Tumor Intrinsic Subtype Is Reflected in Cancer-Adjacent Tissue

Abstract

Introduction Overall survival of early-stage breast cancer (BC) patients is similar for those who undergo breast conserving therapy (BCT) and mastectomy, however, 10-15% of women undergoing BCT suffer ipsilateral breast tumor recurrence. The risk of recurrence may vary with BC subtype. Understanding the gene expression of the cancer-adjacent tissue and the stromal response to specific tumor subtypes is important for developing clinical strategies to reduce recurrence risk. Methods We utilized two independent data sets to study gene expression data in cancer-adjacent tissue from invasive BC patients. Complementary in vitro cocultures were used to study cell-cell communication between fibroblasts and specific BC subtypes. Results Our results suggest that intrinsic tumor subtypes are reflected in histologically-normal cancer-adjacent tissue. Gene expression of cancer-adjacent tissues shows that triple negative (Claudin-low or Basal-like) tumors exhibit increased expression of genes involved in inflammation and immune response. While such changes could reflect distinct immune populations present in the microenvironment, altered immune response gene expression was also observed in cocultures in the absence of immune cell infiltrates, emphasizing that these inflammatory mediators are secreted by breast-specific cells. In addition, while triple negative BCs are associated with upregulated immune response genes, Luminal breast cancers are more commonly associated with estrogen-response pathways in adjacent tissues. Conclusions Specific characteristics of BCs are reflected in the surrounding histologically-normal tissue. This commonality between tumor and cancer-adjacent tissue may underlie second primaries and local recurrences. Impact Biomarkers derived from cancer-adjacent tissue may be helpful in defining personalized surgical strategies or in predicting recurrence risk.

Digital histologic analysis reveals morphometric patterns of age-related involution in breast epithelium and stroma

“…The 20 micron section width was selected to maintain tissue integrity from non-fixed tissues and to ensure histologically-representative samples as very few samples were unable to produce viable sections at 20 micron width. The central portion of the tissue specimen was used for nucleic acid extraction as described elsewhere(7). If frozen specimens were not available (2.0% of patients), paraffin-embedded tissues were used for sectioning and digital annotation.…”

Race-associated biological differences among Luminal A breast tumors

“…We compared gene expression in normal ( RM) , cancer-adjacent normal and tumor ( UNC337 + NKI295 ) datasets. Reduction mammoplasty samples were from previous reports [10, 11] and from the Normal Breast Study, a study of patients undergoing surgery at UNC Hospitals [12]. All patients provided informed consent via a protocol approved by the Institutional Review Board of the University of North Carolina at Chapel Hill.…”

A review of the importance of immune responses in luminal B breast cancer

“…Gene network analysis predicted activation of TNF-a/IFNg signaling pathways in immune-enabled tumors and activation of the transforming growth factor-b (TGF-b) pathway in immunedisabled tumors. 13 Gene expression studies of BC-adjacent tissues showed that the TNBC microenvironment had increased expression of genes involved in inflammation 14 and revealed further subtypes, some with a low immune response defined by a minimal T cell infiltrate and effector function, and high frequency of suppressive M2-like macrophages, and others with a high immune response and low frequency of M2-like macrophages. 15 These data imply that communication between tumor cells and other cells in cancer-adjacent tissue contributes to BC progression and/or metastasizing potential; the same is likely to be true for Luminal B BC (Fig.…”