Serum S100A8/S100A9 is associated with increased risk of brain metastasis in patients with inflammatory breast cancer

ABSTRACT Background Inflammatory breast cancer (IBC) is a rare and highly aggressive form of breast cancer with an increased propensity to metastasize to distant organs including the brain. Higher serum levels of the calcium-binding proteins S100A8/A9, particularly of S100A9, have emerged as a clinically and biologically significant factor in aggressive breast cancers that are associated with poorer prognosis, tumor progression, and resistance to therapy. However, its contribution in IBC specifically remains undefined. Here, we investigated whether serum levels of S100A8/A9 predict outcomes in patients with IBC. Methods Serum S100A8/A9 levels were measured in a cohort of 304 IBC patients using ELISA assay. S100A8/A9 levels were categorized by their third quartile value (S100A8/A9-low ≤ 3 rd quartile; S100A8/A9-high > 3 rd quartile). Overall survival (OS) and breast cancer-specific survival (BCSS) were analyzed with Kaplan-Meier curves, log-rank tests, and Cox proportional hazard regression models. The cumulative incidence of any metastases and the cumulative incidence of brain metastases were analyzed using Aalen-Johansen method, Gray test, and Fine-Gray models. Results The 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/A9 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/A9 serum levels had poor OS ( P =0.01) and BCSS ( P =0.007) and had a higher risk of developing brain metastasis ( P =0.01) but not other metastasis. On multivariate analysis, high S100A8/A9 serum levels were independently associated with reduced OS (hazard ratio [HR]=1.7, 95% CI 1.1 to 2.6, P =0.01), reduced BCSS (HR=1.8, 95% CI 1.2 to 2.8, P =0.006), and increased cumulative incidence of developing brain metastasis (subdistribution hazard ratio (sHR)=1.8, 95% CI 1.1 to 3.0, P =0.03). Conclusions In patients with IBC, high serum levels of S100A8/A9 are an independent prognostic factor for brain metastasis and poor clinical outcomes. These findings support the potential of S100A8/A9 as predictive biomarker for identifying increased risk of brain metastasis and unfavorable prognosis in patients with IBC.