Genomic biomarkers of CNS-specific outcomes in patients with breast cancer brain metastases.

2028 Background: The diagnosis of brain metastasis (BM) is a life- and prognosis-altering event for patients with breast cancer (BC). The standard of care for the management of limited BM remains ablation with stereotactic radiosurgery (SRS). There are no established genomic biomarkers to guide CNS-directed treatment among patients with breast cancer brain metastases (BCBM). Methods: We retrospectively reviewed clinical and genomic features of a cohort of patients who received SRS for newly diagnosed BCBM between 2010 and 2021 at Memorial Sloan Kettering Cancer Center (MSK). Next-generation genomic sequencing (NGS) was performed using the MSK-IMPACT assay, covering all exonic and selected intronic regions for up to 505 genes. Time-to-CNS progression (TTCP) and overall survival (OS) were analyzed using multivariable Fine-Gray and Cox proportional hazards models, respectively, adjusted for clinically relevant factors. Relevant clinical factors and genomic alterations present at an instance at 5% or greater were included in the univariate and multivariate analyses, completed for the overall cohort and BC receptor subtypes. Results: From 2010-2021, 260 patients were identified; 123 (47%), 74 (28%), and 63 (24%) patients had hormone receptor-positive (HR+), HER2+, and triple-negative (TN) disease, respectively. 116 (45%) patients had 1 BM and 184 (71%) patients had at least 1 BM greater than 1 cm in axial diameter. Median follow up for the overall cohort was 18 months (Interquartile range (IQR) 9, 36). Among patients who progressed, median TTCP was 6 (IQR 4, 13) and 6 (4, 13), 11 (5, 18), and 4(3, 8) months for the overall cohort, and HR+, HER2+, and TN subgroups, respectively. Median OS was 19 (95% CI 16, 23) and 15 (13, 21), 58 (39, --), and 13 (11, 20), for the overall cohort, and HR+, HER2+, and TN subgroups, respectively. In the overall cohort, shorter TTCP was associated with TN subtype, >5 BMs, and pathogenic alterations in MYC, AGO2, PTEN, AURKA, and NF1 (p < 0.05); decreased OS was associated with non-HER2+ subtype, presence of extracranial metastatic disease, and oncogenic alterations in TP53, CDH1 and NF1 (p < 0.05). In stratified analyses by receptor subtype, shorter TTCP was associated with oncogenic alterations in GAB2 and PTEN in the HR+ subgroup, AURKA, DDR2, and NF1 in the HER2+ subgroup, and with MYC and RB1 in the TN subgroup (p < 0.05). Conclusions: In this large clinico-genomic analysis of CNS-specific outcomes in BC, we identified clinical and putative genomic biomarkers associated with BCBM receiving SRS that could be used to risk stratify patients and optimize treatment strategies.