Clinicopathologic and molecular features of Krukenberg tumors from gastric cancer (GC): A single-institution experience.

4043 Background: Krukenberg tumors (KTs), ovarian metastases most commonly arising from gastric adenocarcinoma, represent an aggressive and understudied metastatic phenotype, frequently associated with diffuse-type gastric cancer (GC). The molecular determinants underlying this metastatic pattern remain poorly characterized. We aimed to define the clinicopathologic and genomic landscape of GC-associated KTs. Methods: We conducted a retrospective review of 103 patients with metastatic gastric or gastroesophageal junction adenocarcinoma treated at City of Hope (2020–2025). Twenty-two patients with confirmed KTs were identified. Clinicopathologic data were extracted from electronic medical records. Next-generation sequencing (NGS) for KTs was performed on primary or metastatic tumor specimens. Survival outcomes were estimated using the Kaplan-Meier method, with progression-free survival (PFS) and overall survival (OS) reported with 95% confidence intervals (CIs). Results: The median age at diagnosis was 45 years (range, 30–64). HER2 positivity was infrequent (14%), and PD-L1 expression was heterogeneous across tumors. Genomic profiling demonstrated recurrent alterations in TP53 (53%), ARID1A (20%), CDH1 (13%), KRAS (13%), and PIK3CA (13%). Notably, 86.4% of KTs exhibited CLDN18.2 immunohistochemical expression > 75%, and 80% of patients had low PD-L1 CPS scores ( < 5). The CLDN18::ARHGAP26 fusion was detected in 30% of sequenced tumors, representing a highly recurrent structural alteration. Median PFS was 9 months (95% CI, 4–15), and median OS was 17 months (95% CI, 5–30). Conclusions: GC–associated KTs demonstrate a distinct molecular architecture enriched for diffuse-type genomic features, including frequent TP53 mutations and recurrent CLDN18::ARHGAP26 fusions, aligning with the poor prognosis observed in this cohort. Our findings establish CLDN18 fusions as a recurrent molecular hallmark of GC–associated ovarian metastases, providing novel clinicopathologic insight into mechanisms of ovarian metastatic tropism. Importantly, the high prevalence of CLDN18.2 protein expression identifies a biologically actionable therapeutic vulnerability. CLDN18.2-directed strategies may represent an effective biomarker-driven treatment approach capable of achieving disease control without reliance on surgical intervention. These data define a high-risk, biologically distinct metastatic phenotype and support precision-guided therapeutic targeting, in this clinically aggressive patient population.