Biologic and Patient Variation Affecting Breast Cancer Treatment Effectiveness Restricted; Files Only

Collin, Lindsay (Summer 2020)

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Breast cancer is a heterogeneous disease, consisting of intrinsic subtypes with variable prognosis and targeted treatment approaches. Advancements in national screening programs, diagnostic work-up, and biomarker driven treatment protocols have contributed to improvements in breast cancer outcomes, with an average 5-year survival of 90% for women diagnosed with breast cancer. Despite this substantial progress, the risk of recurrence remains high. Approximately 20–40% of women will develop a recurrence, even 20 years or more after their initial diagnosis. In this dissertation, we sought to characterize the calendar trends in breast cancer recurrence, and evaluate patient-level characteristics and biomarkers that may contribute to breast cancer recurrence risk.

The source population to carry out the proposed aims includes women diagnosed with breast cancer and recorded with the Danish Breast Cancer Group (DBCG) clinical database, which contains information on all breast cancer diagnoses and follow-up for a recurrence in Denmark. In Aim 1a, we describe 5-year and 10-year age-adjusted breast cancer recurrence rates over a 40-year period. Trends in recurrence rates showed a steady decline over the study period. In Aim 1b, we evaluated the utility of the trend-in-trend pharmacoepidemiologic analytic method to estimate the population-level effect of the introduction of adjuvant therapies on breast cancer recurrence risk based on changes in clinical guidelines. Although this approach was not feasible to evaluate all therapies, we report that the risk of recurrence associated with the introduction of guideline tamoxifen for premenopausal women diagnosed with estrogen receptor positive breast cancer in 1999 decreased by one-half (OR=0.52, 95%CI: 0.25, 1.85), which was consistent with results from clinical trials.

In Aim 2, we estimated the association between early discontinuation of endocrine therapy and rate of breast cancer recurrence in a cohort of premenopausal women diagnosed with breast cancer. Women who discontinued endocrine therapy had 1.7 times the estimated rate of breast cancer (95%CI: 1.3, 2.1) compared with those who completed at least five years of therapy.

In Aim 3a, we evaluated the prognostic and predictive effects of 17β-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) and rate of breast cancer recurrence in a cohort of premenopausal women. Women diagnosed with tumors positive for HSD17B1 had an increased estimated rate of recurrence (HR=1.4, 95%SI: 1.0, 2.9) compared with women diagnosed with tumors that lacked expression for the marker. In contrast, a 10-unit increase in the HSD17B2 h-score corresponded to a decrease in the estimated rate of recurrence (HR=0.85, 95%SI: 0.69, 1.1). In Aim 3b, we similarly evaluated the prognostic and predictive effects of HSD17B1 and HSD17B2 and breast cancer recurrence, but in a population-based case control study of primarily postmenopausal women. Results in this study aim did not suggest an important association between either biomarker and breast cancer recurrence.

The findings of this dissertation demonstrate improvements in breast cancer outcomes over time, provide a discussion on the methodologic approaches to estimate the population-level impact of changes to guideline therapy using the trend-in-trend design, highlight the importance of endocrine therapy persistence among premenopausal women, the potential prognostic utility of HSD17B1 and predictive utility of HSD17B2 on breast cancer recurrence among premenopausal women diagnosed with breast cancer.

Table of Contents

Table of Contents

Chapter 1 : Introduction and Background. 1

Overarching Goal and Specific Aims. 2

Background. 3

Breast Cancer Recurrence Risk. 3

Introduction and progression of adjuvant therapies in Denmark. 4

Overview of and adherence to endocrine therapy. 8

Factors Impacting Adherence. 9

Effect of Nonadherence on Breast Cancer Outcomes. 10

Prognostic and Predictive Biomarkers of Breast Cancer Recurrence. 10

Molecular Targets for Tamoxifen Treatment Efficacy. 12

Estrogen Metabolism in Pre and Postmenopausal Women. 12

Tamoxifen Resistance. 13

Data Sources. 14

Denmark. 14

Danish Registry System.. 14

Danish Breast Cancer Group Clinical Database. 15

Predictors of Breast Cancer Recurrence (ProBe CaRe) study populations. 16

Preliminary Work. 19

Cohort Profile: the Predictors of Breast Cancer Recurrence (ProBe CaRe) premenopausal breast cancer cohort study in Denmark. 20

Bayesian Pathway Analysis for Complex Interactions. 21

Metabolic pathway analysis and effectiveness of tamoxifen in Danish premenopausal breast cancer patients. 21

Expression of survivin does not appear to influence breast cancer recurrence risk. 22

Chapter 2 : The Population-Level Effect of Adjuvant Therapies on Breast Cancer Recurrence: A 30-year perspective in Denmark. 25

Abstract 25

Introduction. 27

Methods. 31

Study Population. 31

Tumor and Treatment Characteristics. 32

Breast Cancer Recurrence. 32

Statistical Analysis. 33

Results. 35

Discussion. 44

Chapter 3: Association between early discontinuation of adjuvant endocrine therapy and recurrence among premenopausal women diagnosed with breast cancer in a Danish population-based cohort 49

Abstract 49

Background. 51

Methods. 53

Study Population. 53

Exposure: Early Discontinuation. 53

Covariates. 55

Statistical Analysis. 55

Results. 56

Discussion. 61

Chapter 4: 17β-Hydroxysteroid Dehydrogenases 1 and 2: potential markers for breast cancer recurrence and tamoxifen resistance among premenopausal women diagnosed with breast cancer in Denmark. 66

Abstract 66

Introduction. 68

Methods. 69

Study Population. 69

Data Collection from Danish Registries. 70

Tissue Microarray (TMA) Construction and Immunohistochemistry. 70

TMA Core Scoring. 71

Exposure Assessment 73

Validation Study. 74

Statistical Analysis. 75

Quantitative Bias Analysis. 75

Results. 79

Cumulative Incidence Curves. 82

Validation Substudy and Quantitative Bias Analysis. 84

Conventional Analyses. 84

Discussion. 87

Chapter 5: 17β-hydroxysteroid dehydrogenase 1:2 and breast cancer recurrence: a Danish population-based study. 92

Abstract 92

Introduction. 94

Methods. 95

Study Population. 95

Data Collection from Danish Registries. 96

Tissue Microarray Construction and Immunohistochemistry. 97

TMA Core Scoring. 98

Analytic Variables. 99

Expression of HSD17B1 and HSD17B2. 99

Breast Cancer Recurrence. 99

Covariates. 99

Statistical Analysis. 100

Quantitative Bias Analysis. 101

Results. 101

Cytoplasmic Ratio of HSD17B1:HSD17B2 Expression. 104

Quantitative Bias Analysis. 106

Discussion. 107

Chapter 6 : Summary of Results, Future Research. 110

The Role of Epidemiology in Making Statements About Policy. 111

The Role of Epidemiology in Making Statements About Policy. 112

Review of Major Findings. 112

Future Directions. 116





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