease stage, pathological findings, biomarker status, imaging findings, previous treatment, and patient-specific factors.

Future Horizons in Gastric Cancer Therapy

The future of gastric cancer treatment is promising, with novel modalities such as targeted therapies, antibody-drug conjugates, and cellular therapies actively under investigation. Agents targeting CLDN18.2, alongside CAR-T cell therapies and other antibody-drug conjugates, are currently being explored in clinical trials. To stay informed on the latest evidence, regulatory approvals, and biomarker testing requirements, clinicians should refer to current clinical guidelines, which serve as supportive tools rather than replacements for clinical judgment.

Personalized management of gastric cancer is becoming increasingly complex, requiring treatment strategies to be tailored based on disease stage, tumor biology, individual patient circumstances, and therapeutic goals.

Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, a clinical guideline, or a recommendation for any specific treatment.

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