Breast Cancer Survival Outcomes and Tumor-Associated Macrophage Markers: A Systematic Review and Meta-Analysis

INTRODUCTION: Tumor-associated macrophages (TAMs) in breast cancer are associated with a poor prognosis. Early studies of TAMs were largely limited to the pan-macrophage marker CD68, however, more recently, an increasing number of studies have used CD163, a marker expressed by alternatively activated M2 macrophages and TAM subsets. We hypothesized that CD163-positive (CD163+) TAMs would be a better predictor of survival outcomes in breast cancer compared to CD68+ TAMs. METHODS: We performed a systematic literature search of trials (from 1900 to August 2020) reporting overall survival (OS) or progression-free survival (PFS), breast cancer-specific survival (BCSS), TAM phenotype, and density. Thirty-two studies with 8446 patients were included. Meta-analyses were carried out on hazard ratios (HRs) for survival outcomes of breast cancer patients with a high density of TAMs (CD68+ and/or CD163+) compared to a low density of TAMs. RESULTS: A high density of TAMs (CD68+ and/or CD163+) was associated with decreased OS (HR 1.69, 95% CI 1.37–2.07) and reduced PFS (HR 1.64; 95% CI 1.35–1.99). Subgrouping by CD marker type showed a lower OS for high density of CD163+ TAMs (HR 2.24; 95% CI 1.71–2.92) compared to a high density of CD68+ TAMs (HR 1.5; 95% CI 1.12–2). A high density of TAMs (CD68+ and/or CD163+) in triple-negative breast cancer (TNBC) cases was associated with lower OS (HR 2.81, 95% CI 1.35–5.84). CONCLUSION: Compared to CD68+ TAMs, a high density of CD163+ TAMs that express a similar phenotype to M2 macrophages are a better predictor of poor survival outcomes in breast cancer.