Abstract
The tumor microenvironment plays a critical role in breast cancer progression. Here, we investigated tumor‐infiltrating lymphocytes (TILs) and associations with macrophage numbers, tumor stromal elastosis, vascular invasion, and tumor detection mode. We performed a population‐based retrospective study using data from The Norwegian Breast Cancer Screening Program in Vestfold County (2004–2009), including 200 screen‐detected and 82 interval cancers. The number of TILs (CD45+, CD3+, CD4+, CD8+, and FOXP3+) and tumor‐associated macrophages (CD163+) was counted using immunohistochemistry on tissue microarray slides. Lymphatic and blood vessel invasion (LVI and BVI) were recorded using D2‐40 and CD31 staining, and the amount of elastosis (high/low) was determined on regular HE‐stained slides. High numbers of all TIL subsets were associated with LVI (p ≤ 0.04 for all), and high counts of several TIL subgroups (CD8+, CD45+, and FOXP3+) were associated with BVI (p ≤ 0.04 for all). Increased levels of all TIL subsets, except CD4+, were associated with estrogen receptor‐negative tumors (p < 0.001) and high tumor cell proliferation by Ki67 (p < 0.001). Furthermore, high levels of all TIL subsets were associated with high macrophage counts (p < 0.001) and low‐grade stromal elastosis (p ≤ 0.02). High counts of CD3+, CD8+, and FOXP3+ TILs were associated with interval detected tumors (p ≤ 0.04 for all). Finally, in the luminal A subgroup, high levels of CD3+ and FOXP3+ TILs were associated with shorter recurrence‐free survival, and high counts of FOXP3+ were linked to reduced breast cancer‐specific survival. In conclusion, higher levels of different TIL subsets were associated with stromal features such as high macrophage counts (CD163+), presence of vascular invasion, absence of stromal elastosis, as well as increased tumor cell proliferation and interval detection mode. Our findings support a link between immune cells and vascular invasion in more aggressive breast cancer. Notably, presence of TIL subsets showed prognostic value within the luminal A category.
Highlights
Mammography screening identifies a subset of breast cancers with a better prognosis than expected based on standard histopathologic and molecular prognostic features [1,2,3]
Based on the importance of the tumor immune microenvironment (TIME) in breast cancer [14,15,16,17,18,19], the purpose of our present study was to investigate the relationship between tumor-infiltrating lymphocytes (TILs) and tissue macrophages with the presence of vascular invasion and stromal elastosis in breast cancers stratified by detection mode, as these relationships may be of potential prognostic value and relevant for treatment strategies
High levels of tumorinfiltrating lymphocytes (TILs) subsets are associated with tumor-associated macrophages (TAM) counts, estrogen receptor (ER), HER2, Ki67, stromal elastosis, and breast cancer detection mode
Summary
Mammography screening identifies a subset of breast cancers with a better prognosis than expected based on standard histopathologic and molecular prognostic features [1,2,3]. Increased knowledge of the tumor microenvironment of screen-detected breast cancers is needed to possibly explain their indolent behavior and good prognosis in most of the cases. We reported that deposition of abnormal elastin material (elastosis) in breast cancer stroma is associated with mammographic screen detection, low tumor cell proliferation by Ki67 expression, and a favorable patient prognosis [11]. We found that tumor cell invasion into blood vessels strongly correlates with interval detected breast cancers and a basallike tumor phenotype [12], as well as low stromal elastosis. Tumor-associated macrophages (TAM) expressing CD163 were related to vascular invasion, nonluminal subtypes, and interval breast cancer [13]
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