Abstract PS5-02-19: Impact of HER2 kinase domain mutations on trastuzumab deruxtecan efficacy in HER2 low metastatic breast cancer

Abstract PURPOSE: In metastatic breast cancer (MBC) treatment, HER2 expression is a key factor in determining the indication for trastuzumab deruxtecan (T-DXd). While HER2 mutations have been identified as therapeutic biomarkers for T-DXd in several solid tumors, their clinical relevance in breast cancer has received little attention. Consequently, the impact of HER2 mutations on the efficacy of T-DXd in MBC remains unclear. METHODS: We retrospectively examined 25 Japanese women with HER2-low MBC treated with T-DXd from January 2022 to October 2024. Tumor tissue from primary or metastatic sites was analyzed for four HER2 kinase domain mutations (L755S, D769Y, V777L, and V842I) using droplet digital PCR. These mutations were selected for their potential functional relevance in solid tumors based on recent studies. Treatment efficacy was assessed by time to treatment discontinuation (TTD), and its association with each mutation was examined. Subgroup analysis was performed based on the number of mutations (single vs. multiple). Results: Clinicopathological characteristics are summarized in the Table. The frequencies of the four HER2 kinase domain mutations were as follows: L755S (64%), D769Y (32%), V777L (8%), and V842I (92%), with notable variation by mutation site. Tumors harboring D769Y tended to have a higher Ki67 labeling index (p = 0.027), suggesting increased proliferation activity. Patients with the L755S mutation had a shorter median TTD than those without the mutation (32 vs. 41 weeks), suggesting a potential association with reduced sensitivity to T-DXd. No apparent differences in TTD were observed for D769Y, V777L, or V842I mutations. Patients with multiple (≥ 2) mutations had a significantly shorter median TTD than those with a single mutation (30 vs. 52 weeks). CONCLUSION: Specific HER2 kinase domain mutations may influence the response to T-DXd in HER2-low MBC. This is the first study to report the frequencies of these four mutations and to assess mutation-specific differences in treatment duration using real-world data. Citation Format: Y. Horimoto, M. Oshi, A. Yamada, Y. Ueki, R. Semba, R. Wu, H. Kusama, T. Kawate, F. Murakami, T. Ishikawa, G. Kutomi, J. Watanabe. Impact of HER2 kinase domain mutations on trastuzumab deruxtecan efficacy in HER2 low metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-02-19.