PS2-05-19: Immuno- and Molecular-Profiling of Breast Cancer Metastasis in the CNS

Abstract Introduction: Breast cancer brain metastasis (BCBM) represents a significant clinical challenge with poor prognosis. Certain breast cancer subtypes, notably HER2-positive and triple-negative breast cancer (TNBC), are associated with a higher risk of brain metastasis. Understanding these unique properties, distinct from primary tumors, is crucial for therapeutic strategies. In this study, we aimed to characterize key biomarkers in BCBM to enhance understanding of their distinct molecular and immunological profiles. Methods: We retrospectively evaluated 36 intracranial BCBM from 36 patients for hormone receptor (ER/PR), HER2-status (including HER2-low and -ultra-low), proliferation (Ki-67), PD-L1 expression, tumor-infiltrating lymphocytes (TILs) as well as PIK3CA mutations. Biomarker frequencies were compared against published data from primary breast cancer cohorts (TCGA, METABRIC, SEER, KEYNOTE-355). Results: The BCBM cohort exhibited a significantly skewed subtype distribution compared to primary breast cancer. While primary breast cancer is predominantly HR+/HER2- (Luminal A/B HER2-) (approx. 74.4%), this subtype comprised only 16.7% (6/36) of our BCBM cases. Conversely, TNBC (44.4%, 16/36) and HER2-positive subtypes (38.9%, 14/36) were notably overrepresented in our cohort compared to their prevalence in primary breast cancer (approx. 11.4% and 14.2%, respectively). This significant difference suggests a differential propensity for brain metastasis among subtypes and is in line with previous findings. The overall mean Ki-67 was 42.6% and most cases (88.9%, 32/36) showed high proliferation (Ki-67 ≥ 20%), with 75.0% (27/36) demonstrating very high proliferation (Ki-67 ≥ 30%). Subtype-specific Ki-67 levels generally reflected the expected proliferative activity of corresponding primary breast cancer subtypes. PD-L1 expression (22C3, CPS ≥ 10%) was very low, found in only 2.8% (1/36) of cases. A slightly larger subset (8.3%, 3/36) met the IC positivity criterion (IC ≥ 1%) with SP142. This low prevalence of actionable PD-L1 expression in BCBM contrasts sharply with the higher rates observed in primary TNBC (e.g., 38% for CPS ≥ 10% in KEYNOTE-355). Furthermore, TILs were significantly lower compared to primary breast cancer and across all subtypes; only 5.9% cases had high TILs (>=60%) compared to the 19% for primary found in literature. This suggests a very different tumor microenvironment for metastasis to the CNS, with implications for immunotherapy efficacy. PIK3CA analysis revealed 20% (6/30) of cases with mutations and no significant deviation from the expected frequencies in respect of the molecular subtype. Conclusion: Our findings indicate that BCBMs exhibit a distinct molecular landscape characterized by an enrichment of TNBC and HER2-positive subtypes with high proliferation (Ki-67). PD-L1 expression and TILs appears to be markedly lower than in primary breast cancer, especially in TNBC. These insights highlight the unique biology of BCBM, emphasizing the need for biomarker analysis on metastatic tissue to guide personalized therapeutic strategies. Citation Format: N. Abele, M. Berner, R. Stöhr, H. Arndt, C. Mawrin, R. Erber. Immuno- and Molecular-Profiling of Breast Cancer Metastasis in the CNS [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 PS2-05-19.