Selective Estrogen Receptor Degraders in the Arsenal against Estrogen Receptor Positive Breast Cancer

In 2018, there were an estimated 18.1 million new cancer cases (17.0 million excluding non-melanoma skin cancer) and 9.6 million cancer deaths (9.5 million excluding nonmelanoma skin cancer) [1]. In women, breast cancer is the most commonly diagnosed cancer as well as the leading cause of cancer death, estimated to be 11.6% [1,2]. Although more than 70% of breast cancer patients in most high-income countries are diagnosed in stages I and II, only 20%-50% of patients in the majority of low- and middle-income countries are diagnosed in these stages [3]. In fact, most studies in the developed world show an association between an advanced clinical stage of breast cancer and any delay of more than 3 months between the development of symptoms and the initiation of treatment [3]. According to the American Cancer Society [4], estrogen receptor-positive (ER+) breast cancer is the most common type of breast cancer and approximately 2 out of 3 cases of breast cancer are hormone receptorpositive; most of which are ER+; meaning that there are estrogen receptors on the surface of the cell that bind to estrogen. It is well-established that early detection and diagnosis of breast cancer can lead to timely therapeutic/surgical interventions that can increase the chances of survival. While there are intrinsic challenges with the diagnosis and treatment selection strategies, there is optimism for the development of new therapeutics that target ER+ breast tumors [5,6]. Accordingly, the purpose of this article is to highlight challenges in diagnosis of ER+ breast tumors and to describe the therapeutic potential of selective targeting of the estrogen receptor. While the pharmacological concepts of receptor agonists, antagonists and partial agonists are well-accepted, the idea of selective estrogen receptor degraders (SERDs) is rapidly emerging as a novel therapeutic approach for ER+ breast cancer. SERDs are the third class of hormone therapy to be developed against hormone positive breast cancer, with oral agents being considered as a novel fourth class. Presently, there are no oral agents available for clinical use in the treatment of ER+ breast cancer, however; there are some candidates at various phases of development and others undergoing clinical trials.

Mammography is considered as the current standard for the detection of breast cancer [5], however; the interpretation is open to considerable variation [7], and appears to be less effective for women under 40 years of age and in women with dense breasts, less sensitive to small tumors (less than 1 mm, about 100,000 cells), and does not provide any indication of disease outcome [8,9]. The identification of early-stage cancer cells provides the best prognosis. Several other approaches for the diagnosis of breast cancer have been undertaken, including MRI, ultrasound, computerized tomography, positron emission tomography, biopsy and both genetic and proteomic biomarkers. However, there are some limitations to these techniques, such as cost, time involved, interpretation as well as the efficacy of these technologies in the detection of breast cancer in younger women. Thus, there is an urgent need for the development of a highly sensitive, accurate, reproducible and rapid early-stage breast cancer detection/ diagnostic system. Currently, the most common method for the detection of ER+ breast cancer is immunohistochemistry (IHC) [10]. It is interesting to note that the presence of ER+ states as determined through IHC does not predict the course of the disease, but does serve as a strong marker for the choice of hormone therapy to be applied [11].

Three main classes of pharmacotherapies that are currently being used in clinical settings for the treatment of ER+ breast cancer are aromatase inhibitors (AIs), selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs). Currently, AIs and SERMs are widely regarded as the most common agents in clinical settings, whereas SERDs have significant research and development potential. Fulvestrant, a marketed SERD, received approval by the Food and Drug Administration (FDA) in 2002 [12]. Fulvestrant, commonly referred to as Faslodex, is an intramuscular injection, which oncologists have accepted as an ER antagonist. It is proposed that when bound to the ER, receptor dimerization and energy-dependent nucleo-cytoplasmic shuttling actions are impaired. Functionally, this results in unstable nuclear functioning, causing the ER protein to become rapidly degraded [13,14]. This evokes a downregulation of receptor activity, leading to a marked decrease of estrogen production [5,13]. With a halflife of 50 days, Fulvestrant achieves maximal concentration after 5 days post-injection [13]. Fulvestrant has specific indications of use intramuscularly as an initial endocrine based therapy for the treatment of ER+ breast cancers. It is used as the current standard of care agent for women who have been shown to have the estrogen receptor 1 (ESR1) mutations, which preclude other hormone therapies from functioning. Fulvestrant, however, is not without its problems. Despite its clinical efficacy, the use of this SERD has been limited by the quantity of the drug that can be administered in a single intramuscular injection, as well as the increased stress that is put on patients through drug injections [15]. In terms of expansion for the development of additional SERD drugs, currently there are a number of promising agents that are at various phases of clinical development, including clinical trials. One of the more advanced SERDs in clinical trials is Elacestrant, which shows promise in overcoming the ESR1 mutation. Elacestrant is a novel, nonsteroidal, orally bioavailable SERD in Phase III that is comparing its efficacy against Fulvestrant [16]. This class of pharmacological therapy for ER+ breast cancer shows great promise for interventional sciences as it progresses through research and development. Further clinical research is needed for the development of novel SERDs that may be administered orally with high bioavailability.

Breast cancer remains a pervasive disease globally, where well-established concepts of early detection and diagnosis leads to opportune therapeutic interventions to increase the chance of survival. While surgical and radiation therapies exist and are highly effective, pharmacological treatments that target specific ER+ breast tumors demonstrate great confidence for future research for the scientific community, specifically in the area of SERDs, which are both novel and effective.

Infrastructural support was provided by the St. Boniface Hospital Foundation.

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