ERα-targeted endocrine therapy, resistance and the role of GPER

Abstract

Endocrine therapy is an effective option for the treatment of estrogen receptor alpha (ERα)-positive breast cancers. Unfortunately, a large fraction of women relapse with endocrine-resistant tumors. The presence of constitutively active ERα mutants, found in a subset of relapse tumors, is thought to be an important endocrine resistance mechanism and has prompted the search for more effective anti-hormone drugs that can effectively inhibit these mutant versions of the receptor. The G protein-coupled estrogen receptor (GPER), is also thought to contribute to the development of endocrine resistance, in part, due to its activation by clinically used selective estrogen receptor modulators and downregulators (SERMs/SERDs). Therefore, next-generation drugs should be screened for potential activity towards GPER. Here we highlight the need for truly ERα-selective SERMs and SERDs that do not cross-react with GPER for the treatment of ERα-positive breast cancers.

Introduction

Estrogen (17β-estradiol, E2) plays a role in various physiological processes, but is best known for its role in female reproduction and breast tissue development [1]. It exerts its effects through three known estrogen receptors: ERα, ERβ and GPER (formerly known as GPR30) [2–4]. ERα and ERβ, termed the classical estrogen receptors, are ligand-activated nuclear transcription factors that primarily exert estrogen-mediated genomic signaling inside the cell [5, 6]. Unlike the classical ERs, GPER is a G protein-coupled receptor that for the most part mediates estrogen-induced rapid, non-genomic signaling that results in the initiation of an array of downstream signals, including the activation of the mitogen-activated protein kinase (MAPK)/ERK and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways, calcium mobilization and cAMP production, via the transactivation of the epidermal growth factor receptor (EGFR) [4, 7]. However, GPER can also, to a certain extent, modulate transcription of genes, such as c-fos [8, 9]. Like GPER, the classical ERs also mediate E2-induced rapid, non-genomic signaling, which is thought to occur through a membrane-bound fraction of the receptors, resulting in rapid downstream signals similar to those activated by GPER [10]. Thus, overlapping signaling pathways between the classical ERs and GPER exist.

Aside from its physiological roles, ERα is also an important initiator and driver of breast cancer [11]. Due to its role and prevalence in the majority of breast cancers (~70%), ERα has been an important molecular target for the treatment of ERα-positive breast cancers [12]. ERβ, on the other hand, is generally downregulated in breast cancers, making it a potentially less desirable therapeutic target [13–15]. However, some groups have observed increased expression of ERβ in breast cancer samples and have reported that ERβ correlates with improved patient outcome [16, 17]. Due to conflicting reports on potential roles of ERβ in breast cancer, this review will focus on ERα [15]. Inhibition of ERα signaling by endocrine therapy, using selective estrogen receptor modulators (SERMs, such as tamoxifen), the selective estrogen receptor downregulator (SERD) fulvestrant, and aromatase inhibitors (AIs, e.g. letrozole and exemestane), has shown great clinical success in treating ERα-positive breast cancers [18, 19]. Unfortunately, a large fraction of patients relapse with endocrine therapy-resistant tumors that no longer respond to the primary therapy.

Endocrine resistance has become a major clinical hurdle in the treatment of ERα-positive breast cancers and approaches to overcome this resistance are an ongoing area of research. Several resistance mechanisms have been described, including the emergence of constitutively active mutant forms of ERα (e.g. Y537S and D538G), in relapse tumors that are resistant to current ERα-targeted endocrine therapies [20–22]. GPER has also been suggested to contribute to the development of endocrine resistance, possibly through its cross-reaction with tamoxifen and other clinically utilized SERMs and SERD, yet its role remains unclear [23].

In this review we highlight a) current endocrine therapies for the treatment of ERα-positive breast cancers, b) the role of mutant ERα as an endocrine resistance mechanism and c) the potential role of GPER in the development of endocrine resistance. We also discuss currently developing ERα-targeting compounds and why their potential cross-reactivity to GPER should be taken into consideration in the development of new therapies.

Breast cancer endocrine therapies

Endocrine therapy is effective at treating ERα-positive breast cancers and has prolonged the lives of millions of women [18, 19]. It focuses on inhibiting the growth of ERα-positive breast cancers by blocking the activation of the ERα, and thus its downstream proliferative and pro-survival signaling. Endocrine therapy achieves this either by directly blocking estrogen binding to ERα (using SERMs or SERDs) or by decreasing the plasma levels of circulating estrogen by inhibiting its production (using Als).

