Abstract 2111: Impact of HER2 Expression on trastuzumab deruxtecan(T-DXd) efficacy

Abstract Background: T-DXd is an FDA-approved anti-HER2 Antibody Drug Conjugate (ADC), which has shown clinical efficacy in breast cancers with either overexpression or low-level expression of HER2. The benefit of T-DXd across the spectrum of HER2 expression has called into question the relevance of HER2 expression level as relevant parameter for T-DXd sensitivity. We sought to experimentally address the relevance of HER2 expression level upon the degree of T-DXd response. Methods: A series of isogenic models was generated that expressed different levels of surface HER2 using a doxycycline-inducible promoter. These were analyzed for impact of differential expression level upon T-DXd internalization and drug response. Human breast cancer samples were analyzed for HER2 expression levels and association with clinical response to T-DXd under an IRB approved protocol. Results: Induction of different levels of HER2 at specified doxycycline concentrations was verified in multiple models using immunoblotting and FACS. These different levels appeared to correspond to clinical breast cancer immunohistochemistry (IHC) scoring levels to 0, 1+, 2+, and 3+. The models were analyzed for T-DXd response and showed increasing levels of HER2 led to increase lysosomal uptake of T-DXd (p0. 0001). Moreover, elevation of HER2 levels led to lower concentrations of T-DXd needed to suppress tumor growth. Analyses of the effects of increasing levels of HER2 upon xenograft response to T-DXd are ongoing. Finally, retrospective analyses of a cohort of 50 breast cancer patients treated with T-DXd revealed that higher levels of HER2 corresponded to longer time on treatment (time to progression). Conclusion: We observe a consistent relationship between elevated expression of HER2 and breast cancer response to T-DXd. The findings highlight the relevance of HER2 expression level as a biomarker of T-DXd response and support the potential value of therapeutic strategies that can induce HER2 surface expression levels to enhance response. Citation Format: Wanyi Chen, Joshua Drago, Avantika Gupta, Bo Liu, Sarat Chandarlapaty. Impact of HER2 Expression on trastuzumab deruxtecan (T-DXd) efficacy abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 2111.