Following recurrence of estrogen receptor alpha (ER)-positive breast cancer, advanced/metastatic disease is managed with further anti-estrogen therapies, targeted therapies, and DNA-damaging chemotherapies. Nearly all metastatic breast cancers eventually become completely refractory to these therapies. Prior to the approval of tamoxifen, estrogens were frequently used for the treatment of breast cancer. This may seem counterintuitive since we now rely on anti-estrogens for disease management, but response rates to estrogens are similar to those of anti-estrogens in the setting of advanced disease. Approximately 1/3 of anti-estrogen-resistant breast cancers respond to estrogen therapy, translating into ~100,000 new patients each year who could benefit. Similarly, some cancers respond to withdrawal of anti-estrogen therapy, which may be caused by ER transcriptional reactivation. Breast tumor responses to estrogen therapies and anti-estrogen withdrawal have been observed for >70 years, but the lack of A) understanding of the therapeutic mechanism(s), and B) criteria to identify patients likely to benefit have hindered clinical use.
Our studies are providing insight into the mechanism(s) underlying sensitivity of anti-estrogen-resistant breast cancers to estrogen therapy, which will significantly and durably impact the understanding and clinical management of ER+ breast cancer. Identifying molecular markers that predict benefit from estrogen therapy, and the optimal duration of therapy required to maximize anti-cancer effects, will be critical to legitimize this inexpensive, widely accessible, relatively safe and tolerable treatment option, and to provide a precision medicine basis to limit its use to patients with cancers likely to respond. Understanding this mechanism will also reveal candidate drug targets to enhance the anti-cancer effects of ER reactivation.