SERMs and SERDs

SERMs are a class of small molecules that act as antagonists of ERα by competing with estrogen for binding to the receptor, thereby blocking the recruitment of co-regulators to the receptor [24]. Their activity is tissue specific, acting as ERα antagonists in the breast, while functioning as ERα agonists in the bone and uterus [25, 26]. Currently FDA-approved SERMs include tamoxifen, raloxifene and toremifene (Figure 1).

Figure 1.

Structures of the SERMs tamoxifen, toremifene and raloxifene and the SERD fulvestrant.

Tamoxifen (Nolvadex®, Soltamox®), the most prescribed SERM, has shown great success in the clinic for both the treatment and prevention of ERα-positive breast cancers in pre- and post-menopausal women, showing a significant decrease in ERα-positive breast cancer-related mortality and recurrence rates when taken over a 5 (and up to 10) year period [27, 28]. Unfortunately, due to its agonist activity in the endometrium, women taking tamoxifen experience up to a 7.5-fold increased risk of developing endometrial cancer [25, 29, 30]. Patients taking tamoxifen also have an increased risk of developing thromboembolisms [31, 32]. However, these risks do not tend to outweigh the benefits of the drug. Compared to tamoxifen, raloxifene (Evista®) carries a lower risk of developing thromboembolisms, but is less effective at preventing invasive breast cancer [33]. Nevertheless, raloxifene significantly decreases the risk of developing invasive breast cancer in post-menopausal women with osteoporosis [34]. Raloxifene is currently approved for the prevention of invasive breast cancer in post-menopausal women with osteoporosis. The third FDA-approved SERM, toremifene (Fareston®), also increases the risk of developing thromboembolisms, but data regarding its causal role in developing endometrial cancer is limited [35]. Toremifene is approved for the treatment of advanced ERα-positive breast cancers in post-menopausal women. To date, tamoxifen is the only SERM approved for the treatment of ERα-positive breast cancers in pre-menopausal women.

SERDs are a class of small molecules that, like SERMs, act as antagonists of the ERα. However, unlike SERMs, SERDs not only antagonize the receptor, but also induce its degradation, resulting in a decrease in ERα protein levels [36]. Furthermore, SERDs are “pure” antagonists of the ERα, in that they do not show agonist properties in other tissues [37]. Currently, fulvestrant (Faslodex®, Figure 1) is the only FDA-approved SERD and is used for the treatment of metastatic ERα-positive breast cancers in post-menopausal women with disease progression following prior endocrine therapies.

Aromatase inhibitors

Aromatase inhibitors (Als) are a class of small molecules that block the production of estrogen by inhibiting the enzyme aromatase (CYP19A1) [38]. They have been highly effective in the clinic for the treatment of ERα-positive breast cancers in post-menopausal women [39]. In fact, they are more efficacious than tamoxifen in this setting [19, 40]. However, this class of drugs has significant side-effects, including muscle/joint pain, bone loss, hot flashes and insomnia, causing over 30% of patients to discontinue treatment [41–43]. Nevertheless, Als are highly effective in the treatment of ERα-positive breast cancers and are becoming a more popular standard first-line endocrine therapy option for post-menopausal women. Currently FDA-approved Als include the reversible Als anastrozole (Arimidex®) and letrozole (Femara®) and the irreversible Al, exemestane (Aromasin®) (Figure 2).

Figure 2.

Structures of the AIs exemestane, anastrozole and letrozole.

Endocrine resistance

Endocrine therapy is the standard of care for the treatment of ERα-positive breast cancers. Unfortunately, some 30% of patients eventually develop acquired endocrine resistance to the initial therapy, with reports suggesting that this number may be as high as 40–50% [18, 44]. Several mechanisms have been proposed to account for the development of endocrine resistance, including alterations in growth factor signaling (e.g. overexpression of the EGFR or HER-2), changes in the expression of ERα and its co-activators/co-repressors, mutations in ERα, changes in the metabolism of tamoxifen and tamoxifen-induced GPER signaling (discussed later) [22, 45–47].

