Next Article in Journal
The Neuroblastoma Microenvironment, Heterogeneity and Immunotherapeutic Approaches
Previous Article in Journal
Molecular Characterization and Therapeutic Opportunities in KRAS Wildtype Pancreatic Ductal Adenocarcinoma
Previous Article in Special Issue
Aggressive Angiomyxoma of the Lower Female Genital Tract: A Review of the MITO Rare Tumors Group
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cancers
Volume 16
Issue 10
10.3390/cancers16101862
cancers-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Novel Endocrine Therapeutic Opportunities for Estrogen Receptor-Positive Ovarian Cancer—What Can We Learn from Breast Cancer?

by
Tine Ottenbourgs
1 and
Els Van Nieuwenhuysen
2,*
1
Gynaecological Oncology Laboratory, KU Leuven, Leuven Cancer Institute, 3000 Leuven, Belgium
2
Department of Gynaecology and Obstetrics, University Hospitals Leuven, BGOG and Leuven Cancer Institute, 3000 Leuven, Belgium
*
Author to whom correspondence should be addressed.
Cancers 2024, 16(10), 1862; https://doi.org/10.3390/cancers16101862
Submission received: 26 March 2024 / Revised: 6 May 2024 / Accepted: 9 May 2024 / Published: 13 May 2024
(This article belongs to the Special Issue Rare Gynecological Cancers)
Browse Figures
Review Reports Versions Notes

Abstract

:

Simple Summary

Low-grade serous ovarian cancer is a rare type of ovarian cancer that usually has an indolent growth and affects younger women. It has markers that suggest it might respond to hormone therapy, but unfortunately, this treatment does not work well for many patients because the cancer becomes resistant to it. We do not fully understand why this happens. In breast cancer, similar resistance mechanisms are studied, so we are exploring if we can apply what we learn there to improve treatment for this type of ovarian cancer. This review looks at why hormone therapy might stop working in ovarian cancer and explores new ways to make it more effective. The goal is to find better treatment options for patients with advanced low-grade serous ovarian cancer, who currently do not have many choices for treatment.

Abstract

Low-grade serous ovarian cancer (LGSOC) is a rare ovarian malignancy primarily affecting younger women and is characterized by an indolent growth pattern. It exhibits indolent growth and high estrogen/progesterone receptor expression, suggesting potential responsiveness to endocrine therapy. However, treatment efficacy remains limited due to the development of endocrine resistance. The mechanisms of resistance, whether primary or acquired, are still largely unknown and present a significant hurdle in achieving favorable treatment outcomes with endocrine therapy in these patients. In estrogen receptor-positive breast cancer, mechanisms of endocrine resistance have been largely explored and novel treatment strategies to overcome resistance have emerged. Considering the shared estrogen receptor positivity in LGSOC and breast cancer, we wanted to explore whether there are any parallel mechanisms of resistance and whether we can extend endocrine breast cancer treatments to LGSOC. This review aims to highlight the underlying molecular mechanisms possibly driving endocrine resistance in ovarian cancer, while also exploring the available therapeutic opportunities to overcome this resistance. By unraveling the potential pathways involved and examining emerging strategies, this review explores valuable insights for advancing treatment options and improving patient outcomes in LGSOC, which has limited therapeutic options available.

