Abstract Background: The incidence of central nervous system (CNS) metastases in breast cancer is increasing. While local treatments such as surgery and radiation remain standard, systemic therapies have shown promise in HER2-positive disease. However, data on the efficacy of systemic therapy in HER2-low breast cancer with CNS involvement remain limited. This study describes outcomes of upfront systemic therapy in HER2-low breast cancer patients with CNS metastases treated at a single institution. Methods: We retrospectively reviewed breast cancer patients with CNS metastases treated at Henry Ford Health between Jan 2014 and July 2024. HER2-low status was defined as: HER2 immunohistochemistry 1+, or 2+ with negative fluorescent in situ hybridization (FISH). Eligible patients received no concurrent local CNS therapy; prior local treatment was permitted if unrelated to the studied lesions. CNS responses were to be assessed using the Response Assessment in Neuro-Oncology for brain metastases (RANO-BM) or the modified RANO-LM (leptomeningeal metastases) criteria. Results: Sixteen HER2-low patients were included. The median age was 56 years (range, 38-93); 63% (n = 10) were African American. Most (75%) had hormone receptor-positive disease, and 53% presented with de novo metastatic disease. Thirteen patients (81%) had HER2 IHC 1+, and only three had HER2 IHC 2+/FISH-negative disease. The majority (88%) had parenchymal CNS metastases; one patient had leptomeningeal disease, and one had both. Eight patients (50%) had prior CNS metastases, and 38% received local therapy before study inclusion. Notably, a significant proportion of patients (88%) had non-measurable disease by RANO-BM criteria (lesions 10 mm), with 69% having lesions smaller than 5 mm. Systemic therapies for the CNS disease included cytotoxic chemotherapy in seven patients (44%), trastuzumab deruxtecan (T-DXd) in four (25%), abemaciclib in two (13%), other CDK4/6 inhibitors in two (13%), and sacituzumab govitecan in one (6%). Commonly utilized chemotherapy included taxanes (paclitaxel or nab-paclitaxel) in 4 of 7 patients. In the 16 patients, the overall response rate (ORR) was 31.3%, the disease control rate (DCR) was 56.3%, the median duration of response (DOR) was 7 months, and the median progression-free survival (PFS) was 2 months. In a comparison cohort of HER2-positive patients (n=17), ORR was 53%, DCR was significantly higher at 94% (p=0.017), with similar DOR (5 months), and numerically longer PFS (3 months, p=0.351). Outcomes among the African American patients (n=10) mirrored the overall HER2-low group, with ORR 30%, DCR 50%, DOR 5 months, and PFS 1 month. Notably, the patients with HER2 IHC 2+ tumors (n=3; all HR+) experienced higher benefit (ORR 67%, DCR 100%) with no disease progression at last follow-up. HER2-low patients treated with T-DXd (n=4) demonstrated a DCR of 75%, with only one progression. Chemotherapy yielded a poor ORR of 29%, though two patients achieved complete CNS responses with taxane-based regimens. Conclusion: This “real-world” experience highlights modest intracranial activity of systemic therapy in HER2-low breast cancer with CNS metastases. Although response rates were lower than in HER2-positive counterparts, HER2 2+ tumors and patients treated with T-DXd showed encouraging outcomes. These findings support the need for prospective studies focusing on HER2-low CNS disease and suggest T-DXd as a promising therapeutic option, even in the absence of concurrent local treatment. Additionally, our study underscores a unique challenge in the management of breast cancer and brain metastases: CNS lesions are often smaller than the 10 mm threshold typically required for clinical trial eligibility, necessitating special attention and adapted approaches for response assessment. Citation Format: B. Ghimire, L. Rogers, M. Girgis. Efficacy of systemic therapy in HER2-low breast cancer with CNS metastases: a “real-world” experience 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 PS5-05-28.
Ghimire et al. (Tue,) studied this question.