In the late 1990s, Zhang et al. reported the identification of three ESR1 (the gene encoding ERα) mutations in metastatic breast cancer samples [48]. One of the mutations, Y537N, was found to cause constitutive activation of the receptor, even in the absence of estrogen. More importantly, this mutation made the receptor less sensitive to inhibition by tamoxifen (the maximum tested dose was 100 nM). This led to the proposal that mutations of this site could contribute to breast cancer progression and endocrine resistance. Similar findings regarding mutations at the Y537 codon were previously reported by Weis et al. in a structure-activity relationship study [49]. More recently, studies identified several ESR1 mutations (e.g. E380Q, Y537S, Y537C and D538G) that were highly enriched in up to 55% of metastatic breast cancer samples of patients who relapsed while on endocrine therapy [20, 21, 50–52]. Importantly, these mutations were for the most part absent in matched primary breast tumors as well as primary breast tumors, in general, pointing to a possible role in endocrine resistance. However, several of these mutations have been identified at low frequencies in primary breast tumors (<1–3%), but at a far lower level than in relapse tumors [21]. The most commonly occurring mutations were Y537S and D538G, located in the ligand-binding domain (LBD) of ERα. These mutations result in constitutive activation of the receptor by inducing a ligand-bound confirmation of the receptor in the absence of estrogen. More specifically, they stabilize helix 12, an important structural component in the LBD of ERα, in a closed agonist-bound confirmation, thereby exposing a co-regulator binding site on the receptor that is normally only revealed following the binding of estrogen. This stabilized ligand-bound confirmation also makes the mutant receptor less susceptible to inhibition by tamoxifen and fulvestrant, by impairing access to the ligand binding pocket of the receptor [21, 50, 53]. These observations support the role of these mutations in endocrine resistance in response to not only AIs, but also SERM- and SERD-based therapies. Interestingly, the Y537S mutation has been reported to be more resistant than the D538G mutation, to in vivo inhibition by fulvestrant [54].

Clinical data of patients that have relapsed while on an AI therapy have shown that the Y537S and D538G mutants are associated with more aggressive relapse tumors [55]. This aggressive phenotype could be due to the unique transcriptome induced by the Y537S and D538G mutants (compared to that of wildtype ERα) that includes the modulation of pro-metastatic genes [56]. This merits further research into genes that are specific targets of the mutant forms of ERα, as potentially new therapeutic targets for the treatment of relapsed breast tumors expressing mutant ERα. Interestingly, in a retrospective analysis of the FERGI trial (a comparison of treatment with a PI3K inhibitor + fulvestrant versus placebo + fulvestrant, in ERα-positive breast cancer patients with locally advanced or metastatic disease), Spoerke et al. did not observe a difference in the control placebo + fulvestrant arm of the trial with respect to progression-free survival (PFS) between patients harboring wildtype ESR1 versus patients harboring mutated ESR1, as measured using circulating tumor DNA [57]. This underlines the complexity of tumor heterogeneity and how the presence of other mutations alongside ESR1 mutations could potentially influence ERα-targeted endocrine therapies. Furthermore, it could imply that ESR1 mutations are more important in endocrine resistance in a hormone-deprived setting (e.g. in patients on AI therapies) than in tumors that relapse on SERM/SERD therapies.

Nevertheless, the presence and activity of mutant forms of ERα in the metastatic relapse setting have become a highly studied resistance mechanism and are now strongly considered in the development of next-generation SERMs and SERDs (discussed in the next section). We acknowledge the existence of other resistance mechanisms that are important in treating ERα-positive breast cancers, but these will not be covered in this review. We direct the reader to comprehensive reviews on other mechanisms cited earlier in this section.

Current status of next-generation SERMs and SERDs

Acquired endocrine resistance is a major clinical problem in treating ERα-positive breast cancers. The presence of the Y537S and D538G ERα mutants in many relapse tumors highlights the need for the development of improved SERMs and SERDs that can effectively inhibit both the wildtype and clinically-observed mutant forms of ERα [21, 50, 51]. Such new drugs could be effective in treating relapse tumors harboring the mutant receptor and improve disease stabilization, thereby prolonging the lives of patients.