1. Introduction

Low-grade serous ovarian cancer (LGSOC) is a rare histologic subtype of epithelial ovarian carcinoma, accounting for approximately 10% of all ovarian cancer cases [1]. It is clinically, histologically, and molecularly distinct from the most common type of ovarian cancer, high-grade serous ovarian cancer (HGSOC). Generally, women with LGSOC are diagnosed at a younger age (43–55 years) and have a prolonged overall survival [1]. LGSOC is often characterized by high estrogen and progesterone receptor positivity. Additionally, they usually show an activated mitogen-activated protein kinase (MAPK) pathway with KRAS and BRAF mutations and, unlike patients with HGSOC, demonstrate a wild-type TP53 expression pattern [2].
LGSOC has a good prognosis in the early stages of the disease, but treating advanced and recurrent cases of the disease poses significant challenges. The current treatment approach to LGSOC primarily relies on the treatment strategies of HGSOC, involving debulking surgery and platinum-based chemotherapy, even though LGSOC is considered to be potentially resistant to chemotherapeutic agents. In recurrent cases, reported overall response rates (ORRs) to chemotherapy range from 2.1% to 17% [3,4]. These numbers emphasize that there is a need for the development of improved, more tailored treatment strategies, especially in the recurrent setting, where no standard-of-care treatment is available [5]. These treatment strategies should be focused on the molecular characteristics of LGSOC in order to improve clinical outcomes.
Numerous studies have emphasized the similarities between LGSOC and estrogen receptor-positive (ER+) breast cancer. The first similarity is the expression of the estrogen receptor (ER). The majority of LGSOCs have a strong ER positivity, and most tumors also demonstrate positivity for the progesterone receptor [6,7]. Additionally, both cancer types have a relatively indolent disease course, compared with their hormone receptor-negative or high-grade counterparts. They may progress slowly over time, allowing for long-term management strategies [6].
In early-stage ER+ breast cancer, endocrine therapy has led to significant reductions in both recurrence and mortality rates [8]. However, in the metastatic and recurrent setting, resistance to treatment and disease progression inevitably occurs, despite initial responses to endocrine therapy [9]. The response to endocrine therapy may be influenced by acquired or intrinsic factors that contribute to endocrine resistance. In metastatic or advanced breast cancer, acquired resistance typically emerges after an initial response to therapy, which generally occurs after six or more months of treatment. In contrast, metastatic or advanced breast cancers that are intrinsically resistant may not respond to treatment within a shorter timeframe, typically less than 6 months [10].
According to published data, the level of ER expression has been identified as the most reliable predictor of sensitivity to endocrine therapy in breast cancer [11]. Therefore, endocrine therapy is also commonly used in the treatment of recurrent ER+ ovarian cancer. However, no study has shown that ER positivity is related to the response to endocrine therapy in LGSOC, or ER+ ovarian cancer in general. Reported ORRs to endocrine therapy in LGSOC range between 9% and 14%, with aromatase inhibitors showing the highest ORRs [12,13]. Besides these minimal ORRs, endocrine therapy demonstrates a relatively high clinical benefit of around 60% in LGSOC [12,14].
In ER+ metastatic breast cancer, multiple mechanisms of resistance have been characterized. However, in ER+ ovarian cancer, these mechanisms remain largely unexplored. Given the similarities between ER+ breast cancer and ER+ ovarian cancer, we tried to uncover mechanisms of endocrine resistance in LGSOC. By extrapolating insights from these mechanisms observed in ER+ breast cancer, we can generate potential hypotheses of endocrine resistance in LGSOC that warrant further investigation. Moreover, this review aims to promote the exploration of innovative therapeutic approaches to overcome the challenge of endocrine resistance in rare ovarian cancer, where treatment options are currently limited.

2. Mechanisms of Estrogen Receptor Signaling

ER signaling is a complex process mediated by various estrogen receptor isoforms, including estrogen receptor alpha (ERα, ESR1) and estrogen receptor beta (ERβ; ESR2), both primarily functioning in the cell nucleus. Estrogen binds to the ER, resulting in receptor dimerization. The ligand-bound ER dimers translocate from the cytoplasm to the nucleus. In the nucleus, ER dimers bind to specific DNA sequences known as estrogen receptor elements (EREs), located in the promoter regions of the target genes. This ER-mediated transcriptional regulation leads to changes in the expression of target genes involved in various cellular processes, including cell proliferation, survival, differentiation, and metabolism. This classical genomic signaling is further enhanced via G protein-coupled estrogen receptor 1 (GPER1), a membrane-bound protein receptor that binds estrogen and activates multiple downstream signaling cascades such as the MAPK/ERK pathway and PI3K/AKT/mTOR pathway [15]. This so-called non-genomic signaling can elicit rapid cellular responses, including changes in cell proliferation, migration, and survival [16].
In ER+ breast cancer, estrogen signaling primarily involves the classical ER-mediated transcriptional activation of target genes leading to cancer cell proliferation and survival [16].
In ER+ ovarian cancer, the role of estrogen signaling is less well defined, and other pathways may be more influential in driving tumor growth and progression [17]. In ovarian cancer models, the role of ERα in the growth regulation of ovarian cancer cells has been shown in vitro and in vivo [15].

3. Possible Mechanisms of Endocrine Resistance

Although the majority of ER+ breast cancer initially responds to endocrine therapy, approximately 15% to 20% of tumors inherently show resistance to the therapy and an additional 30% to 40% develop resistance over time [18]. In LGSOC, endocrine therapy is often used for recurrent disease [12,13]. However, more than 85% of recurrent LGSOCs are not responsive to endocrine therapy, demonstrating endocrine resistance is an even greater challenge in these types of tumors.

3.1. ESR1 Alterations

Alterations in the ESR1 gene can potentially reduce the responsiveness of LGSOC to endocrine therapy, especially aromatase inhibitors (e.g., letrozole, anastrozole, exemestane, etc.), as suggested by findings in breast and endometrial cancers [19,20,21,22,23,24,25].

3.1.1. Loss of ER Expression

In some cases, breast cancer cells may lose their ER expression over time, resulting in the decreased efficacy of endocrine therapy [18,26]. The transcriptional repression of the ESR1 gene might be caused by epigenetic modifications, including the abnormal CpG island methylation of the ER promoter and histone deacetylation mediated by histone deacetylase enzymes. These modifications result in a condensed nucleosome structure that restricts the transcription process [27]. In ovarian cancer, the loss of ER has not been documented yet.

