Efficacy of systemic therapy in breast cancer with CNS metastases: “Real-world” experience.

2025 Background: The incidence of CNS metastases in breast cancer is rising. While local therapies such as surgery and radiation remain standard, data on upfront systemic therapies for active brain metastases, especially HER2-negative patients, is limited. This study examines upfront systemic therapy efficacy for CNS metastases in breast cancer patients at a single institution, including a majority African American (AA) population. Methods: A retrospective chart review included breast cancer patients with CNS metastases treated at Henry Ford Health (January 2014–July 2024). Eligible patients had not received concurrent local therapy; prior local therapy was permitted if unrelated to the studied lesions. CNS response was to be assessed using RANO-BM (defines measurable disease as lesions > 10 mm) for parenchymal and modified RANO-LM criteria for leptomeningeal disease (LMD). Results: Among 35 patients (20 AA, 13 Caucasian), with a median age of 54 years, HER2-positive was the most common receptor type (49%), followed by HR-positive (37%) and triple-negative (14%); nearly half (46%) had HER2-low disease. Parenchymal metastases were predominant (86%); three had co-existing LMD, and two others had only LMD. Most metastases were multiple; 91% had lesions < 10 mm. 43% had prior WBRT or SRS to unrelated lesions. HER2-positive patients had the highest CNS overall response rate (ORR, 53%) and disease control rate (DCR, 94%), followed by HR-positive (ORR 31%, DCR 69%) and triple-negative (ORR and DCR 20%). Median PFS did not significantly differ between receptor groups (p = 0.130). Trastuzumab-deruxtecan (T-Dxd) was the most common regimen (10/35) and within HER2-positive and HR-positive groups. T-Dxd achieved CNS ORR of 60%, DCR of 90%, and median PFS of 16 months. Tucatinib-based regimens showed a 100% DCR with median PFS of six months. Other therapies, including sacituzumab, abemaciclib, and trastuzumab-emtansine, showed stable disease as the best response. Among AAs, HR-positive was the most common receptor type (50%). These patients had ORR of 35% and DCR of 65%. T-Dxd maintained ORR of 60% and DCR of 80%. Of five patients with LMD, three were HER2-positive, and two were HR-positive, with an ORR of 60%, and DCR of 80%. Conclusions: This “real-world” experience highlights that, at our institution, most patients with breast cancer and CNS metastases considered for upfront systemic therapy lack measurable disease (91% having lesions < 10 mm) typically required for clinical trials. Nonetheless, the response rate aligns with published experiences. In addition, we included patients with LMD, who are often excluded in trials. Our data also suggests impressive CNS responses with T-Dxd, both overall and in AA patients. The management of brain metastases and LMD in these patients is best approached in a multidisciplinary format.