Currently, for women with advanced metastatic ERα-positive breast cancer that has relapsed while on endocrine therapy, therapeutic options are limited. In this setting, the SERD fulvestrant has shown the most promising results in extending PFS, either as a monotherapy or in combination with targeted therapies like cyclin-dependent kinase 4/6 (CDK4/6) inhibitors [58, 59]. With regard to the presence of ESR1 mutations, Fribbens et al. analyzed ESR1 mutations in baseline plasma from the SOFEA trial (comparing exemestane versus fulvestrant-containing therapies) and the PALOMA3 trial (comparing fulvestrant + placebo versus fulvestrant + the CDK4/6 inhibitor palbociclib) [60]. They found that fulvestrant provided a significant benefit over exemestane in patients with tumors harboring ESR1 mutations. However, treatment with fulvestrant had a modestly worse PFS outcome for patients with ESR1 mutations when compared to patients with wildtype ESR1. The latter result is not surprising given that mutant forms of ERα are less sensitive to fulvestrant and require higher drug concentrations to be fully inhibited [20, 21, 54]. The currently approved dosage of fulvestrant (500 mg) has been shown to be ineffective in fully blocking ERα in tumors, and in turn associated with early disease progression [61]. Taken together, the aforementioned observations imply that achieving higher plasma levels of fulvestrant could be of great therapeutic benefit, especially with regard to relapse tumors harboring ESR1 mutations. Unfortunately, fulvestrant has poor pharmacological properties, requiring it to be administered through painful, monthly intramuscular injections, thereby limiting the maximum achievable dose of the drug. As a consequence, the development of new, more bioavailable SERMs/SERDs that possess better pharmacological properties, while also efficaciously inhibiting ERα mutants, is the goal of much current research.

The small molecule ZB716 (Figure 3), a boronic acid-modified version of fulvestrant with high oral bioavailability, is an example of how improving the bioavailability of a drug can lead to higher plasma levels [62–64]. Liu et al. showed that ZB716 achieved over 10 times higher plasma levels than fulvestrant when orally administered to mice and that ZB716 has similar levels of efficacy (compared to fulvestrant) in vitro [62]. Similarly, Guo et al. showed that ZB716 achieved higher plasma levels in both the blood and tumors in xenograft models [64]. The latter study also demonstrated that ZB716 is more efficacious than fulvestrant in tumor growth inhibition in a cell line-derived xenograft model. Interestingly, ZB716 displayed no observed benefit (versus fulvestrant) in inhibiting tumor growth in a patient-derived xenograft (PDX) model.

Figure 3.

Structures of the currently in-development orally bioavailable SERDs AZD9496, LSZ102, GDC-0927, ZB716 and the orally bioavailable SERM bazedoxifene.

Several new SERDs are currently being developed and assessed in clinical trials to treat advanced endocrine-resistant breast cancers (Figure 3). AZD9496, an orally bioavailable SERD developed by AstraZeneca, has been shown to be highly effective at inhibiting ERα-positive breast cancer cells in vitro and in vivo, while also being highly effective at binding and degrading wildtype and mutant forms of ERα (the binding IC₅₀ values for AZD9496 are >6-fold improved versus those of fulvestrant) [65, 66]. Furthermore, Weir et al. showed that AZD9496 inhibited the growth of a PDX tumor harboring the D538G ERα mutant [66]. A phase 1 clinical trial of AZD9496 was recently completed and indicated that the drug is tolerated at the maximum tested dose (600 mg), even showing some early signs of disease stabilization over a 12 month period [67].

Another orally bioavailable SERD, G1T48, developed by G1 Therapeutics Inc., is effective at inhibiting ERα-positive tumor growth in in vivo models of tamoxifen and aromatase resistance [68]. Furthermore, G1T48 inhibits the growth of ERα-Y537S- and ERα-D538G-expressing breast cancer cells. G1T48 also showed synergistic inhibition in a tamoxifen-resistant xenograft model when used in combination with the novel CDK4/6 inhibitor, G1T38. G1T48 recently entered a Phase 1 clinical trial () for initial in-human safety testing in women with advanced ERα-positive breast cancer.

Other orally bioavailable SERDs, including LSZ102 (Novartis Pharmaceuticals, ), SAR439859 (Sanofi Inc., ) and GDC-0927 (Genentech Inc., ) are also currently being evaluated both in the lab and in clinical trials as potentially new therapeutic agents for the treatment of advanced ERα-positive breast cancers [69–73]. Newly emerging SERDs show promising results as potential ERα-targeting breast cancer therapies, but only time will tell if any of these compounds are efficacious in patients and gain clinical approval.

