Editor’s Note: The “2024 CSCO Gastric Cancer Expert Committee Academic Annual Meeting,” hosted by the Beijing Hiskey Clinical Oncology Research Foundation, CSCO Gastric Cancer Expert Committee, and Hangzhou Oriental Clinical Oncology Research Center, was held in Beijing. Renowned experts gathered to discuss the latest advances, challenges, and opportunities in gastric cancer diagnosis and treatment, aiming to drive progress in gastric cancer prevention and care. At the meeting, Dr. Rongbo Lin from Fujian Cancer Hospital delivered an insightful presentation titled “Clinical Pathology and Molecular Features of New Targets in Gastric Cancer.” Below is a summary of the key content.Advances in Molecular Subtyping of Gastric Cancer
As research progresses, gastric cancer studies have transitioned from traditional histological classifications, such as Lauren and WHO classifications, to molecular subtyping, notably the TCGA and ACRG classifications. The Cancer Genome Atlas (TCGA) identifies four molecular subtypes of gastric cancer (GC): Epstein-Barr virus-positive (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN).
Despite its heterogeneity, molecular subtyping of gastric cancer is still in its early stages, requiring further exploration of the mechanisms underlying its development. Beyond the key signaling pathways highlighted in TCGA, other dysregulated pathways, such as MAPK, HER2, PI3K/AKT/mTOR, HGF/c-Met, FGF/FGFR, HIF-1α, CLDN18.2, p53, Wnt/β-catenin, NF-κB, PDL-1/PD-1/CTLA-4, MSI-H, and TGF-β, also play pivotal roles in gastric cancer pathogenesis. Understanding these pathways provides critical insights into tumor mechanisms and potential avenues for targeted therapy.
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Clinical, Pathological, and Molecular Characteristics of New Targets in Gastric Cancer
CLDN18.2
CLDNs are integral components of tight junctions, regulating epithelial permeability, barrier function, and polarity. In normal gastric epithelial cells, CLDN18.2 is sequestered within tight junction complexes. However, during malignant transformation, disruptions in cell polarity and structural changes expose CLDN18.2 on the surface of G/GEJ adenocarcinoma cells, making it an accessible and promising therapeutic target.
The SPOTLIGHT and GLOW studies reported effective CLDN18.2 IHC results in 4,507 patients, revealing high expression (≥75% of tumor cells with strong CLDN18.2 membrane staining) in 1,730 patients (38.4%). The prevalence of high CLDN18.2 expression ranged from 24% to 44% across different regions.
A retrospective study in Japan analyzed 408 gastric cancer cases, identifying 98 (24.0%) as CLDN18.2-positive. The study found no significant differences in CLDN18.2 positivity rates among the four molecular subtypes or correlations with biomarkers such as HER2, PD-L1, and MSI-H/dMMR. Additionally, studies indicate that CLDN18.2 is not a prognostic biomarker for overall survival (OS) in advanced G/GEJ adenocarcinoma, irrespective of treatment.
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CLDN18.2 and Immunotherapy Outcomes
Research suggests a complex relationship between CLDN18.2 expression and immunotherapy outcomes. A retrospective analysis of 536 advanced gastric cancer patients enrolled in the CT041-CG4006 and CT041-ST-01 trials (2019–2021) used two CLDN18.2 positivity thresholds: ≥40% tumor cells (2+, 40%) and ≥70% tumor cells (2+, 70%). Findings revealed that patients with CLDN18.2-positive tumors had shorter OS. First-line treatment in CLDN18.2-positive patients showed no significant progression-free survival (PFS) difference between chemotherapy alone and chemotherapy plus immune checkpoint inhibitors (ICI). Furthermore, CLDN18.2 positivity and treatment line were identified as adverse factors for irPFS in multivariate analyses.
Another study involving 80 gastric cancer patients, 60 of whom received anti-PD-1/PD-L1 therapy, demonstrated poor predictive value of CLDN18.2 expression for treatment response. However, negative prognostic effects on irPFS (P=0.068) and irOS (P=0.044) were observed, suggesting that CLDN18.2-positive gastric cancer may exhibit a “cold” immune phenotype with limited immune cell infiltration and an immunosuppressive tumor microenvironment. This highlights CLDN18.2’s role in shaping tumor immune landscapes and influencing immunotherapy responses.
Despite these findings, further research is needed to elucidate the mechanisms behind these associations and their implications for gastric cancer management.
