Abstract P3-05-22: Serum S100A8/S100A9 levels are associated with increased risk of brain metastasis in patients with aggressive breast cancer
Authors: Villodre Emilly S. , Hu Xiaoding , Song Juhee , Gomez Kristen , Su Xiaoping , Reuben James , Ueno Naoto T. , Tripathy Debu , Krishnamurthy Savitri , Debeb Bisrat 
Published: March 2023

Abstract
Background: Inflammatory breast cancer (IBC) is a rare and extremely aggressive form of breast cancer with an increased propensity to disseminate to distant organs such as the brain; indeed, a previous study reported that 37% of patients with HER2+ IBC present with brain metastasis as the first site of relapse. Our group recently generated new sublines from HER2+ IBC that exhibited a high brain metastatic propensity and further demonstrated that the stress response protein N-myc downstream regulated gene 1 (NDRG1) is a driver of breast cancer brain metastasis. Transcriptome analysis comparing NDRG1-expressing brain-metastasizing and NDRG1-depleted brain-non-metastasizing cells revealed prominent downregulation of two S100 calcium binding proteins, S100A8 and S100A9, in NDRG1-depleted cells. S100A8/S100A9 are known to facilitate the homing of tumor cells to the brain and lung pre-metastatic niche. Recent studies elegantly demonstrated a critical role for S100A9 in brain relapse and radioresistance in brain metastasis mouse models. The purpose of the present study was to evaluate whether S100A8/S100A9 serum levels predict the risk of brain metastasis in aggressive breast cancers. Methods: In a retrospective cohort of 304 IBC patients, we measured serum S100A8/S100A9 levels by using ELISA. Overall survival (OS) and breast cancer-specific survival (BCSS) were analyzed using Kaplan-Meier curves, log-rank test, and Cox proportional hazard regression. Results: The overall median follow-up time was 64 months. Forty-six percent of patients had estrogen receptor (ER)-negative tumors, 61.3% were stage III-IV, 77% high grade, 16.8% received adjuvant chemotherapy and 53.6% received adjuvant radiation. On univariate analysis, S100A8/S100A9 levels, disease stage, ER status, PR status, HER2 status, adjuvant chemotherapy, and adjuvant radiation therapy were significantly associated with OS and BCSS. Patients with high S100A8/S100A9 serum levels (&gt;3rd quartile vs. ≤ 3rd quartile) had poor OS (p=0.01) and BCSS (p=0.006). Also, patients with high S100A8/S100A9 serum levels had a higher risk of developing brain metastasis (p=0.01). S100A8/S00A9 serum levels was not significantly correlated with any other metastasis. On multivariate analysis, high S100A8/S100A9 serum levels was independently associated with reduced OS (hazard ratio [HR] = 1.8, 95% CI 1.1 to 3.0, p=0.01), reduced BCSS (HR = 1.8, 95% CI 1.2 to 2.8, p=0.006) and increased risk of developing brain metastasis (HR = 2.1, 95% CI 1.2 to 3.8, p=0.01). Conclusions: We found that having high levels of serum S100A8/S100A9 is an independent prognostic factor for reduced OS and BCSS and for the development of brain metastasis in patients with IBC. Thus, S100A8/S100A9 may represent a biomarker for unfavorable clinical outcome and brain metastasis in patients with aggressive breast cancers.
Citation Format: Emilly S. Villodre, Xiaoding Hu, Juhee Song, Kristen Gomez, Xiaoping Su, James Reuben, Naoto T. Ueno, Debu Tripathy, Savitri Krishnamurthy, Bisrat Debeb. Serum S100A8/S100A9 levels are associated with increased risk of brain metastasis in patients with aggressive breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-05-22.