The overarching goal of the proposed research is to investigate whether presence of CLS-B, a marker of local tissue inflammation, can be used as a biomarker to identify breast cancer patients who would benefit from statin therapy for reducing breast cancer recurrence. The proposed research will leverage existing tissue biobanks linked with clinical and prescription datasets for Danish women diagnosed with non-metastatic, invasive breast cancer between 2004 and 2010 (estimated N=490).

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Although national and philanthropic efforts have sought to reduce and eliminate breast cancer (BC) mortality disparities over the past few decades, they have not only persisted—but widened. Additionally, due to incomplete capture of recurrence data, no previous investigation has identified drivers of disparities in BC recurrence following a diagnosis of early-stage (I–IIIA) disease. In Georgia, where economic and racial/ethnic disparities are among the greatest in the United States, the sources of BC outcome disparities are unresolved, and likely arise from the interplay of causal and contributing factors at multiple levels—from cell to society. Approximately 40% of all BC survivors will suffer a recurrence during their lifetime, and clinical data suggest a higher risk of recurrence in minority and low-income women. Our proposal will be the first to estimate risks and rates of BC recurrence by demographic characteristics, consider intersectionality in BC outcome disparities, and use a multilevel decomposition approach to identify potential targets for intervention.

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Although national and philanthropic efforts have sought to reduce and eliminate mortality disparities in metastatic breast cancer (MBC) over the past few decades, they have not only persisted—but widened. Additionally, due to incomplete capture of recurrence data, no previous investigation has quantified disparities in distant recurrence following a diagnosis of early-stage breast cancer. In Georgia, where economic and racial/ethnic disparities are among the greatest in the United States, the sources of mortality disparities in MBC are unresolved, but likely include proximal (e.g., individual demographics, tumor biology, and comorbid conditions), intermediate (e.g., physical and social contexts), and distal factors (e.g., institutional contexts). MBC is almost always terminal, and about half of patients experience disease progression within 1-year of treatment. Given the mortality burden of MBC, documented disparities, and diversity of Georgia with respect to all major demographic characteristics, now is a pivotal time to characterize the pathways contributing to inequities in MBC prognosis.

The objective of this proposal is to comprehensively characterize—in a large diverse population of women diagnosed with breast cancer in Georgia, (2013-2017)—the contributions of proximal, intermediate, and distal determinants of disparities in two outcomes: a) distant metastases among ~30,000 women diagnosed with stage I–IIIA breast cancer (Aim 1); and b) mortality among ~2,000 women diagnosed with stage IIIB–IV breast cancer (Aim 2), using multiple data streams (e.g., cancer registry, discharge, administrative claims, hospital and census data).

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The scientific premise of the proposed study is that PBBs induce endocrine-sensitive carcinogenesis via epigenetic changes in immune- and estrogen-related pathways. Our overarching goal is to advance understanding of EDC-related carcinogenesis by investigating the DNA methylome. To achieve this goal we propose to examine the incidence of endocrine sensitive cancers, and DNA methylation as a causal driver, in the PBB Registry. Our specific aims are to: (1) assess the incidence of overall breast cancer, estrogen-receptor (ER) positive breast cancer, and other endocrine-sensitive cancers (prostate, thyroid, uterine) in the PBB Registry and compare incidence rates by PBB exposure level; (2) compare DNA methylation patterns among breast cancer cases and non-cancerous controls from existing peripheral blood samples and examine differences by PBB exposure level; (3) explore DNA methylation as a causal link between PBB exposure and incidence of ER+ breast cancer using causal inference methodologies (e.g., mediation analyses). (4) Obtain tumor tissue from about 5 cancer cases in the PBB cohort to determine the feasibility of obtaining a larger sample for future NIH-supported research.

The Michigan PBB Registry represents a unique opportunity to determine the carcinogenicity of BFRs given the well-characterized exposure and more than 40-year follow-up. It also presents a rare opportunity to examine epigenetic patterns in relation to documented EDC exposures in cancer cases. Research on the epigenetic role of EDCs in carcinogenesis has not been thoroughly investigated; thus data generated from this study will inform mechanistic hypotheses and pathways that can be thoroughly interrogated in future NIH-supported projects using newly ascertained tumor tissue.

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Polybrominated biphenyls (PBBs) are persistent endocrine-disrupting chemicals (EDCs) that may increase risks of endocrine-sensitive cancers, including estrogen-receptor-positive breast cancer, by interfering with endogenous hormones. While their chemical analogues PCBs are classified as carcinogens, carcinogenic evidence for PBBs is less definitive. The Michigan PBB Registry, with records of 7,400 individuals exposed through a large-scale agricultural contamination in 1973-74 and followed since 1976, offers a unique population in which to study cancer in relation to PBB exposures. Research in this cohort has suggested increased risks of breast cancer and provided insight into potential mechanisms, including aberrant DNA methylation in estrogen- and immune-related regions and altered estrogen levels. This study will identify newly diagnosed cases of breast cancer and other endocrine-sensitive cancers in this population, which will provide a large pool of cases for our planned NIH proposal exploring aberrant DNA methylation as a mediator of the PBB-cancer link. A pilot study will examine DNA methylation in banked blood samples of cases and controls and determine the feasibility of obtaining tumor tissue for the planned NIH proposal. This unique cohort, followed for >40 years with well-documented exposures and banked biospecimens, provides a rare opportunity to understand mechanistic pathways linking environmental exposures to carcinogenesis.

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Breast cancer is the most common cancer diagnosed among U.S. women. The discovery and treatment of breast cancers has improved, but survival differences continue. African-American women have greater deaths across all types of breast cancer. While many social, economic, lifestyle, and biologic factors contribute to survival differences, we believe that fat and its impact on the cancer environment is an important factor. More African-American women are obese than Whites, and obesity has been linked to increased odds of breast cancer occurring again, spreading to other locations, and death. In older women (>50 years), most of the hormones that drive breast cancer are from total body fat. But, certain changes specific to breast fat may influence breast cancer. Early data show that one of these changes may be development of crown-like structures (CLS). CLS of the breast (CLS-B) has been linked to greater inflammation, hormones, and poor survival among White women. We believe that CLS-B are more common in African-American than White women across body size, and that they are related to worse survival leading to the observed differences by race. This award would support the first study of obesity, CLS-B presence, and related outcomes in group of African-American and similar White women being treated for breast cancer (400 women total). Our study will advance the understanding of obesity and the breast cancer environment, as well as explain the value of CLS-B as a predictor of treatment response, breast cancer outcomes, and possible driver of differences among African-American women.

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Triple-negative breast cancer (TNBC) has a poor prognosis, and disproportionately affects African-American women. Obesity is a risk factor for TNBC, a poor prognostic factor for all molecular subtypes of breast cancer, and is most prevalent among African-American women which underscores the importance of uncovering how obesity contributes to poor prognostic subtypes and outcomes in this vulnerable population. This pilot study aims to identify obesity-associated methylation signatures in the breast tumor tissue of 50 women and to understand whether these signatures differ by race or subtype. We subsequently aim to explore obesityassociated methylation in matched blood, as a potential biomarker of susceptibility, and examine the association between obesity-related methylation and the presence of crown-like structures within the breast adipose tissue. We will execute these aims by using well-characterized clinical data and tumor specimens from the Breast Satellite Tissue Bank. We posit that obesity not only alters the breast tumor methylome, but these alterations are: (1) most apparent among African-American women; (2) could be identified in surrogate tissue; and (3) contribute to features of the tumor microenvironment. Importantly, this pilot study will generate the preliminary data necessary to apply for extramural grant support and will ultimately help to narrow the disparity gap.

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