Abstract: Tamoxifen has been shown to reduce the risk of developing estrogen receptor (ER)-positive breast cancer by at least 50%, in both pre- and postmenopausal women. The cur­rent challenge is to find new agents with fewer side effects and to find agents that are specifically suitable for premenopausal women with ER-negative breast cancer. Other selective estrogen receptor modulators (SERMs), such as raloxifene, arzoxifene, and lasofoxifene, have been shown to reduce the incidence of breast cancer by 50%–80%. SERMs are interesting agents for the prevention of breast cancer, but longer follow-up is needed for some of them for a complete risk–benefit profile of these drugs. Aromatase inhibitors have emerged as new drugs in the prevention setting for postmenopausal women. In the Mammary Prevention 3 (MAP3) trial, a 65% reduction in invasive breast cancer with exemestane was observed, and the Breast Cancer Intervention Study-II trial, which compared anastrozole with placebo, reported a 60% reduction in those cancers. Although SERMs and aromatase inhibitors have been proven to be excellent agents in the preventive setting specifically for postmenopausal women and ER-positive breast cancer, newer agents have to be found specifically for ER-negative breast cancers, which mostly occur in premenopausal women.

Keywords: breast cancer, preventive therapy, selective estrogen receptor modulators, aromatase inhibitors, high-risk women


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Introduction

Breast cancer is by far the most common cancer in women worldwide, with an esti­mated 1.67 million new cancers diagnosed in 2012.1 Breast cancer is associated with a variety of lifestyle choices, such as obesity, later onset of first childbirth, and the use of hormone replacement therapy, which is also increasing in the developing world. Breast cancer still remains the second cause of cancer death in the developed world. There has been a trend toward reduction of breast cancer mortality, due to advanced early detection and better therapeutic strategies. However, breast cancer incidence and mortality have remained extremely high.

The identification of women who are at high risk of developing the disease, which typically means a 5-year breast cancer risk of 1.67% or higher, is key to chemopreven­tion of breast cancer. Traditionally, women are categorized as being high risk for breast cancer due to their family history. However, new developments in the ability to predict and modify breast cancer risk have been found. One example is mammographic density, which in terms of population attributable risk, accounts for more breast cancers than family history.2 Targeting women at high risk of developing breast cancer identified by biomarkers, such as breast density, atypical hyperplasia, or lobular carcinoma in situ, with a high population attributable risk,3 and offering them agents that reduce their risk of developing the disease are likely to lead the way in developing this approach to cancer prevention.

Chemoprevention is the use of drugs, vitamins, food supplements, vaccines, or other agents to try to reduce the risk, delay the development, or recurrence of cancer, and it is a promising strategy for cancer prevention.4 It is therefore crucial to identify as precisely as possible which types of breast cancers can be prevented by specific agents.

Here, a comprehensive review of breast cancer pre­vention approaches for women at high risk of developing the disease will be presented. Most will be dedicated to the discussion of selective estrogen receptor modulators (SERMs), of which tamoxifen is the most widely studied and has been used in the past few decades to treat breast cancer; and it has also been shown to reduce the incidence of invasive breast cancer. Furthermore, results have been reported on aromatase inhibitors (AIs) for breast cancer prevention in women at high risk of the disease, which will also be discussed in this overview.

Selective estrogen receptor modulators

SERMs are chemically diverse compounds with the capa­bility to bind to estrogen receptors (ERs). They have both selective agonist and antagonist abilities on a variety of organs, which contain ERs.