3.1.2. Mutations in the ESR1 Gene

Mutations in the ligand-binding domain of the ESR1 gene (Figure 1) are observed in resistant breast cancer cells [21,28]. Activating ESR1 mutations can contribute to tumor cell resistance through several mechanisms. In metastatic breast cancer, about 50% of endocrine-resistant cases are associated with an ESR1 mutation. However, merely having an ESR1 mutation is not enough to cause complete endocrine resistance [21,29].
  • Ligand-independent activation
The most common mutations in the ESR1 gene are D538G and Y537S (Figure 1). They can alter the structure and function of the receptor, leading to reduced binding affinity to endocrine therapies and a decreased response to treatment. These activating mutations in the ligand-binding domain of ESR1, especially in helix 12, are an important mechanism of resistance to aromatase inhibitors [20,30]. Aromatase inhibitors block the aromatase enzyme and, therefore, inhibit the conversion of androgens into estrogens. This mechanism of action leads to a significant decrease in estrogen levels in the body. Normally, ERα requires the binding of estrogen to become activated. However, with an activating ESR1 mutation, the receptor can be constitutively active even in the absence of estrogen. This means that the tumor cells can continue to grow and proliferate, despite the inhibition of estrogen production caused by aromatase inhibitors.
In recent publications, ESR1 mutations have been detected in a subset of patients with LGSOC and uterine endometrioid carcinomas, highlighting the potential significance of these mutations in hormone-responsive gynecological malignancies. There are some case reports of ESR1 mutations identified in LGSOC tumors. More specifically, McIntyre et al. detected an ESR1 Y537S mutation in one patient with LGSOC when analyzing 26 primary tumor samples [19]. Additionally, Stover et al. also identified an ESR1 Y537S mutation in a patient with LGSOC. This patient had a sustained response to endocrine therapy for 5 years but developed progressive disease with an isolated recurrent lesion that harbored an ESR1 Y537S mutation [25]. Gaillard et al. reported the frequency of ESR1 mutations in gynecological malignancies, which was relatively low overall (3.0% of all cases). Whether ESR1 mutations are enriched in low-grade gynecological malignancies could not be determined because of the restricted information regarding tumor histology subtypes [24]. Fader et al. investigated ESR1 Y537S mutations in three patients diagnosed with recurrent LGSOC, but no mutations were detected [31].
Stergiopoulou et al. evaluated the frequency and the clinical relevance of ESR1 mutations in HGSOC. They reported the presence of ESR1 mutations in 9 out of 60 (15%) FFPE samples and in 11 out of 80 (13.8%) circulating tumor DNA (ctDNA) samples from advanced and metastatic ovarian cancer patients. However, these samples included all types of ovarian cancer [32]. Besides this study and the case reports mentioned before, there has been a lack of subsequent reports regarding the identification of ESR1 mutations in ovarian cancer. Therefore, further investigations are needed to explore the prevalence and clinical implications of ESR1 mutations in LGSOC. These ESR1 mutations can be monitored using ctDNA, making it a promising tool to predict endocrine resistance in these patients [33].
  • Activation of alternative signaling pathways
ESR1 mutations can lead to the activation of downstream signaling pathways, like for example the PI3K/AKT/mTOR pathway, which can promote cell survival and growth. The activation of alternative pathways can compensate for the inhibition of estrogen signaling caused by endocrine therapy and render the tumor cells resistant to treatment [21]. Consequently, the effectiveness of endocrine therapy can be compromised when cancer cells harbor activating ESR1 mutations. These mutations allow ER signaling pathways to remain active and alternative growth-promoting pathways to promote tumor growth. To overcome this resistance, strategies may involve targeting these modified signaling pathways and developing novel therapies that specifically target these ESR1 mutations [21].