FGFR (Fibroblast Growth Factor Receptor)
FGFR proteins, part of the receptor tyrosine kinase family, include FGFR1, FGFR2, FGFR3, and FGFR4. Oncogenic signaling via the FGFR pathway contributes to multiple cancers, including gastric and cholangiocarcinomas. FGFR2 amplification is the most common FGFR alteration in gastric cancer, leading to FGFR2 protein overexpression and pathway activation. Depending on the scoring methods and definitions used across studies, FGFR2b overexpression rates range from 4% to 51.3%. Standardized criteria for FGFR2 overexpression and amplification remain undefined.
A meta-analysis involving eight studies and 2,377 patients evaluated the clinical and pathological impact of FGFR2 amplification in gastric cancer. Results indicated:
- A significantly higher lymph node metastasis rate in FGFR2-amplified tumors (OR=3.93, P<0.00001).
- Strong correlation between FGFR2 amplification and poorly differentiated or undifferentiated adenocarcinomas (OR=2.36, P=0.04).
- Poor survival outcomes for FGFR2-amplified gastric cancer patients (HR=2.09, 95% CI: 1.68–2.59, P<0.00001).
A single-center study in Japan analyzed 547 gastric/GEJ cancer samples, highlighting the clinical and molecular characteristics of FGFR2b expression. Approximately 30% of tumors exhibited FGFR2b expression at any 2+/3+ level, with 44.4% lacking other actionable biomarkers such as HER2, PD-L1, MMR, or CLDN18.2, suggesting these patients may not benefit from currently approved targeted therapies.
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MET (Mesenchymal-Epithelial Transition Factor)
The MET proto-oncogene encodes the c-MET protein, which binds to hepatocyte growth factor (HGF). Aberrant activation of the MET pathway drives tumorigenesis across several cancers, including gastric, lung, and hepatocellular carcinomas. MET pathway alterations include MET gene mutations, amplifications, and protein overexpression.
Positive rates for MET amplification in gastric cancer, as detected by FISH, range from 1.5% to 8.3%, while MET protein overexpression detected by IHC varies between 26% and 82%.
A study involving 168 gastric cancer patients revealed that MET amplification correlates with Lauren classification, with higher amplification rates in diffuse-type than intestinal-type tumors (15% vs. 2%, P=0.04). However, Lauren classification showed no significant correlation with MET protein expression.
A meta-analysis of 14 studies encompassing 2,258 patients assessed MET amplification and overexpression as prognostic factors for overall survival (OS). Results indicated:
- MET amplification increased the risk of death (HR=2.82, 95% CI: 1.86–4.27).
- MET overexpression also correlated with poor prognosis (HR=2.57, 95% CI: 1.97–3.35).
Studies suggest potential interactions between MET, HER2, and PD-L1. In a cohort of 313 patients stratified by HER2 and MET positivity, MET positivity was significantly higher in HER2-positive patients than HER2-negative ones (60% vs. 36%, P=0.03). Another study of 816 patients showed a trend toward higher MET overexpression rates in HER2-positive tumors (9.7% vs. 5.1%, P=0.164). MET is believed to regulate PD-L1 expression via the AKT-dependent pathway, with c-MET and PD-L1 protein expressions showing significant positive correlations (n=355, χ²=9.363, P=0.002). These findings suggest that MET may influence immune evasion and immune homeostasis through PD-L1 regulation.
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Summary and Outlook
Beyond established biomarkers, many genes and pathways, such as CLDN18.2, FGFR2, and MET, play critical roles in gastric cancer pathogenesis.
- CLDN18.2: As a new predictive biomarker, it has gained recognition in the latest domestic and international guidelines. Despite its high prevalence in gastric cancer (38%), CLDN18.2 overlaps minimally with existing biomarkers. While its expression does not affect chemotherapy prognosis, CLDN18.2-positive gastric cancers often exhibit a “cold” immune phenotype with limited immune cell infiltration, reducing immunotherapy efficacy. Further research is needed to explore its prognostic implications and underlying mechanisms.
- FGFR2 and MET: Both alterations are negatively associated with survival outcomes in gastric cancer and exhibit minimal overlap with other biomarkers. FGFR2 amplification/overexpression correlates with aggressive clinical features, while MET expression potentially interacts with HER2 and PD-L1 to drive tumor progression and immune evasion.
Ongoing research into these targets will provide new strategies and directions for personalized treatment in gastric cancer, ultimately improving patient outcomes.
