Aromatase Inhibitors, Mammographic Density, and Plasma Steroid Hormones
Co-Principal Investigators: Celine Vachon, Ph.D., Mayo Clinic Cancer Center; Paul Goss, F.R.C.P., M.B.B.Ch., Ph.D., Dana-Farber/Harvard Cancer Center
Why Mammographic Density?
The mammogram image is composed of light and dark regions that represent different tissue types in the breast. Fat is radiographically translucent and appears dark on the mammogram while dense tissues (like the cells lining ducts and stroma) appear light on the mammogram. Numerous studies suggest that women who have a greater percent of light regions on their mammogram for their age (or higher breast density) have a three to five fold increased risk for breast cancer. Breast density is hormonally responsive as can be seen in the positive associations between breast density with not having children, late age at first birth, and never having breast-fed and inverse associations with age and postmenopausal status. Also, breast density changes with the initiation of hormonal therapies. Current users of hormone replacement therapy consistently have increased breast density, with a greater increase seen in women using combination therapy (estrogens plus progestins). Users of tamoxifen consistently experience decreases in breast density. Three studies to date have shown that increases in breast density over time are associated with increased breast cancer. Thus, increases and decreases in breast density seen with hormone therapy might indicate who will or will not benefit from a certain therapy.
Will Aromatase Inhibitors Reduce Density?
The aromatase inhibitors (AIs) are a class of drugs that have been shown to be of value in both early and late breast cancer. These include anastrozole (Arimidex), exemestane (Aromasin) and letrozole (Femara) However, not all women will benefit from this therapy and we would like to be able to understand which women will not respond favorably in order to provide alternative treatments. Breast density may help us to target these women. AIs block an enzyme that is involved with producing estrogens in postmenopausal women; thus AIs result in significant reductions of estrogens in the breast. Because mammographic density is estrogen responsive, we hypothesize that breast density also will decrease with aromatase inhibition. We propose a study to examine the effect of aromatase inhibitors (AI) on breast density and compare to changes in breast density seen among a group of women of the same age not on hormonal therapy over a similar time frame. We also propose to investigate whether changes in breast density are correlated with changes in hormone and drug levels as well as whether they are genetically influenced. These results could provide evidence that breast density may be used as a marker of individual response to therapy.
What Is the Impact of Steroidal versus Non-Steroidal AIs?
To test our hypotheses, we have added onto an ongoing clinical trial (NCIC CTG, MA-27) that is designed to address the impact of a steroidal vs. nonsteroidal third generation AI regimen in the treatment of postmenopausal women with early stage (I, II) estrogen-receptor positive primary breast cancer. We are obtaining mammograms and risk factor information before randomization (pretreatment) and at one and two year follow-up on approximately 500 women enrolled on this trial (250 on each type of AI). We will match these women to 500 women with similar age and mammogram history selected from a large Mayo Mammography Cohort. We will ascertain mammograms from two time points, estimate breast density and examine whether there are changes in breast density in women using AI therapy and how these changes compare to women not on therapy. Finally, with blood also collected at these two time points, we will try to understand factors responsible for these changes in density, including hormone level changes, drug levels and genes.
Understanding how breast density reacts to AIs is important since changes in breast density might indicate individual responses to AI therapy that correlate with outcome. Thus, instead of waiting until until problems develop, women could be provided early information on their likelihood of response to therapy and provided alternatives if necessary.
In collaboration with another large grant on pharmacogenomics at Mayo Clinic, called the Pharmacogenetics Research Network and led by Richard Weinshilboum, M.D., Mayo researchers will also examine whether changes in hormones and breast tissue, resulting from aromatase inhibitors, are influenced by genetics. By providing an understanding of these changes and their genetic influences, the results of this research could help predict the effectiveness of aromatase inhibitors in specific patients.