3.2. Crosstalk between ER and Growth Factor Signaling Pathways

As depicted below, breast cancer cells can activate alternative signaling pathways, such as growth factor receptor pathways (e.g., HER2, EGFR, and FGFR), MAPK/ERK pathway, and PI3K/AKT/mTOR pathway, due to alterations (mutations or amplifications) in multiple genes. Subsequently, this can activate alternative survival and cell proliferation signals and contribute to endocrine resistance (Figure 2).
  • Growth factor receptor pathways
Research has shown that the amplification of HER2 (ERBB2), a receptor tyrosine kinase (RTK), can lead to the activation of the alternative MAPK/ERK pathway and PI3K/AKT/mTOR survival pathways. Both intracellular pathways play an important role in gene expression regulation, cellular growth, motility, and survival [34].
ERBB2 amplification also occurs in LGSOC, with reported rates ranging from 1.5% to 11.5% [35,36]. The clinical significance of ERBB2 amplification in LGSOC is not yet fully understood. Anglesio and colleagues found that ERBB2-activating mutations are associated with an increase in the activity of the MAPK/ERK signaling pathway [36]. However, further research is necessary to better understand the role of ERBB2 amplification in LGSOC and to develop new treatment strategies.
Aberrations in components of the MAPK pathway, including NF1, KRAS/NRAS/HRAS, BRAF, and MAP2K1, are often reported in metastatic breast cancer [29,37]. Alterations in these genes may lead to increased or uncontrolled cell proliferation, leading to resistance to endocrine therapy in breast cancer [38]. As mentioned before, LGSOC is also molecularly characterized by MAPK pathway mutations. Several studies have reported KRAS mutations in 16–44% of cases, BRAF in 2–20%, and NRAS in as many as 26% of cases [39]. Further studies are necessary to investigate the correlation between these mutations and endocrine resistance in ER+ ovarian cancer.
The hyperactivation of the PI3K/AKT/mTOR pathway has also been associated with endocrine resistance in ER+ breast cancer [40,41,42]. A study performed by Beltrame et al. in ovarian cancer showed mTOR missense mutations in HGSOC and LGSOC [43]. However, it seems evident that LGSOC is characterized by a relatively low frequency of aberrations in the PI3K/AKT/mTOR pathway [44,45]. The phase II trial in patients with unresectable LGSOC comparing the combination of pimasertib, a MEK inhibitor, with SAR245409, a PI3K inhibitor, to pimasertib alone was terminated early due to high rates of discontinuation and low ORRs [46].

3.3. Epigenetic Modification

Endocrine resistance has previously been shown to be associated with epigenetic alterations in breast cancer, including DNA methylation, chromatin accessibility, histone modifications, and the binding of different transcription factors, due to their effect on gene expression [47,48]. Differential DNA methylation has been implicated in endocrine-resistant tumors [49]. For example, in breast cancer, different methylation profiles were found between tamoxifen-sensitive and tamoxifen-resistant cell lines [50]. Another study showed that the hypermethylation of estrogen-responsive enhancers modulates endocrine response in cell lines, which could be used to identify patients who positively respond to endocrine therapy [51]. Furthermore, the methylation profile of estrogen-responsive enhancers can increase during endocrine therapy and differ between endocrine-sensitive and endocrine-resistant patients [52].
In ER+ breast cancer, several preclinical studies and early-phase clinical trials have investigated the efficacy of epidrugs in combination with endocrine therapies or other targeted agents in ER+ breast cancer [47]. While some promising results have been observed, further research is needed to determine the optimal treatment combinations, patient selection criteria, and long-term outcomes.
MiRNAs have the capacity to regulate ER expression. In breast cancer, they play pivotal roles in both normal breast development and breast tumor formation [53]. Research states that miRNAs are dysregulated in endocrine-resistant breast cancer [53,54]. Several upregulated as well as downregulated miRNAs and their targets have been associated with endocrine resistance. These identified miRNAs can be useful as predictive serum biomarkers for developing endocrine resistance. In this way, patients who will or will not benefit from endocrine therapy can be determined.
In LGSOC, epigenetic research has not been explored yet.

4. Novel Potential Therapeutic Strategies

In the treatment of ER+ breast cancer, emerging endocrine therapies are being developed to overcome common mechanisms of endocrine resistance, for example, ESR1 mutations, including combination therapies and next-generation selective estrogen receptor degraders (SERDs) and selective estrogen receptor modulators (SERMs), but also other new classes of endocrine therapies [55]. In this regard, it is important to understand that resistance to endocrine therapy can be agent-dependent. For instance, when aromatase inhibitor therapy has failed, tumors can still respond to alternative endocrine therapy approaches, including a different class of aromatase inhibitors (steroidal versus non-steroidal), SERMs (e.g., tamoxifen) or SERDs (e.g., fulvestrant) or other next-generation endocrine therapies [56].

4.1. Combination Therapies with Molecularly Targeted Agents

In ER+/HER2- breast cancer, the use of molecularly targeted therapies in combination with endocrine therapy has been widely explored. These compounds include cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, mitogen-activated protein/extracellular signal-regulated kinase (MEK) inhibitors, and PI3K/mTOR inhibitors. The main goals are to improve patient outcomes by targeting multiple pathways and to reduce side effects and the development of resistance to therapy [57]. Following encouraging outcomes in clinical trials in ER+ breast cancer, distinct molecularly targeted combination agents have also been or are being tested in patients with LGSOC (Table 1) [58].

