Abstract 3341: The co-expression and prognostic significance of the HER-family members, EGFRvIII, CD44, CD109 and Claudin 18.2 in patients with stomach adenocarcinoma

Abstract Stomach cancer remains a major cause of death worldwide. While targeted therapies with anti-HER2 monoclonal antibodies (mAbs) such as trastuzumab, antibody-drug-conjugate trastuzumab deruxtecan, and more recently zolbetuximab, an anti-claudin 18.2 (CLDN 18.2) mAb, have been approved for the treatment of stomach cancer, many patients may not respond or have a response of short duration to such treatments. Therefore, there is an urgent need for identification of novel biomarkers for the response to therapy, and the development of more effective therapeutic interventions. In the past few decades, the crosstalk between the HER-family and other biomarkers such as cancer stem cells have been proven to promote tumorgenicity, metastasis and resistance to anti-HER2 therapy. Therefore, in this study, for the first time, we examined the relative expression levels, and prognostic significance of all members of the HER-family, the type-III EGFR mutant (EGFRvIII), CD44, CD109, and CLDN 18.2 in patients with stomach cancer by immunohistochemistry. The staining was scored at different cut off values (i.e. >5%, 10%, 20% and 50% of tumours with positive staining), the cellular location, and the intensity of staining. In addition, the prognostic significance of the expression and co-expression of these biomarkers were also investigated. We found the expression of wild-type EGFR (12.8%), HER2 (82.1%), HER3 (9.0%), HER4 (33.3%), EGFRvIII (33.3%), CD44 (41.0%), CD109 (60.3%) and CLDN 18.2 (39.7%) in tumour specimens from 78 patients. Furthermore, the expression of HER2 was accompanied with the co-expression of EGFR (9%), HER3 (8%), HER4 (27%), EGFRvIII (28%), CD44 (33%), CD109 (49%) and CLDN18.2 (32%) in the cases examined respectively. [SK1] [SK2] Interestingly, at a cut-off value of >5% of tumour cells with positive staining, the co-expression of HER2/EGFRvIII (7.26 vs 4.43 years, P=0.028), EGFRvIII/CD44 (7.02 vs. 2.17 years, P=0.003) HER2/EGFRvIII/CD44 (6.93 vs. 2.33 years, P=0.011), and CD109/CLDN 18.2 (7.01 vs 3.99 years, P= 0.021) were associated with a poorer overall survival. Moreover, the membranous expression of CD109 (7.06 vs. 3.93 years, P=0.028), and its co-expression with EGFRvIII/CD44 were also associated with a poorer overall survival (7.01 vs 1.65 years, P=0.0009) and a higher risk of poor overall survival [SK3] (HR=4.21, P=0.0009) as well as CLDN 18.2 immunostaining of intensity of 3+ (6.83 vs. 3.50 years, P=0.032). All these remained as independent prognostic factors for overall survival in multivariate analysis. Taken together, our results suggest co-expression of HER-2 with other members of the HER family, EGFRvIII, CD44, CD109 and CLDN 18.2 occurs in patients with stomach cancer and warrants further investigation on the predictive value of such biomarkers for the response to therapy with inhibitors to HER family members and CLDN 18.2. Citation Format: Tina Al-Janaby, Izhar Bagwan, Said Khelwatty, Helmout Modjtahedi. The co-expression and prognostic significance of the HER-family members, EGFRvIII, CD44, CD109 and Claudin 18.2 in patients with stomach adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3341.