| Sumario: | Simple Summary: Gastric cancer remains difficult to treat, especially when it has spread. A protein called Claudin18.2 is found on many stomach cancer cells and is being studied as a possible target for new drugs. This study looked at 189 patients with HER2-negative gastric cancer to understand whether Claudin18.2 could also help predict how well patients respond to a common treatment: chemotherapy combined with immunotherapy. We found that tumors with Claudin18.2 had lower levels of another protein called PD L1, which is linked to immunotherapy response. However, Claudin18.2 status did not affect treatment outcomes—patients with or without this protein had similar survival and response rates. These findings suggest that Claudin18.2 is more useful as a direct drug target rather than as a test to guide immunotherapy choices. This study aimed to characterize claudin 18.2 (CLDN18.2) expression in HER2-negative gastric or gastroesophageal junction cancer (GC/GEJC) and to evaluate whether CLDN18.2 status is associated with clinicopathological features and outcomes after first line chemoimmunotherapy. We retrospectively analyzed 189 patients with HER2-negative GC/GEJC treated at our institution from October 2019 to September 2024. CLDN18.2 expression was assessed by immunohistochemistry using two prespecified positivity thresholds: moderate to strong membranous staining (2+) in ≥40% or ≥75% of tumor cells. CLDN18.2 positivity was observed in 92/189 patients (48.7%) using the ≥40% threshold and 69/189 (36.5%) using the ≥75% threshold. PD L1 CPS ≥ 5 was less frequent in CLDN18.2 positive than in CLDN18.2 negative tumors at both thresholds (≥40%: 8.7% vs. 23.7%, p = 0.003; ≥75%: 8.7% vs. 20.8%, p = 0.019). Among 87 patients receiving first line chemoimmunotherapy, CLDN18.2 status was not associated with significant differences in objective response rate, progression free survival, or overall survival. CLDN18.2 positive tumors showed lower PD L1 expression, but CLDN18.2 status did not identify a subgroup with differential benefit from first line chemoimmunotherapy. These findings suggest that CLDN18.2 status does not appear to serve as a predictive biomarker for immune checkpoint inhibitor-based treatment.
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