Purpose: The presence of Her2 amplification is associated with an increased risk of developing brain metastases. Brain metastases in breast cancer can be particularly challenging and have significant implications for prognosis and treatment. Common Her2-targeted therapies and small tyrosine kinase inhibitors have demonstrated the ability to penetrate the blood brain barrier and be effective in treating brain metastases. We investigated the clinico-genomic characteristics and the prognosis of brain metastasis in patients with breast cancer. Experimental design: Patients with breast cancer whose tumors underwent targeted sequencing from 2013-2018 at age 56 years old or younger at three institutions from the American Association of Cancer Research Genomics Evidence Neoplasia Information Exchange Biopharma Collaborative (AACR Project GENIE BPC) registry were selected for data curation. The PRISSMM data model was used for real world outcomes including overall survival. We analyzed clinical and genomic characteristics, treatment, and clinical outcome data among patients with and without brain metastases, stratified by Her2 amplification and hormone-receptor status (Her2+ vs. Her2-/HR+ vs. triple-negative breast cancer (TNBC)). We explored the top 20 most frequently altered genes that were included on at least 20% of sequencing panels. Results: A total of 1019 patients with breast cancer along with their receptor subtype information were included in the study (110 patients were excluded due to either post- mortem sequencing or unknown receptor subtype). Among them, 336 (33%) patients were identified to have developed brain metastasis (n=87 with Her2+; n=181 with Her2-/HR+; and n=68 with TNBC). At time of advanced disease, the brain was the first and only distant site of disease in 41/336 (12%) and detected with extracranial sites of disease in 22/336 (7%) patients. For patients presenting with stage I-III breast cancer, the cumulative incidence of brain metastasis at 5 years from breast cancer diagnosis was higher in those with TNBC (35%; 95% CI: 25, 50) as compared to 24% (95% CI: 16, 37) and 21% (95% CI: 15, 29) for those with Her2+ and Her2-/HR+ subtypes, respectively. Median overall survival from brain metastasis was significantly longer (log-rank p<0.001) for those with Her2+ disease (19m, 95% CI: 13, 36) compared to those with Her2-/HR+ (8.9m, 95% CI: 6.3, 15) or TNBC (7.4m, 95% CI: 4.6, 11). Among patients who ever developed brain metastases, IKZF3 alterations occurred in 71% (20/28) of Her2+ patients but did not occur in either Her2- subtype. Additionally, frequencies of CDK12, MYC, and PTEN alterations differed across subtypes. Conclusions: Brain involvement at metastatic presentation conferred a higher risk of death than brain-sparing metastases. Triple negative and Her2+ histologies were associated with higher risk of brain involvement at metastasis presentation. Further exploration by treatment received across receptor subtypes and genomic alterations will be presented.

Citation Format: Samantha Brown, Hannah E. Fuchs, Jessica A. Lavery, Katherine S. Panageas, Nelson S. Moss. Clinico-genomic characteristics of breast cancer brain metastasis: A multi-institutional analysis from AACR Project GENIE BPC [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B004.