doctoral thesis in breast cancer

IMPACT OF THE BREAST CANCER IMMUNE MICROENVIRONMENT ON RACIAL DISPARITIES AND RECURRENCE

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• Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
• Growing evidence supports the importance of the immune microenvironment in the clinical course of breast cancer, where multiple studies have demonstrated positive prognostic utility of tumor infiltrating lymphocytes among triple-negative and HER2-positive breast cancers. Despite the abundance of studies investigating the immune microenvironment in breast cancer, biomarkers of immune response are lacking, particularly in estrogen receptor (ER)-positive breast cancer, and Black women are underrepresented in these studies. This is important because Black women suffer higher incidence of poor-prognosis subtypes and worse stage-specific mortality. Given the rapidly evolving landscape of immunotherapies in breast cancer and ongoing efforts to expand currently limited treatment eligibility, investigations of the breast cancer immune microenvironment and identification of biomarkers that associate with immune-mediated survival in diverse patient populations, is an unmet clinical need. To address this knowledge gap, the current body of work leveraged three major breast cancer studies rich in molecular, histological, clinical and epidemiological data: 1) the Carolina Breast Cancer Study (CBCS; N= 1,952), a large population-based study designed to investigate racial disparities in breast cancer, 2) The Cancer Genome Atlas (TCGA) breast cancer dataset (N= 1,095), a well-known study with multiple data platforms for each sample, and 3) the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) dataset (N= 1,904). Aim 1 of this study characterized global phenotypes of immune response using cell-type specific markers for 10 immune cell populations and evaluated associations with clinical and demographic variables, and recurrence. Aim 2 leveraged RNA expression profiling to investigate markers of genomic instability in association with breast cancer immunogenicity and immune-mediated patterns of recurrence. This work identified strong associations between phenotypes of immune response and tumor subtype, grade, patient age, BMI and self-reported race. In addition, RNA-based pathway assessment of genomic instability markers (HRD, APOBEC, and TP53 pathways) identified immunogenic tumors with strong adaptive immune responses that associated with recurrence-free survival regardless of ER status. Collectively, this work contributes novel findings about the breast cancer immune microenvironment that may aid in precision medicine approaches for breast cancer prevention and intervention, and highlights the importance of diversity in impactful and equitable clinical research.
• breast cancer
• immune microenvironment
• Epidemiology
• disparities
• genomic instability
• https://doi.org/10.17615/t7kp-1598
• Dissertation
• In Copyright - Educational Use Permitted
• Calhoun, Benjamin C
• Hoadley, Katherine A
• Troester, Melissa A
• Love, Michael I
• Williams, Scott E
• Doctor of Philosophy
• University of North Carolina at Chapel Hill Graduate School

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