Aside from orally bioavailable SERDs, the already clinically-approved SERM/SERD hybrid, bazedoxifene (Figure 3), is also gaining more interest as a potential therapeutic agent for treating ERα-positive advanced breast cancers. Bazedoxifene, which is already used in hormone replacement therapy and for the prevention of post-menopausal osteoporosis, exhibits favorable efficacy in various endocrine-resistant breast cancer models [74–77]. Furthermore, Fanning et al. reported that bazedoxifene inhibits the activity of the Y537S and D538G mutant forms of ERα, offering structural insights into its inhibitory mechanism [78]. Its activity in models of endocrine resistance and its well tolerated drug profile, make bazedoxifene a candidate that could prove efficacious in treating ERα-positive breast cancers.

GPER: a culprit in endocrine resistance?

The non-classical estrogen receptor, GPER, has gained attention as a possible player in the development of endocrine resistance in breast cancer. This theory stems from clinical observations that found a significant increase in the expression of GPER in relapse tumors of patients that had undergone prior tamoxifen therapy [23, 79]. Furthermore, GPER expression has been shown to correlate negatively with relapse-free survival, further indicating an unfavorable role of the receptor in endocrine resistance [79]. Recently, Ignatov et al. reported the opposite, finding a positive correlation between GPER-expression and disease-free survival. However, this correlation was not statistically significant [80]. Interestingly, they did report that treatment with tamoxifen was less beneficial than an AI-based therapy in patients with GPER-positive breast tumors.

In vitro data also supports the clinical observations that point to a negative role for GPER in endocrine resistance. Ignatov et al. showed that tamoxifen-induced proliferation of tamoxifen-resistant MCF-7 cells could be abrogated by downregulation of GPER [47]. Similar findings were reported by Mo et al. who showed that GPER-inhibition, using the GPER-selective antagonist G15, could “re-sensitize” tamoxifen-resistant cells to tamoxifen [23, 81]. Tamoxifen-induced proliferation, via a GPER-mediated pathway, has also been observed in other cell types [8, 82].

Some elucidation for a role of GPER in endocrine resistance came from Catalano et al. who showed that tamoxifen-resistant MCF-7 cells expressed higher levels of aromatase [83]. Increased aromatase expression could potentially create a local increase in estrogen levels, thereby allowing tumors to overcome the inhibitory effects of tamoxifen and AI therapies. Importantly, the increased aromatase expression could be reverted back to baseline levels by reducing GPER expression or inhibiting its function using G15.

Zekas et al. also provided a potential mechanism for GPER in endocrine resistance [84]. They observed that tamoxifen and fulvestrant, through a GPER-mediated pathway, induce the translocation of the pro-apoptotic transcription factor Forkhead box protein O3a (FOXO3a) out of the nucleus. Nuclear expulsion of FOXO3a is a phenotype that is associated with its inactivation and promotes a pro-survival state [85–87]. Importantly, knockdown of GPER abrogated the observed ligand-induced translocation of FOXO3a. It was suggested that tamoxifen-induced inactivation of FOXO3a could provide a fraction of tumor cells with a survival advantage to overcome inhibitory effects of tamoxifen mediated through ERα, eventually leading to the acquisition of endocrine resistance through mutations.

An important observation linking GPER to endocrine resistance was provided by Mo et al. [23]. They reported that a tamoxifen-resistant MCF-7 tumor could be “re-sensitized” to tamoxifen treatment of mice with a combination of tamoxifen and G15. Importantly, mono-therapy with either tamoxifen or G15 had no effect on tumor growth. This implies that pro-survival signaling by GPER (through its downstream target Akt) is possibly overcoming the tamoxifen-induced apoptotic signaling (via ERα), a consequence of tamoxifen-mediated activation of GPER (discussed in the next section).

The body of scientific data pointing to a role for GPER in endocrine resistance has been met with some contradictory reports. A small number of publications have reported that activation of GPER, using the GPER-selective agonist G-1, induces cell death of breast cancer cells [88–90]. Whether this cell death is caused by hyperstimulation of GPER or is a possible off-target effect due to the high doses of G-1 tested, remains unclear and warrants further investigation. Nevertheless, these findings do not diminish the numerous observations implying a pro-survival role for GPER in endocrine resistance.

