Investigating determinants of breast adipose tissue inflammation and tamoxifen effectiveness among breast cancer patients Restricted; Files Only
Maliniak, Maret (Fall 2023)
Published
Abstract
Background: Breast cancer has a complex, multifactorial etiology and is highly heterogeneous. The recognition of breast cancer’s heterogeneity has led to a more personalized approach to prevention and treatment.
Despite progress in targeted prevention strategies and therapies for breast cancer, the risk of recurrence remains high and breast cancer remains the leading cause of cancer death among women worldwide. Identifying drivers of poor prognosis is essential to optimize approaches to therapy and improve outcomes.
To better understand heterogeneity in breast cancer outcomes, the overarching goal of this dissertation is to investigate, among breast cancer patients, determinants of 1) obesity-related breast adipose tissue inflammation and 2) tamoxifen effectiveness.
In Aim 1, we examined whether breast tissue composition, as reflected by mammographic breast density, is associated with breast adipose tissue inflammation, as indicated by the presence of crown-like structures in the breast (CLS-B) among women diagnosed with invasive breast cancer and treated at an Emory University-affiliated hospital. Using multivariable-adjusted modified Poisson regression models, we found that compared to having dense breasts, women with fatty breasts had a lower prevalence of CLS-B at diagnosis (PR=0.71, 95% CI: 0.48, 1.05). Women with a high BMI (≥30 kg/m2) and dense breasts had the highest prevalence of CLS-B.
In Aim 2, we investigated neighborhood deprivation as a potential upstream driver of breast adipose tissue inflammation in the same cohort of breast cancer patients as Aim 1. Using multivariable-adjusted modified Poisson regression models, we found that women living in high deprivation neighborhoods at diagnosis had a lower prevalence of CLS-B than women living in low deprivation neighborhoods (PR=0.61; 95% CI: 0.39, 0.94).
In Aim 3, we evaluated interaction between genetic variants involved in tamoxifen metabolism and transport and two biomarkers related to local estrogen production (HSD17B1 and HSD17B2 expression) on the hazard of breast cancer recurrence among premenopausal women diagnosed with ER-positive breast cancer and initially treated with tamoxifen. Using a Bayesian pathway analysis approach, we found strong evidence of interaction between HSD17B2 expression and genetic variation in UGT2B7 (Bayes factor=130).
Together, these studies provide insight into the complex processes underlying heterogeneity in breast cancer outcomes.
Table of Contents
1. Chapter 1: Background and Literature Review.. 1
1.1. Breast cancer: progress in personalized medicine but persistent challenges. 1
1.2. Obesity and breast cancer. 4
1.2.1. Obesity and incidence of breast cancer. 5
1.2.2. Obesity and breast cancer outcomes. 6
1.3. Crown-like structures in the breast: early evidence. 8
1.3.1. Adiposity and CLS-B.. 9
1.3.2. CLS-B and breast cancer risk. 11
1.3.3. CLS-B and breast cancer prognosis. 11
1.3.4. Other potential drivers of CLS-B.. 13
1.4. Estrogen receptor-positive breast cancer. 20
1.4.1. Tamoxifen treatment for breast cancer. 21
1.4.2. Identifying drivers of tamoxifen effectiveness. 22
2. Chapter 2: Specific aims. 24
Specific Aims. 26
3. Chapter 3: Joint associations of BMI and mammographic breast density on the presence of crown-like structures in the breast adipose tissue of breast cancer patients. 28
3.1. Abstract 28
3.2. Introduction. 30
3.3. Methods. 31
3.3.1. Study Population. 31
3.3.2. Mammographic breast density, BMI, and covariate assessment 32
3.3.3. CLS-B assessment 32
3.3.4. Statistical Analysis. 33
3.4. Results. 35
3.5. Discussion. 36
4. Chapter 4: Neighborhood deprivation and the presence of crown-like structures in the breast adipose tissue of breast cancer patients. 56
4.1. Abstract 56
4.2. Introduction. 58
4.3. Methods. 59
4.3.1. Study population. 59
4.3.2. Neighborhood deprivation index (NDI) 60
4.3.3. Crown-like structures in the breast (CLS-B) 62
4.3.4. Statistical analysis. 62
4.4. Results. 64
4.5. Discussion. 66
5. Chapter 5: Interaction between expression of 17β-hydroxysteroid dehydrogenases 1 and 2 and tamoxifen metabolism on the hazard of breast cancer recurrence: A Bayesian pathway analysis. 83
5.1. Abstract 83
5.2. Introduction. 85
5.3. Methods. 86
5.3.1. Study population. 86
5.3.2. Selection of high priority variants and genotyping. 87
5.3.3. HSD17B1 and HSD17B2 biomarkers assessment 89
5.3.4. Follow-up for breast cancer recurrence. 90
5.3.5. Statistical analyses. 90
5.3.6. ALPS Bayesian pathway analyses. 91
5.3.7. Conventional Cox regression. 92
5.4. Results. 94
5.5. Discussion. 97
6. Chapter 6: Summary of findings and future research. 124
6.1. Summary of findings. 124
6.2. Future research directions. 127
7. References. 129
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