Abstract 484P
Background
Claudin 18.2 (CLDN18.2) overexpression has recently emerged as a therapeutic target in advanced GEC. CLDN18::ARHGAP fusions are pathognomonic for GEC, but their biologic relevance in this malignancy is poorly understood. We analyzed the correlation of CLDN18::ARHGAP fusions with other molecular parameters, patient characteristics, and clinical outcomes in a large clinico-genomic database.
Methods
DNA and RNA (whole transcriptome) sequencing was performed for patient tumor samples submitted to Caris Life Sciences. CLDN18::ARHGAP fusions were identified from RNA transcripts. CLDN18 (43-14A; ≥2+, ≥75%) and HER2 (4b5; ≥3+, ≥10%) protein levels were determined by IHC. TMB-High (TMB-H) was defined as ≥10 mutations/Mb. Significance was tested using Mann-Whitney, Fisher’s Exact, or Chi-squared tests. Real-world overall survival (OS) was obtained from insurance claims data and calculated from collection date to time of last contact; associated hazard ratios (HR) and p-values were calculated using the Cox proportional hazard model.
Results
Among 4430 GEC cases, 262 patients (5.9%) harbored a CLDN18::ARHGAP fusion, primarily CLDN18::ARHGAP26(N=226). Fusion-positive patients were more commonly female (64% vs 41%, p<0.0001) and younger (median age=58 vs 66, p<0.0001), had more HER2 (9.7% vs 3.4%, p<0.0001) and HER3 (10.5% vs 3.8% p<0.0001) mutations, fewer RHOA (0% vs 7.5%, p<0.0001), CDH1 (3.9% vs 20.4%, p<0.0001), and KRAS (2.7% vs 10.0%, p=0.0001) mutations, and were less often TMB-H (4.8% vs 13.9%, p=0.0001) or dMMR/MSI-H (3.9% vs 9.5%, p=0.0021). There were no significant differences in HER2 or HER3 mRNA levels by fusion status, though fewer fusion-positive cases were HER2 IHC+ (2.7% vs 6.0%, p=0.0461). Median CLDN18.2 expression (22.0 vs 10.9 TPM, p<0.0001) and CLDN18 IHC+ status (79.6% vs 47.9%, p<0.0001) was higher in fusion-positive cases. There was no significant difference in median OS between fusion-positive and -negative cohorts (15.6 and 13.6 months, respectively, HR=0.893, p=0.1978).
Conclusions
CLDN18::ARHGAP fusions characterize GECs with distinct clinical and biologic features. Future studies will determine if these cancers can expand the pool of patients considered for CLDN18-targeted therapy.
Legal entity responsible for the study
West Cancer Center.
Funding
Caris Life Sciences.
Disclosure
A. Fifield, K. Sweeney, M. Oberley: Financial Interests, Personal, Full or part-time Employment: Caris Life Sciences. All other authors have declared no conflicts of interest.