4.1.1. CDK4/6 Inhibitors Combinations

In patients with advanced and metastatic ER+ breast cancer, the addition of CDK4/6 inhibitors to endocrine therapy has significantly increased survival rates [59,60,61]. Several trials have investigated the efficacy and safety of CDK4/6 inhibitors and they have been approved for the treatment of advanced ER+ and early high-risk breast cancer [60,61,62,63].
The results of these trials can form the rationale for designing clinical trials with the same drug combination in patients with ER+ ovarian cancer. Preclinical research demonstrated the biological activity of palbociclib in ovarian cancer cells with low p16 expression [64]. However, the use of CDK4/6 inhibitors as a single agent in a phase II clinical trial showed limited benefits in recurrent ovarian cancer with Rb-proficiency and low p16 expression, with a median progression-free survival (PFS) of 3.7 months [65,66]. In this trial, all types of epithelial ovarian tumors were included; no distinction was made between HGSOC and LGSOC. Nevertheless, combination therapies with CDK4/6 inhibitors seem to have potential in the treatment of LGSOC. Colon-Otero et al. found a promising clinical benefit of ribociclib in combination with letrozole in three out of three patients with recurrent LGSOC, including one complete response and two partial responses [67].
Upcoming and ongoing clinical trials testing the efficacy of CDK4/6 inhibitors in combination with endocrine therapy in LGSOC are listed in Table 1 [68].

4.1.2. MEK Inhibitor Combinations

Previous research has shown that mitogen-activated extracellular signal-regulated kinase (MEK) inhibitors increase PFS and ORRs in patients with recurrent LGSOC [69], with ORRs ranging between 15% and 26%. However, there is some evidence that the addition of another therapy to MEK inhibitors, for example, endocrine therapy or targeted therapy, can improve the ORRs even more [70,71].
In advanced breast cancer, the addition of selumetinib (a MEK inhibitor) to fulvestrant resulted in a poor tolerance and worse disease control rate than with fulvestrant alone [72]. The authors hypothesize selumetinib may have deteriorated the effect of fulvestrant.
However, in an ovarian cancer mouse model, the addition of a MEK inhibitor to fulvestrant improved the tumor response compared with a MEK inhibitor alone [73]. Additionally, a case report of a heavily pretreated and endocrine- and platinum-resistant patient with LGSOC treated with trametinib and fulvestrant revealed a PFS of 9 months [71]. In an upcoming trial in patients with LGSOC, the combination of regorafenib, a multikinase inhibitor, with fulvestrant will be investigated to provide more insight into the efficacy of MAPK pathway inhibitors in combination with endocrine therapy (NCT05113368).
Additionally, there is some evidence that combination therapies with inhibitors of the MAPK pathway and inhibitors of the PI3K/AKT/mTOR pathway could provide benefits in LGSOC because they might have a synergistic activity [74]. However, additional studies investigating the efficacy of combined MEK and PI3K inhibition are necessary to evaluate its utility in LGSOC [46].

4.1.3. PI3K/mTOR Inhibitors Combinations

For the treatment of advanced ER+ breast cancer, several clinical trials have evaluated combinations of endocrine therapy and inhibitors of the PI3K/AKT/mTOR pathway, including mTOR inhibitors and dual PI3K/mTOR inhibitors [75]. In the SOLAR-1 trial, treatment with the PI3Kα-specific inhibitor alpelisib in combination with fulvestrant improved outcomes in patients with PIK3CA-mutated ER+ advanced breast cancer [76].
The phase II basket study in ER+ recurrent, metastatic gynecological cancers, including LGSOC, which aims to evaluate the efficacy of letrozole in combination with alpelisib or ribociclib (ACTRN12621000639820), is an expansion upon the PARAGON trial, which focused on the use of single-agent anastrazole [13]. It aims to assess whether combining letrozole with alpelisib or letrozole with ribociclib results in a higher ORR. Participants will be allocated to one of the two treatment groups based on the PIK3CA mutation status.
In the BOUQUET trial, a study evaluating the efficacy and safety of multiple biomarker-driven therapies in patients with recurrent and advanced rare epithelial ovarian tumors, several combination therapies were introduced based on alterations in the tumor DNA. In Table 1, a detailed overview of the different therapies in the BOUQUET trial is defined. However, this trial was prematurely terminated due to unknown reasons.
Additional clinical trials on the combination of molecularly targeted agents with endocrine therapy are strongly warranted to investigate their synergistic effect in ER+ ovarian cancer. In the future, it is imperative for clinical trials to incorporate a broader array of biomarkers for patient selection. This proactive approach will significantly augment the overall efficacy and clinical benefit of the trial participants.

