Abstract PS3-01-10: Patterns of metastasis according to germline BRCA1/2 mutation status in patients with HER2-negative metastatic breast cancer

Abstract Background: Germline pathogenic variants (PVs) in BRCA1/2 are found in approximately 5% of patients with breast cancer (BC) and are associated with different clinical characteristics and subtype distributions. BC exhibits subtype-specific patterns of metastasis according to hormone receptor (HR) and HER2 status. Although limited, existing evidence suggests that germline BRCA1/2 PVs may be associated with a higher frequency of metastasis to specific sites, such as the central nervous system (CNS). However, these findings are often confounded by differences in subtype distribution among BRCA1/2 PV carriers. In this study, we investigated the association between germline BRCA1/2 mutation status and the patterns and frequency of metastasis across BC subtypes. Methods: Patients treated for HER2-metastatic BC at Istituto Oncologico Veneto between 2007 and 2025 and with known germline BRCA1/2 mutation status were retrospectively identified. Data on metastatic sites at initial diagnosis of metastatic BC and throughout the disease course (last follow-up) were collected. CNS involvement was defined as the presence of either brain metastases or leptomeningeal disease. Overall survival (OS) was defined as the time from the first diagnosis of metastatic BC to death from any cause or last follow-up. Results: A total of 184 patients were identified: 33 BRCA1 PV carriers, 28 BRCA2 PV carriers, and 123 noncarriers. Overall, 131 patients presented a HR+ BC and 53 a triple negative BC (TNBC). TNBC was more frequent among BRCA1 carriers (n=21, 63.3%), while HR+ BCs were more common among BRCA2 carriers (n=23, 82.1%) and noncarriers (n=96, 78.0 %; p<0.001). At initial diagnosis of metastatic BC, BRCA1/2 carriers with a HR+ BC presented a lower incidence of bone metastases compared to noncarriers (31.4% vs 51.0%, p=0.046). In contrast, no differences in metastatic site distribution at first metastatic BC diagnosis were observed among patients with TNBC. Median follow-up from stage IV disease diagnosis was 80.7 months (95%CI 53.5-108.0). At last follow-up, BRCA1/2 carriers with a HR+ BC presented a higher incidence of CNS involvement compared to noncarriers (31.4% vs 14.6%, p=0.030). Among BRCA1/2 carriers with HR+ BC, CNS involvement appeared relatively early, with 23.4% cumulative incidence at 24 months as compared to 5.2% in noncarriers (Gray’s p=0.041). At last follow-up, among patients with TNBC, BRCA1/2 carriers presented a lower incidence of liver metastases compared to noncarriers (34.6% vs 70.4%, p=0.009), while no significant difference in terms of CNS involvement was observed, with high rates in both subgroups (57.7% vs 37%, p=0.219). No significant difference in terms of OS was observed between BRCA1/2 carriers and noncarriers, both among patients with HR+ BC (39.2 vs 47.6 months, respectively; p=0.246) and among those with TNBC (25.8 vs 15.8 months, respectively; p=0.467). Conclusions: Germline BRCA1/2 PV are associated with distinct metastatic patterns among patients with HER2-negative BC. In the HR+ disease, carriers had relatively fewer bone metastases at diagnosis and presented a higher risk of CNS involvement over time. These findings may inform tailored radiological surveillance strategies. Citation Format: M. Bottosso, G. Griguolo, L. Trovò, S. Tognazzo, G. Faggioni, E. Mioranza, G. Vernaci, D. Massa, V. Faso, D. Napetti, A. Menichetti, S. Zovato, M. Dieci, V. Guarneri. Patterns of metastasis according to germline BRCA1/2 mutation status in patients with HER2-negative 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 PS3-01-10.