Abstract Background: In the DESTINY-Breast12 trial, individuals with HER2-positive (HER2+) metastatic breast cancer (mBC) who received trastuzumab deruxtecan (T-DXd) had similar progression-free survival (PFS) regardless of the presence of brain metastases (BrM). We sought to evaluate time to treatment discontinuation or death (TTD), time to next treatment (TTNT; a surrogate for PFS), and overall survival (OS) using real-world data to assess patients (pts) outside of a clinical trial setting for both HER2+and HER2-low mBC. Methods: We used the Integra Connect PrecisionQ real-world de-identified electronic health record database of 3 million cancer pts across 500 sites of care to identify 374 HER2+ mBC pts and 512 HER2-low mBC pts for the analysis. Eligible pts were adults with HER2+ or HER2-low mBC with ≥2 documented visits who initiated T-DXd between 1-1-2020 and 5-31-2024, with observation through 11-30-2024. The index date was the initiation of T-DXd. Documentation of BrM was determined at or prior to index date. Patient data included structured data supplemented with data obtained via chart abstraction. TTD, TTNT, and OS by documentation of BrM were analyzed using Kaplan-Meier analysis. Unadjusted hazard ratios (HR) were estimated using Cox proportional hazard models. Results: A total of 374 HER2+ pts were identified, including 94 with documented BrM and 280 without. The median age at index was 62.5 (interquartile range IQR 54, 71) years. A total of 512 HER2-low pts were identified, 80 of whom had documented BrM and 432 of whom did not. The median age at index was 65 (IQR 56, 71) years. Pts with HER2+ mBC did not have statistically significant differences in median TTD, TTNT, or OS regardless of the presence of BrM. However, pts with HER2-low mBC without BrM had significantly longer median TTD (5.5 months vs. 3 months, logrank p=0.002), TTNT (7.2 months vs. 5.8 months, logrank p=0.002), and OS (15.8 months vs. 10.2 months, logrank p0.001) compared to those with BrM. Conclusions: This real-world comparison of T-DXd treatment reaffirmed findings from DESTINY-Breast12 in which PFS did not differ among HER2+ mBC pts based on the presence of BrM. While this study showed significantly longer median TTD, TTNT, and OS in HER2-low mBC pts without BrM compared to those with BrM, further research and larger samples sizes are needed to understand how the line of therapy for T-DXd impacts these findings. Citation Format: V. Gorantla, R. Choksi, F. Kudrik, S. Reddy, S. Reganti, S. Rosenfeld, G. Cioffi, D. Parris, A. Rui, M. Gart, C. Wall, B. Wang, P. Varughese, J. Donegan, L. Morere, R. Geller, J. Scott, D. Patt. Real-world comparison of trastuzumab deruxtecan treatment outcomes in HER2-positive or HER2-low metastatic breast cancer patients with and without brain metastases 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 PS5-05-19.
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