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    Real-World Studies

    Molecular and Immunologic Profiling of HER2-Low Advanced Gastric Cancer

    Shin et alGastric Cancer

    Molecular and Immunologic Profiling of HER2-Low Advanced Gastric Cancer
    In a retrospective analysis of 1067 patients with advanced gastric cancer evaluated at Samsung Medical Center between October 2019 and March 2025, HER2-low disease accounted for 14.7% (n = 157) of cases, compared with 75.4% (n = 805) HER2-negative (IHC 0) and 9.8% (n = 105) HER2-positive (IHC 2+/ISH+ or IHC 3+) tumors. Patients underwent HER2 evaluation and targeted next-generation sequencing to assess genomic alterations, key biomarkers (PD-L1, MSI, EBV, CLDN18.2), and overall survival stratified by first-line treatment regimens.
    The analysis found that HER2-low tumors displayed an immune-active and distinct genomic profile, showing the highest frequency of PD-L1 expression (CPS ≥ 5: 60.1%) and MSI-H status (7.0%), as well as the lowest proportion of all-biomarker-negative cases. ERBB2 copy numbers followed a stepwise increase across the negative, low, and positive subgroups. HER2-low tumors were enriched for DNA damage repair (DDR) gene alterations, including BARD1 and SLX4, and possessed more frequent PI3K/AKT pathway alterations compared with HER2-positive tumors.
    In terms of clinical outcomes, HER2-low status showed no significant association with overall survival in patients treated with chemotherapy alone. In the cohort receiving chemotherapy plus an immune checkpoint inhibitor, median overall survival was 20.0 months in the HER2-low group compared with 16.9 months in comparator patients, which did not reach statistical significance (HR 0.83; p = 0.157). The authors concluded that HER2-low advanced gastric cancer appears to represent a biologically distinct subset marked by DDR alterations, PI3K/AKT activation, and an immune-active biomarker profile.

    Key Takeaways

    • In advanced gastric cancer, HER2-low tumors exhibited the highest rates of PD-L1 positivity (CPS ≥ 5: 60.1%) and MSI-H status (7.0%), alongside enriched DNA damage repair alterations (including BARD1 and SLX4) and more frequent PI3K/AKT pathway alterations than HER2-positive tumors.
    • First-line chemotherapy combined with immune checkpoint inhibitors was associated with a median overall survival of 20.0 months in HER2-low disease versus 16.9 months (HR 0.83; p = 0.157), reflecting a non-significant survival difference, while no survival association was observed in the chemotherapy-only cohort.
    Read the original sourceGastric Cancer