Prevention of ER-Negative Breast Cancer

Abstract

The successful demonstration that the selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene reduce the risk of breast cancer has stimulated great interest in using drugs to prevent breast cancer in high-risk women. In addition, recent results from breast cancer treatment trials suggest that aromatase inhibitors may be even more effective at preventing breast cancer than are SERMs. However, while SERMs and aromatase inhibitors do prevent the development of many estrogen-receptor (ER)-positive breast cancers, these drugs do not prevent the development of ER-negative breast cancer. Thus, there is an urgent need to identify agents that can prevent ER-negative breast cancer. We have studied the cancer preventative activity of several classes of drugs for their ability to prevent ER-negative breast cancer in preclinical models. Results from these studies demonstrate that rexinoids (analogs of retinoids that bind and activate RXR receptors), tyrosine kinase inhibitors (such as EGFR inhibitors and dual kinase inhibitors that block EGFR and HER2/neu signaling), and cyclo-oxygenase 2 (COX-2) inhibitors all prevent ER-negative breast cancer in transgenic mice that develop ER-negative breast cancer. Other promising agents now under investigation include vitamin D and vitamin D analogs, drugs that activate PPAR-gamma nuclear receptors, and statins. Many of these agents are now being tested in early phase cancer prevention clinical trials to determine whether they will show activity in breast tissue and whether they are safe for use in high-risk women without breast cancer. The current status of these studies will be reviewed. It is anticipated that in the future, drugs that effectively prevent ER-negative breast cancer will be used in combination with hormonal agents such SERMs or aromatase inhibitors to prevent all forms of breast cancer.

Despite aggressive screening to detect early breast cancer and significant advances in treatment, breast cancer is still the most common cancer in women excluding skin cancer, and it remains the second leading cause of cancer death in women, exceeded only by lung cancer [1]. Recently, the incidence of breast cancer in the United States has declined. However, the decreased incidence was observed only in women aged 50 years or older and was more evident in estrogen receptor (ER)-positive than in ER-negative cancers. The incidence of ER-negative breast cancer, which has a poor prognosis and often occurs in premenopausal women, has not shown significant change. Therefore, there is an urgent need to prevent ER-negative breast cancer.

Primary prevention approaches of breast cancer can be categorized into prophylactic surgery, lifestyle changes, and chemoprevention. Prophylactic surgeries, which consist of bilateral oophorectomy and bilateral mastectomy, are highly invasive approaches that only apply to women with an extremely high risk of breast cancer, such as hereditary breast cancer. The invasive nature has limited their extensive clinical usage. Although lifestyle changes are considered as safe and natural processes, recent meta-analyses of clinical data failed to demonstrate consistent, strong, and statistically significant association between lifestyle changes and breast cancer incidence, except for regular alcohol consumption and weight gain [2, 3]. These interventions could reduce a women's risk of breast cancer by 5% –10%. Given the limitation of prophylactic surgeries and the modest effect of lifestyle changes, recent breast cancer prevention studies have focused on preventative therapy, which has been shown to be effective in reducing the risk of breast cancer in randomized clinical trials.