5. Next-Generation SERMs and SERDs to Overcome Endocrine Resistance

In ER+ breast cancer, next-generation oral SERMs and SERDs are increasingly being applied in clinical research, both as single agents and in combination with confirmed targeted therapies [38]. Additionally, other novel endocrine therapies, including proteolysis targeting chimeras (PROTACs), selective estrogen receptor covalent antagonists (SERCAs), and complete estrogen receptor antagonists (CERANs) are also emerging (Figure 3).
SERMs competitively bind the ER and exhibit tissue-dependent agonistic or antagonistic properties. In breast tumors, they potentiate an anti-estrogenic effect by downregulating the transcriptional activity of EREs. Tamoxifen is the most commonly used SERM in the treatment of ER+ metastatic breast cancer. However, recently, the development of novel agents has emerged [55].
SERDs also bind the ER and, therefore, inhibit receptor dimerization, causing the degradation and downregulation of the ER. Fulvestrant was the first-in-class approved SERD and is used to treat ER+ metastatic and advanced breast cancer alone, as well as in combination with CDK4/6 inhibitors. However, fulvestrant seems ineffective in patients with advanced breast cancer and ESR1 mutations [77].
In recent years, multiple novel oral SERMs, SERDs, and other next-generation endocrine therapies have been investigated in clinical trials with ER+ breast cancer [78]. An overview of completed trials in advanced and metastatic ER+ breast cancer with new endocrine drug therapies to overcome endocrine resistance can be found in Table 2.
Overall, these new agents have more potent anti-estrogen activities and have properties to overcome endocrine resistance, including the degradation of the ER, higher potency and specificity, and the ability to target ESR1 mutations. These properties could lead to a more effective and durable response in patients with ER+ breast cancer. These novel endocrine agents have shown activity after fulvestrant and CDK4/6 inhibitors, and on mutant ESR1 in breast cancer. Hence, these agents also offer a viable possibility for determining a ‘what comes next’ approach in addressing LGSOC.
Phase II ELAINE demonstrated a numerically improved PFS and ORR with lasofoxifene compared to fulvestrant. These findings support further investigation of lasofoxifene in this patient population [79].
The phase III EMERALD trial demonstrated improved outcomes with the oral SERD elacestrant in ER+ metastatic breast cancer compared with standard-of-care endocrine therapy, including fulvestrant or aromatase inhibitors. These patients progressed on one or two prior lines of endocrine therapy and were pretreated with a CDK4/6 inhibitor [80]. Based on these positive results, elacestrant was granted accelerated FDA approval in November 2023 for the treatment of this patient population.
Among the ESR1-mutated population, a longer prior exposure to CDK4/6 inhibitors was associated with an extended PFS. Additionally, encouraging findings in other novel SERDs, including amcenestrant [81], camizestrant [84], giredestrant, imlunestrant, and rintodestrant, have led to the development of several clinical trials in advanced ER+ breast cancer.
Other novel endocrine therapies including SERMs (e.g., lasofoxifene) [79], PROTACs (e.g., ARV-471) [86], SERCAs (e.g., H3B-6545) [87], and CERANs (e.g., OP-1250) have emerged for the treatment of ER+ breast cancer Table 3.
PROTACs bind to the ER and recruit the E3 ubiquitin-ligase, leading to ER ubiquitination and the subsequent proteasomal degradation of the receptor [86]. SERCAs are a class of compounds that covalently bind to a unique cysteine residue at position 530. This cysteine residue is not present in other hormone receptors, leading to the inactivation of both wild-type and mutant ERs [87]. CERANs inhibit activation function 1 (AF1) and activation function 2 (AF2), both domains of the ER that activate gene transcription. CERANs can bind both wild-type and mutant ERs [88].
However, clinical trial data need to be collected further to draw any strong conclusions about the efficacy and safety of these next-generation anti-estrogens. An overview of ongoing trials in advanced and metastatic ER+ breast cancer with new endocrine drug combination therapies to overcome endocrine resistance can be found in Table 3. Ongoing randomized trials in advanced and metastatic ER+ breast cancer with new endocrine drug combination therapies to overcome endocrine resistance (randomized) and Table 4 (non-randomized).
In ovarian cancer, next-generation SERMs and SERDs are still largely unexplored, despite their potential clinical benefit in ER+ breast cancer. It would be of great interest to explore the activity of these agents in patients with LGSOC, especially when resistance to other endocrine therapeutic agents has been developed.
Table 3. Ongoing randomized trials in advanced and metastatic ER+ breast cancer with new endocrine drug combination therapies to overcome endocrine resistance.