A proposed role for GPER in endocrine resistance and how to circumvent it

SERMs and SERDs are widely used to inhibit ERα signaling in breast cancers. However, contrary to their antagonism towards ERα, currently approved SERMs (tamoxifen and raloxifene) and SERD (fulvestrant) have been shown to act as agonists of GPER in breast cancer cell models, resulting in the activation of the ERK and PI3K pathway [4, 91, 92]. Similarly, many other estrogenic compounds (e.g. xenoestrogens and phytoestrogens) that act on the classical ERs have also been found to act as agonists of GPER [93].

This cross-activation of GPER, particularly by tamoxifen, is a common element seen in all of the observations discussed in the previous section and is a potential clue into the role of GPER in the development of endocrine resistance [23, 47, 83]. In the case of tamoxifen, patients are treated for a minimum of 5 years with cancer relapse often occurring after completion of this 5 year period [18]. It is possible that chronic activation of GPER by tamoxifen, promotes long-term survival of a fraction of primary tumor cells or alternatively breast cancer stem cells. This prolonged survival could grant this subset of tumor cells sufficient time to acquire additional mutations, resulting in resistance to the primary therapy (e.g. acquiring endocrine-resistant ESR1 mutations) and leading to the development of endocrine-resistant relapse tumors (Figure 4). This possible role highlights the potentially significant benefit of developing truly ERα-selective therapeutic antagonists that do not cross-activate GPER. A truly ERα-selective antagonist would lack cross-activation of GPER, and its resulting pro-survival signaling, thus potentially delaying or decreasing the development of endocrine-resistant relapse tumors.

Figure 4. Proposed role of GPER in the development of endocrine resistance.

Tamoxifen (as well as other SERMs and SERDs) inhibits its molecular target (ERα) (red line), but simultaneously cross-activates GPER (green arrow). This cross-activation induces the downstream activation of Akt and other survival signals. Chronic cross-activation of GPER by tamoxifen (over the course of the average 5 year tamoxifen regimen) provides a subset of primary tumor cells with prolonged survival signaling that opposes the inhibitory cell death induced through the tamoxifen-mediated inhibition of ERα. Prolonged survival thus provides this subset of surviving primary tumor cells sufficient time to acquire additional mutations that lead to resistance to the primary therapy, resulting in the development of endocrine-resistant relapse tumors.

At this time, no truly ERα-selective compounds (agonists or antagonists) have been identified in the literature. The current development of next-generation SERDs has focused on the compound’s growth inhibitory potential in models of endocrine resistance, yet none have been assessed for their potential cross-activity towards GPER. Although these new compounds look promising, harboring cross-activity towards GPER could limit their long-term efficacy in treating ERα-positive advanced breast cancers. This emphasizes the potential benefit of truly ERα-selective antagonists. It is worth noting that to date one compound, termed MIBE, has been reported to act as an antagonist towards both the ERα and GPER [94]. However, its efficacy has not yet been assessed in models of endocrine resistance.

Conclusions

Endocrine therapy is a mainstay in the treatment of ERα-positive breast cancers. Although highly effective, resistance to the therapy is common and many mechanisms have been described to account for the development of endocrine resistance, including the emergence of endocrine-resistant ERα mutants (e.g. Y537S and D538G). The constitutively active mutant forms of ERα are effective at overcoming therapeutic intervention with current SERM, SERD and AI-based endocrine therapies. Therefore, next-generation SERDs will need to be effective towards these mutant forms of the receptor. Moreover, new SERDs should be assessed for potential cross-activation of GPER, which is thought to be a causal role for the development of endocrine resistance to currently approved SERMs and SERD. We have proposed a model describing how GPER promotes the development of endocrine resistance through its cross-activation by tamoxifen and fulvestrant, highlighting the need for truly ERα-selective antagonists, and their possible long-term benefits for patients.

Abbreviations

AI

aromatase inhibitor

cAMP

cyclic adenosine monophosphate

CDK

cyclin-dependent kinase

EGFR

epidermal growth factor receptor

FOXO3a

forkhead box protein O3a

GPER

G protein-coupled estrogen receptor

HER-2

human epidermal growth factor receptor 2

LBD

ligand-binding domain

PDX

patient-derived xenograft

PFS

progression-free survival

SERM

selective estrogen receptor modulator

SERD

selective estrogen receptor downregulator