Breast White Adipose Tissue Inflammation and Breast Cancer Outcomes

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ABSTRACT Obesity and excess adiposity at the time of breast cancer diagnosis are associated with increased likelihood of recurrence and cancer-related death. Understanding the mechanisms by which excess adiposity affects breast cancer progression would provide critical insights into strategies to improve patient outcomes. We have identified a novel tissue-based inflammatory biomarker in breast adipose tissue, crown-like structures of the breast (CLS-B), that we have shown to be associated with obesity and dysregulated metabolic factors. The presence of CLS-B, which are comprised of an adipocyte surrounded by a “crown” of macrophages, indicates a state of inflammation in the breast white adipose tissue (B-WATi). We previously reported that B- WATi is associated with metabolic syndrome characteristics. Importantly, B-WATi is associated with increased breast cancer risk and shortened time to recurrence in women with metastatic disease. The Pathways Study, a prospective cohort study of women with invasive breast cancer supported by an NCI cancer epidemiology cohort infrastructure grant, provides an outstanding opportunity to conduct a large- scale, definitive investigation of the pathophysiologic state associated with B-WATi, and to investigate the association of B-WATi with breast cancer outcomes. From January 2006 to May 2013, we enrolled a racially- and ethnically-diverse cohort of 4,505 women soon after a breast cancer diagnosis in Kaiser Permanente Northern California (KPNC). Pathways Study participants provided blood specimens and reported on lifestyle factors, including diet and physical activity. Linkage to KPNC electronic health records captures details of cancer diagnosis and clinical care, and a biorepository of diagnostic slides and formalin-fixed, paraffin- embedded tissue blocks has been created from definitive breast cancer surgeries for all cohort members. We propose to determine B-WATi presence and severity in Pathways Study participants who underwent mastectomy (n=1,982), leveraging the substantial non-tumor breast tissue available in the biorepository. We also propose to assay systemic measures of inflammation and metabolic aberration, and examine measures of adipose tissue distribution in a subset of women with computed tomography (CT) images. Specific Aims are to: 1) Characterize the pathophysiological state of B-WATi in women with invasive breast cancer, including associations with lifestyle factors, adipose tissue distribution, and circulating cytokine and metabolic profiles; 2) Determine the associations between B-WATi and breast cancer outcomes; and, 3) Examine whether the associations between B-WATi and breast cancer outcomes vary by lifestyle factors and other breast cancer prognostic factors such as race/ethnicity, hormone receptor status, stage of disease, and breast cancer treatment. This project brings together ground-breaking and innovative work on B-WATi with the outstanding resources and infrastructure of the Pathways Study. It promises to provide insight into the impact of B-WATi on breast cancer and to identify actionable and modifiable risk factors to improve breast cancer outcomes.