Prognostic Significance of CSF-1R Expression in Early Invasive Breast Cancer

SIMPLE SUMMARY: Experimental evidence suggests that CSF-1/CSF-1R signaling attracts immune cells called macrophages into the tumor microenvironment which promote the capacity of cancer cells to spread. In this study, we investigated CSF-1R protein expression on breast cancer cells and macrophages and their relationship with other immune cells and breast cancer survival. Our results show that cases with high CSF-1R expression on cancer cells, but not macrophages, are associated with inferior survival, particularly in the common hormone receptor-positive breast cancer group, which persists even in the presence of an active anti-tumor host immune response. ABSTRACT: Colony-stimulating factor-1 receptor (CSF-1R) signaling promotes an immune suppressive microenvironment enriched in M2 macrophages. Given that CSF-1R inhibitors are under investigation in clinical trials, including in breast cancer, CSF-1R expression and association with immune biomarkers could identify patients who derive greater benefit from combination with immunotherapies. TIMER2.0 and bc-GenExMiner v4.7 were used to assess the correlation of CSF1R mRNA with immune infiltrates and prognosis. Following a prespecified training–validation approach, an optimized immunohistochemistry assay was applied to assess CSF-1R on carcinoma cells and macrophages on breast cancer tissue microarray series representing 2384 patients, coupled to comprehensive clinicopathological, biomarker, and outcome data. Significant positive correlations were observed between CSF1R mRNA and immune infiltrates. High carcinoma CSF-1R correlated with grade 3 tumors >2 cm, hormone receptor negativity, high Ki67, immune checkpoint biomarkers, and macrophages expressing CSF-1R and CD163. High carcinoma CSF-1R was significantly associated with poor survival in univariate and multivariate analyses. Adverse prognostic associations were retained in ER+ cases regardless of the presence of CD8+ T cells. CSF-1R+ macrophages were not prognostic. High carcinoma CSF-1R is associated with aggressive breast cancer biology and poor prognosis, particularly in ER+ cases, and identifies patients in whom biomarker-directed CSF-1R therapies may yield superior therapeutic responses.