Table 3. Ongoing randomized trials in advanced and metastatic ER+ breast cancer with new endocrine drug combination therapies to overcome endocrine resistance.
Drug(s)Mode of ActionClinical TrialPhase IndicationDesignPrimary EndpointReference
Giredestrant combination therapySERDpersevERA
NCT04546009		IIIER+HER2- advanced or metastatic breast cancer, first-lineGiredestrant combined with palbociclib vs. palbociclib + letrozolePFS, as determined by the investigator according to RECIST v1.1Turner et al. [89]
Camizestrant combination therapySERDSERENA-4
NCT04711252		IIIER+/HER2- advanced or metastatic breast cancer, first-lineCamizestrant combined with palbociclib vs. palbociclib + aromatase inhibitor (anastrozole)PFS, as determined by the investigator according to RECIST v1.1Im et al. [90]
Giredestrant combination therapySERDevERA
NCT05306340		IIIER+/HER2- advanced or metastatic breast cancer, who received previous treatment with a CDK4/6i and ETGiredestrant combined with everolimus vs. physician’s choice of endocrine therapy + everolimusPFS, as determined by the investigator according to RECIST v1.1Mayer et al. [91]
Giredestrant combination therapySERDMORPHEUS
NCT04802759		Ib/IIER+/HER2- advanced or metastatic breast cancer, second- or third-lineGiredestrant alone or combined with abemaciclib, palbociclib, ribociclib, ipatasertib, inavolisib, everolimus, or samuraciclibORR, as determined by the investigator according to RECIST v1.1Oliveira et al. [92]
Camizestrant combination therapySERDSERENA-6
NCT04964934		IIIER+/HER2-, ESR1 mutated, advanced or metastatic breast cancer on first-line aromatase inhibitor + CDK4/6i before disease progressionSwitch to camizestrant combined with CDK4/6 inhibitor vs. continue current treatment with aromatase inhibitor + CDK4/6 inhibitorPFS, as determined by the investigator according to RECIST v1.1Turner et al. [93]
Imlunestrant monotherapy or combination therapySERDEMBER-3
NCT04975308		IIIER+/HER2- advanced or metastatic breast cancer, who received previous treatment with ET, +/− CDKiImlunestrant monotherapy vs. combined with abemaciclib vs. investigator’s choice of endocrine therapyPFS, as determined by the investigator according to RECIST v1.1Jhaveri et al. [94]
Abbreviations: CDKi, cyclin-dependent kinase inhibitor; ER+, estrogen receptor-positive; HER2-, human epidermal growth factor receptor 2-negative; ET, endocrine therapy; PFS, progression-free survival; ORR, overall response rate; SERD, selective estrogen receptor degrader; SERM; selective estrogen receptor modulator; RECIST v1.1, Response Evaluation Criteria in Solid Tumors version 1.1.
Table 4. Ongoing non-randomized trials in advanced and metastatic ER+ breast cancer with new endocrine drug (combination) therapies to overcome endocrine resistance.
Table 4. Ongoing non-randomized trials in advanced and metastatic ER+ breast cancer with new endocrine drug (combination) therapies to overcome endocrine resistance.
Drug(s)Mode of ActionClinical TrialPhase IndicationDesignPrimary OutcomeReference
Rintodestrant combination therapySERDNCT03455270IER+/HER2- advanced or metastatic breast cancer, 2nd-line or moreRintodestrant monotherapy vs. combined with palbociclibDose-limiting toxicity
Recommended phase 2 dose		Adreano et al. [95]
ZN-c5 combination therapySERDNCT04514159IbER+/HER2- advanced or metastatic breast cancer, 2nd-line or more, no prior CDK4/6iZN-c5 combined with abemaciclibMaximum tolerated dose
Recommended phase 2 dose		Keogh et al. [96]
ZN-c5 monotherapy or combination therapySERDNCT03560531I/IIER+/HER2- advanced or metastatic breast cancer, 2nd-line or moreZN-c5 monotherapy or combined with palbociclibMaximum tolerated dose
Recommended phase 2 dose		Abramson et al. [97]
Borestrant monotherapy and combination therapySERDENZENO
NCT04669587		I/IIER+/HER2- advanced or metastatic breast cancer at any lineBorestrant monotherapy and combined with palbociclibSafety and tolerabilityNA
D-0502 monotherapy and combination therapySERDNCT03471663IER+/HER2- advanced or metastatic breast cancer, 2nd-line or moreD-0502 monotherapy and combined with palbociclibSafety and tolerabilityOsborne et al. [98]
ARV-471 monotherapy and combination therapyPROTACNCT04072952I/IIER+/HER2- advanced or metastatic breast cancer, 2nd-line or moreARV-471 monotherapy and combined with palbociclibSafety and tolerabilityHamilton et al. [86]
OP-1250 monotherapyCERANNCT04505826I/IIER+/HER2- advanced or metastatic breast cancer, 2nd-line or moreOP-1250 monotherapySafety and tolerabilityHamilton et al. [88]
H3B-6545 combination therapySERCANCT04288089IbER+/HER2- advanced or metastatic breast cancer, 3rd-line or moreH3b-6545 combined with palbociclibMaximum tolerated dose
Recommended phase 2 dose		Johnston et al. [87]
Abbreviations: CERAN, complete estrogen receptor antagonist; ER+, estrogen receptor-positive; HER2-, human epidermal growth factor receptor 2-negative; PROTAC, proteolysis targeting chimera; SERCA; selective estrogen receptor covalent antagonist; SERD, selective estrogen receptor degrader; SERM, selective estrogen receptor modulator.

