Revisiting Estrogen for the Treatment of Endocrine-Resistant Breast Cancer: Novel Therapeutic Approaches

Abstract

Estrogen receptor (ER)-positive breast cancer is the most common subtype, representing 70–75% of all breast cancers. Several ER-targeted drugs commonly used include the selective estrogen receptor modulator (SERM), tamoxifen (TAM), aromatase inhibitors (AIs) and selective estrogen receptor degraders (SERDs). Through different mechanisms of action, all three drug classes reduce estrogen receptor signaling. Inevitably, resistance occurs, resulting in disease progression. The counterintuitive action of estrogen to inhibit ER-positive breast cancer was first observed over 80 years ago. High-dose estrogen and diethylstilbestrol (DES) were used to treat metastatic breast cancer accompanied by harsh side effects until the approval of TAM in the 1970s. After the development of TAM, randomized trials comparing TAM to estrogen found similar or slightly inferior efficacy but much better tolerability. After decades of research, it was learned that estrogen induces tumor regression only after a period of long-term estrogen deprivation, and the mechanisms of tumor regression were described. Despite the long history of breast cancer treatment with estrogen, this therapeutic modality is now revitalized due to the development of novel estrogenic compounds with improved side effect profiles, newly discovered predictive biomarkers, the development of non-estrogen small molecules and new combination therapeutic approaches.

DREAM On, DREAM Off: A Review of the Estrogen Paradox in Luminal A Breast Cancers

“…The two questions regarding the estrogen paradox were investigated in a series of elegant in vitro experiments by Dr. V.C. Jordan and others in his laboratory who have used ER+ breast cancer cell lines conditioned by long-term estrogen depletion to simulate the five-year post-menopausal gap (reviewed in [ 6 ]). They showed that the response to estrogen alternates between growth induction and suppression.…”

“…This cycling of the response to estrogen between growth induction and suppression mediated by intermittent estrogen exposure and the resulting change in the level of ER has led to the suggestion that “pre-emptively switching between estrogen and estrogen deprivation therapies before resistant tumors emerge is an effective strategy for long-term control of tumor burden” [ 7 ]. This laboratory advancement is driving the development of therapeutics that can condition or assist in estrogen-induced apoptosis [ 6 ] and has served as the basis for at least one large clinical trial, The Study Of Letrozole Extension (SOLE), a phase III randomized clinical trial of continuous vs. intermittent letrozole in post-menopausal women.…”

“…HRT trials that initiate estrogen-only therapy close to the menopause such as the Million Women Study in the UK [ 46 ] have not found an estrogen-induced decrease in breast cancer, raising the question for the above hypothesis—if estrogen is functioning to activate the DREAM pathway, then why is there a need for the five-year gap? For Luminal B cancers, the work by Jordan’s lab has suggested that this period of estrogen depletion leads to an increase in endogenous ER, which is a prerequisite for the apoptotic or growth-inhibitory response to estrogen [ 6 , 7 ]. For Luminal A cancers which have consistently higher levels of ER and we presume are always growth inhibited by estrogen, the question becomes more perplexing.…”