Abstract PO4-14-06: Impact of Serum HER2 Extracellular Domain in Metastatic Breast Cancer Patients Treated with Trastuzumab Deruxtecan (T-DXd)

Abstract Background: Trastuzumab deruxtecan (T-DXd) is a standard of care as 2nd line and after prior chemotherapy for HER2 positive and low metastatic breast cancer (MBC), respectively, based on Destiny Breast03 and 04 results. However, biopsies over time during treatment have shown that HER2 expression is variable. The predictive factors of trastuzumab deruxtecan (T-DXd) for MBC with HER2 positive and low are unclear. The HER2 extracellular domain (HER2-ECD) has been confirmed as a prognosis marker and predictive marker of treatment for HER2-positive MBC. Especially, HER2-ECD is considered a promising biomarker in cases where HER2 expression in metastases is unconfirmed. We hypothesized that HER2-ECD could serve as a biomarker for T-DXd. Patients and methods: A retrospective study of consecutively treated patients in a single center between 2019-2023 with HER2-low and HER2-positive MBC was performed using chart review. HER2 status was diagnosed according to 2020 ASCO-CAP guidelines. HER2-ECD high was defined as 15.0 ng/ml. HER2-ECD was collected prior to T-DXd treatment. We compared overall response (ORR), progression-free survival (OFS), overall survival (OS), and disease control rate (DCR) at HER2-ECD high and low groups. Cox regression analyses were performed to assess the ORR. We used the Kaplan-Meier method to estimate the PFS and OS and the log-rank test to compare each treatment group. Results: A total of 41 MBC patients were included in this study. Patients with HER-positive and HER2-low were 34 and 7, respectively. Among HER2 positive (n=34), HER2-ECD high and low are 14 (41%) and 20 (59%) patients, respectively. Among HER2 low (n=7), HER2-ECD high and low are 3 (43%) and 4 (57%) patients, respectively. Twenty-six patients received T-DM1 prior to T-DXd treatment for MBC with HER2 positive, but no patients received CPT-11 before T-DXd for MBC with HER2 positive and low. The ORR of T-DXd was 89% and 52% in the HER2-ECD high and low groups, respectively (p 0.001). All 6 cases with CR were HER2-ECD high. Among HER2 low group (n=7), ORR of T-DXd was 67% (2/3) and 25% (1/4) in HER2-ECD high and low groups, respectively. The median PFS in the HER2-ECD high group showed longer than the HER2-ECD low group, 21.8 vs. 8.0 months (HR 0.31; 95%CI, 0.13-0.78, p=0.012). Although there were no significant differences in OS, HER2 ECD high group tended to show longer OS (HR 0.23; 95%CI, 0.04-1.16, p=0.07). The DCR was 100% in the HER2 ECD high group and 87% in the low group. Conclusion: T-DXd showed significantly better response and prolonged PFS in the group with high HER2-ECD. HER2-ECD has the potential to become a biomarker for T-DXd. Further study is warranted to assess the HER2-ECD as a biomarker, especially for HER2 low MBC patients treated with T-DXd. Table. Association between the response and the HER2 status or HER2-ECD status Citation Format: Kazuki Nozawa, Maho Kusudo, Nari Kureyama, Akira Nakakami, Rie Komaki, Yuka Endo, Ayumi Kataoka, Haruru Kotani, Akiyo Yoshimura, Masaya Hattori, Masataka Sawaki, Hiroji Iwata. Impact of Serum HER2 Extracellular Domain in Metastatic Breast Cancer Patients Treated with Trastuzumab Deruxtecan (T-DXd) abstract. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-06.