BA12 - Hormone therapy, estrogen metabolism and risk of breast cancer or hip fracture in the WHI hormone trial

Investigator Names and Contact Information

Lew Kuller (KullerL@edc.pitt.edu)

Introduction/Intent

Breast cancer and hip fracture are two of the four highlighted outcomes of the BAA solicitation and represent two of the leading causes of morbidity in postmenopausal women. Within the WHI Hormone Therapy Clinical Trial (WHI-HT), hormone therapy (HT) has been associated with a decrease in hip fracture independent of the type of therapy used. In contrast, regimens containing progestins were associated with a modest increase in breast cancer risk while estrogen-only regimens were not. The mechanisms underlying the relationships between HT and both breast cancer and hip fracture are not well-understood.

The overall objective of this proposal is to examine the roles of estrogen metabolism and hormone therapy in the development of breast cancer and hip fracture within the WHI-HT. We hypothesize that 16α-hydroxy estrone (16α-OHE1) serves as a biomarker of breast cancer risk whereas 2-hydroxy estrone (2-OHE1) serves as a biomarker of hip fracture risk. Furthermore, we hypothesize that how a woman metabolizes estrogen while on postmenopausal HT is predictive of her risk of developing breast cancer or having a hip fracture. Compelling preliminary data support our hypothesis and we propose a case-cohort study within the WHI-HT in order to assess it. Specifically, we will measure baseline and 1-year post-randomization levels of serum estrogen metabolites in women who developed breast cancer or had a hip fracture and in women who did not develop breast cancer or have a hip fracture while participating in the WHI-HT. Baseline and follow-up levels of 16α-OHE1 and 2-OHE1 will be measured using highly-sensitive assays for which we have extensive short and long-term intra-individual and inter-assay validation data. We will assess whether type of HT (estrogen alone or estrogen+progestin) affects estrogen metabolism thereby influencing breast cancer or hip fracture risk. Baseline levels of metabolites will be compared between cases and controls in order to determine whether they are predictive of breast cancer or hip fracture risk. Changes in levels of 2-OHE1 and 16α-OHE1 between baseline and 1-year post-randomization will also be compared between cases and controls on active treatment in order to assess whether absolute changes in estrogen metabolism as a result of HT use influence breast cancer or hip fracture risk. Finally, we will investigate the changes in metabolite ratios and proportions in order to assess whether relative changes in estrogen metabolism as a result of HT use influence breast cancer or hip fracture risk.

The specific objectives of this study are as follows:

1. To confirm the role of estrogen metabolites as biomarkers of breast cancer and hip fracture risk in the WHI-HT. We hypothesize that among women in the WHI-HT,
   • a. compared to women not diagnosed with breast cancer, women diagnosed with breast cancer will have
     • i. greater baseline levels of 16α-OHE1
     • ii lower baseline ratio of 2:16 metabolite levels
   • b. compared to women not experiencing a hip fracture, women experiencing a hip fracture will have
     • i. lower baseline levels of 2-OHE1
     • ii. lower baseline ratio of 2:16 metabolite levels
2. To determine if HT metabolism varies by whether or not the estrogen is opposed by progestin. We hypothesize that compared to use of estrogen (CEE) alone, use of estrogen + progestin `
   • a. greater increase in 16α-OHE1 levels 1 year after randomization
   • b. lesser increase in 2-OHE1 levels 1 year after randomization
   • c. lesser increase in the ratio of 2:16 metabolite levels 1 year after randomization
   • d. a greater proportion of the change in metabolite levels attributed to the change in 16α-OHE1 than to the change in 2-OHE1
3. To determine if how a woman metabolizes estrogen while on HT is associated with risk of breast cancer. We hypothesize that compared to women not diagnosed with breast cancer while on HT, women diagnosed with breast cancer while taking HT have
   • a. greater increase in 16α-OHE1 levels 1 year after randomization
   • b. lesser increase in the ratio of 2:16 metabolite levels 1 year after randomization
   • c. a greater proportion of the change in metabolite levels attributed to the change in 16α-OHE1 than to the change in 2-OHE1
4. To determine if how a woman metabolizes estrogen while on HT is associated with risk of hip fracture. We hypothesize that compared to women not experiencing a hip fracture while on HT, women experiencing a hip fracture while taking HT have
   • a. lesser increase in 2-OHE1 levels 1 year after randomization
   • b. lesser increase in the ratio of 2:16 metabolite levels 1 year after randomization
   • c. a lesser proportion of the change in metabolite levels attributed to the change in 2-OHE1 than to the change in 16α-OHE1

Additionally, host factors such as race and body mass index (BMI) may be important factors in determining how women on HT metabolize estrogen. An exploratory aim of this study is to investigate whether interactions between HT and such host factors are related to estrogen metabolism and risk of breast cancer or hip fracture. Further exploratory aims will assess the effect of hormone therapy and estrogen metabolism on clinical characteristics of breast cancer, including stage, tumor grade and hormone receptor status. Finally, we will use the host of available data on hormones in breast cancer and hip fracture cases and controls in the WHI-HT to explore whether our observations are independent of baseline hormone levels.

Results/Findings Some of the publications related to this ancillary study are: 916.

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Papers section of this website.