Anastrozole efficacy in breast cancer prevention for high-risk women linked to estrogen levels

By Dr. Liji Thomas, MDDec 7 2023Reviewed by Benedette Cuffari, M.Sc.

A new study published in The Lancet Oncology discusses the efficacy of anastrozole, a molecule used to prevent breast cancer in postmenopausal women with a high risk of breast cancer.

Study: Effect of baseline oestradiol serum concentration on the efficacy of anastrozole for preventing breast cancer in postmenopausal women at high risk: a case-control study of the IBIS-II prevention trial. Image Credit: Ground Picture / Shutterstock.com

The role of estrogen in breast cancer

Breast cancer risk in postmenopausal women is increased with higher baseline concentrations of estradiol and testosterone. However, it is not clear how the greater presence of these hormones impacts the effectiveness of hormone-targeting therapies in preventing or treating breast cancer.

High levels of these hormones, as well as lower levels of sex hormone binding globulin (SHBG) resulting in higher levels of free hormones, are known risk factors for breast cancer in postmenopausal women, especially estrogen receptor (ER) positive cancers.

Anastrozole suppresses the activity of an enzyme called aromatase, which converts androgens to estrogens, thus boosting estrogen levels. Earlier reports show that aromatase inhibitors protect women with high estradiol levels but not those with undetectable concentrations; however, other research produced conflicting findings.

The current study examined whether hormone levels affected the efficacy outcomes of aromatase inhibitors, specifically anastrozole, in breast cancer management among postmenopausal women.  

What did the study show?

The data for the study were obtained from the ongoing IBIS-II prevention trial, in which postmenopausal women between 40 and 70 years of age with a high risk of developing breast cancer were randomized to daily oral anastrozole or placebo for five years. Measured outcomes included the association between the ratio of baseline estradiol concentration to that of SHBG and the development of breast cancer within the trial period.

None of the participants used hormone replacement therapy during or within three months prior to the start of the trial. Each woman who developed breast cancer was matched with two controls within the same treatment group, of the same age, and with the same period of follow-up, but were otherwise randomly chosen.

The study aimed to determine the relative increase in cases with a quartile increase in the hormone ratio. The effect of the ratio on breast cancer risk was also assessed, in addition to establishing the relative benefit of using anastrozole as compared to placebo in terms of breast cancer prevention.

Study findings

There were over 3,800 women recruited between February 2003 and January 2012, with a median follow-up of 131 months. During this period, there were 85 cases of breast cancer in the group on anastrozole as compared to 165 in the placebo group, thus indicating that 8.5% of placebo recipients developed breast cancer as compared to 4.4% in the anastrozole group.

Comparing 72 cases and 140 controls from the anastrozole group with 142 cases and 274 controls in the placebo group, a higher baseline hormone ratio tended to be associated with a higher risk of breast cancer in the latter group only, with 25% more cases as the ratio rose.

The effect of the ratio on breast cancer risk was raised by 20% in the placebo group. No noticeable difference was observed with ER-positive tumors. The relative benefit of anastrozole was observed from the second quartile onwards, with the risk decreasing by about 50% overall.  

What are the implications?

Like many previous studies, the current study reports that higher hormone levels are associated with an increased risk of breast cancer but lower levels of SHBG. For the first time, this study demonstrates that aromatase inhibitors are most effective in preventing breast cancer in postmenopausal women with a high estradiol-SHBG ratio; however, its effectiveness may be minimal if the ratio is low.  

This is supported by another study, which showed a better response to aromatase inhibitors with higher estradiol concentrations. The current research mainly included White European women with a family history of breast cancer.

Previously, the use of anastrozole as an adjuvant was found to reduce distant recurrence to a greater extent than tamoxifen, a selective ER modulator (SERM), which has been used to reduce breast tissue density and prevent breast cancer in women with breast intraepithelial neoplasia. Tamoxifen efficacy showed no association with estradiol levels, unlike another SERM, raloxifene.

Considering the relatively low cost of hormone measurements, the findings suggest that serum hormones should be measured more routinely and integrated into risk management decisions. These efforts will help identify women who may receive the most significant benefit from anastrozole and other aromatase inhibitors.

More extensive studies in different demographic and clinical settings are needed to validate these results and explore the utility of anastrozole as an adjuvant therapy. The adverse effects of aromatase inhibitors as opposed to SERMs, associations of the sex hormones with other risk factors, and the application of hormone concentrations in selecting the right agent from these two classes should also explored in future research.