This study systematically integrates clinical evidence on HER2 heterogeneity testing and novel targeted agents, providing critical guidance for optimizing individualized treatment strategies in gastric cancer, with direct applicability particularly in multi-line therapy selection and dynamic biomarker monitoring.
Literature Overview
The article, 'Chinese guidelines for HER2-targeted therapy in gastric and gastroesophageal junction adenocarcinoma (2025 Edition)', published in the Journal of Hematology & Oncology, systematically explores the latest advances and clinical practice standards for HER2-targeted therapy in gastric cancer and gastroesophageal junction adenocarcinoma (GC/GEJC). Based on extensive evidence-based medical data, the article proposes an updated HER2 classification system and provides systematic recommendations on testing standards, treatment strategies, and resistance management, aiming to enhance the precision of therapy.Background Knowledge
Gastric cancer is a highly prevalent malignant tumor in China, with most patients diagnosed at an advanced stage and poor prognosis, resulting in a median overall survival of approximately 12 months. Although targeted therapies have significantly improved outcomes for certain patient populations, the traditional binary classification of HER2 as 'positive/negative' based on protein expression and gene amplification can no longer meet current precision medicine needs. The current research bottleneck for HER2 lies in tumor heterogeneity, dynamic evolution, and primary or acquired resistance to targeted therapies, which prevent some patients from benefiting from standard treatments. Additionally, traditional tissue biopsies are limited by spatial and temporal heterogeneity, making it difficult to fully reflect the tumor's molecular profile. The key innovation of this guideline is the integration of clinical data from novel detection technologies (e.g., liquid biopsy) and next-generation targeted agents (e.g., antibody-drug conjugates, ADCs), proposing a four-tier HER2 expression classification (high, intermediate, low, and null), thereby expanding the eligible population for HER2-targeted therapy and optimizing treatment pathways. This strategy not only challenges the traditional definition of HER2-positivity but also provides a theoretical foundation for future precision interventions based on expression density gradients.
Research Methods and Experiments
The authors conducted a systematic evaluation of existing clinical evidence using the GRADE system, integrating key clinical trial data including ToGA, KEYNOTE-811, DESTINY-Gastric01, and RC48-C008, and combined with epidemiological characteristics of the Chinese population, established a HER2 testing and treatment recommendation pathway tailored for Chinese patients. The study employed a multidisciplinary collaboration model involving pathologists, oncologists, and molecular diagnosticians to develop standardized IHC and FISH testing protocols, and proposed strategies for utilizing liquid biopsy when tissue samples are unavailable. By analyzing clinical features and treatment responses across different HER2 expression subgroups, the study clarified the differential efficacy of ADCs in HER2-intermediate and HER2-low expressing populations, supporting a continuous target density model.Key Conclusions and Perspectives
Research Significance and Prospects
The release of this guideline marks a new era in precision therapy for gastric cancer, transitioning from single-target detection to multidimensional dynamic assessment. Its impact on drug development includes accelerating the development of ADCs targeting HER2-low and HER2-intermediate tumors, and promoting dose-optimization studies based on target density. In clinical monitoring, the guideline emphasizes the importance of liquid and repeat biopsies, enabling real-time adjustment of treatment strategies. For disease modeling, the classification system provides reference standards for constructing PDX or genetically engineered mouse models that better reflect clinical heterogeneity, such as using HER2 point mutations or low-expression transgenic mice to simulate different expression gradients.
Conclusion
This guideline provides an authoritative, systematic, and up-to-date clinical pathway for HER2-targeted therapy in Chinese gastric cancer patients. By introducing a four-tier HER2 classification system, it not only redefines the treatable population but also expands the application boundaries of ADCs, enabling more patients to benefit from precision therapy. The guideline emphasizes the importance of standardized testing, heterogeneity management, and dynamic monitoring, bridging translational research between laboratory and clinical practice. From bench to bedside, this study lays the foundation for a treatment ecosystem covering the full spectrum of HER2 expression, driving a paradigm shift from 'one-size-fits-all' to 'continuous spectrum' therapy. In the future, integrating single-cell sequencing, organoid models, and AI-assisted pathological analysis may further refine the functional status of HER2, enabling truly individualized interventions and ultimately improving long-term survival and quality of life for gastric cancer patients.
