Abstract P1-02-26: Biomarkers in metastatic breast cancer with brain metastases – a subanalysis of matched tumor samples of the BMBC registry

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Abstract Background: The incidence of brain metastases (BM) from primary breast cancer (BC) increased over the past decades. Despite the increasing incidence of BM in BC, the biology and development of BM are still poorly understood. Therefore, it is crucial to understand the pathogenesis of BM development in order to find prophylactic and therapeutic approaches. The Brain Metastases in Breast Cancer Registry (BMBC) has collected clinical data of more than 4000 BC pts. with BM and tumor tissue samples (n= 400). Methods: For this study, gene expression data (HTG EdgeSeq Oncology Biomarker Panel) was generated from BM and the corresponding primary BC tissue samples (n= 76), followed by differential gene expression analysis. Molecular subtypes were classified according to classical IHC (ultralow, 0, 1+, 2+, 3+) based on HER2 protein overexpression and additionally Absolute Intrinsic Molecular Subtyping (AIMS) was assessed using HTG data. Results: In total 76 corresponding BM and primary BC tissue samples were included in this analysis. Median age at BM diagnosis was 55 years. 50% of the patients had singular BM, 27.6% 2-3 BM and 22.4% >=4 BM. 46.7% were HER2-pos., 17.3% triple-negative and 36.0% ER-positive. Subtypes according to AIMS in BC were 35.5% HER2-pos., 27.6% lum. A, 17.1% lum. B, 14.5% basal-like and 5.3% normal-like. Distribution of AIMS subtypes in the corresponding BM were 43.4% HER2-pos., 11.8% lum. A, 22.4% lum. B, 21.1% basal-like and 1.3% normal-like. Following AIMS switches could be identified from BC to BM: Lum. A BC switches to lum. B and HER2-pos. BM; primary normal-like BC switch to lum. A, HER2-pos. and basal-like BM; primary lum. B BC switch to HER2-pos., normal-like, lum. A BM; primary HER2-pos. BC switch to lum. B and basal-like BM. There were no AIMS switches detected in basal-like BC to BM. AIMS subtypes in BC and BM were not statistically associated with overall survival in patients with metastatic BC and BM (primary BC p= 0.13; BM p= 0.19). HER2 IHC in primary BC were: 7.1% ultralow, 44.6% IHC 0, 16.1% 1+, 32.1% 3+. HER2-IHC in BM were: 12.5% ultralow, 37.5%, IHC 0, 14.3% 1+, 5.4% 2+ and 30.4 % 3+. HER2 switches from primary BC to BM were detected as following: ultralow to IHC 1+, 0, ultralow; IHC 0 to ultralow, 1+ and 0; IHC 1+ to ultralow, 0, 1+, 2+ and 3+; IHC 3+ to 1+, 2+ and 3+. HER2 status was not statistically associated with OS in BC and BM (Primary BC p= 0.42 and BM p= 0.46). Among the significantly upregulated genes (logFC > 0.58) in BMs in comparison to primary tumors heat shock proteins (HSPA1B), mitochondria-related genes (COX5 and MRPL13) as well as cell cycle-related factors (CDC20, CCNF and PTTG1) were detected. Conclusions:Our analysis identified AIMS subtype and HER2 IHC classification switches from primary BC to BM in matched pairs that could be relevant for prognosis and treatment decisions. In addition, our preliminary differential gene expression analyses showed clear differences in various cellular processes between BC and BM tissues. Whether these differences reflect a selection process or rather an adaptation mechanism to a new environment remains to be investigated. Citation Format: Elena Laackmann, Kerstin Riecke, Sivaramakrishna Rachakonda, Volkmar Müller, Isabell Witzel, Marcus Schmidt, Klaus Junker, Peter A. Fasching, Mustafa Aydogdu, Leticia Oliveira-Ferrer, Paul Jank, Kristina Lübbe, Maria M. Karsten, Thomas Karn, Patricia von Kroge, Julia Teply-Szymanski, Thomas Decker, Martin Peters, Akira Hattesohl, Marion van Mackelenbergh, Marc Thill, Uta Ringsdorf, Anika Pehl, Christoph Mundhenke, Tanja Fehm, Julia Rey, Bärbel Felder, Sibylle Loibl, Carsten Denkert, Elena Laakmann. Biomarkers in metastatic breast cancer with brain metastases – a subanalysis of matched tumor samples of the BMBC registry [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-02-26.

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