6. Future Directions

Initiating clinical trials to investigate the efficacy of novel endocrine combination therapies, previously shown successful in breast cancer, is one of the most important goals of future research on low-grade serous ovarian cancer. Especially in patients already treated with traditional endocrine therapies who developed endocrine resistance to this treatment. Next-generation endocrine therapeutic agents, designed to specifically target mechanisms of endocrine resistance, are emerging in the field of breast cancer and represent a pivotal area of research in ER+ ovarian cancer.
Patient-derived ovarian cancer organoid models could provide a powerful tool to screen novel endocrine combination therapies in the future [99,100]. These models present a promising platform for preclinical drug testing and screening, accelerating the discovery of effective treatments and exploring the repurposing of existing medicines for new indications, including rare cancers. Ultimately, this may lead to the development of tailored therapeutic approaches and improved outcomes for patients.

7. Conclusions

Research on the mechanisms of endocrine resistance in ER+ ovarian cancer is currently limited. Although there may be some overlap in the mechanisms of endocrine resistance between ER+ breast cancer and ER+ ovarian cancer, there are also distinct differences. As a result, findings from studies on ER+ breast cancer cannot be directly applied to ER+ ovarian cancer, highlighting the need for further research. Therefore, it is crucial to develop translational research models to identify biomarkers that can predict response or resistance to endocrine (combination) therapies and to define novel treatment strategies.
In ER+ breast cancer, the utilization of endocrine combination therapies has demonstrated enhanced efficacy, resulting in improved control of breast cancer and lowered rates of recurrence. Ongoing research endeavors aim to refine these endocrine combination therapies for ER+ breast cancer, particularly in cases of endocrine-resistant disease. This involves assessing novel agents such as next-generation SERDs and SERMs, as well as investigating alternative combinations.
Exploring next-generation SERDs and SERMs in the context of ER+ ovarian cancer presents a promising area of research. While current clinical data regarding their application in ER+ ovarian cancer remain scarce, the ongoing research and clinical trials hold promise for the emergence of innovative and efficacious treatment strategies for this complex disease.

Author Contributions

Conceptualization, T.O. and E.V.N.; methodology, T.O. and E.V.N.; validation, T.O. and E.V.N.; data curation, T.O.; writing—original draft preparation, T.O.; writing—review and editing, E.V.N.; visualization, T.O.; supervision, E.VN. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data Availability Statement

All primary data cited in this review are published as noted in the references section and available in the public domain.

Conflicts of Interest

E.V.N. reports consulting fees from Regeneron, Oncoinvent, AstraZeneca, Roche, Seagen, Novartis, Merck, and Verastem. T.O. declares no conflicts of interest.

References

  1. Schmeler, K.M.; Gershenson, D.M. Low-Grade Serous Ovarian Cancer: A Unique Disease. Curr. Oncol. Rep. 2008, 10, 519–523. [Google Scholar] [CrossRef]
  2. Zwimpfer, T.A.; Tal, O.; Geissler, F.; Coelho, R.; Rimmer, N.; Jacob, F.; Heinzelmann-Schwarz, V. Low Grade Serous Ovarian Cancer—A Rare Disease with Increasing Therapeutic Options. Cancer Treat. Rev. 2023, 112, 102497. [Google Scholar] [CrossRef]
  3. Gershenson, D.M.; Sun, C.C.; Bodurka, D.; Coleman, R.L.; Lu, K.H.; Sood, A.K.; Deavers, M.; Malpica, A.L.; Kavanagh, J.J. Recurrent Low-Grade Serous Ovarian Carcinoma Is Relatively Chemoresistant. Gynecol. Oncol. 2009, 114, 48–52. [Google Scholar] [CrossRef]
  4. Grabowski, J.P.; Harter, P.; Heitz, F.; Pujade-Lauraine, E.; Reuss, A.; Kristensen, G.; Ray-Coquard, I.; Heitz, J.; Traut, A.; Pfisterer, J.; et al. Operability and Chemotherapy Responsiveness in Advanced Low-Grade Serous Ovarian Cancer. An Analysis of the AGO Study Group Metadatabase. Gynecol. Oncol. 2016, 140, 457–462. [Google Scholar] [CrossRef]
  5. Grisham, R.N.; Slomovitz, B.M.; Andrews, N.; Banerjee, S.; Brown, J.; Carey, M.S.; Chui, H.; Coleman, R.L.; Fader, A.N.; Gaillard, S.; et al. Low-Grade Serous Ovarian Cancer: Expert Consensus Report on the State of the Science. Int. J. Gynecol. Cancer 2023, 33, 1331–1344. [Google Scholar] [CrossRef]
  6. Gershenson, D.M.; Sun, C.C.; Lu, K.H.; Coleman, R.L.; Sood, A.K.; Malpica, A.; Deavers, M.T.; Silva, E.G.; Bodurka, D.C. Clinical Behavior of Stage II–IV Low-Grade Serous Carcinoma of the Ovary. Obstet. Gynecol. 2006, 108, 361–368. [Google Scholar] [CrossRef]
  7. Wong, K.K.; Lu, K.H.; Malpica, A.; Bodurka, D.C.; Shvartsman, H.S.; Schmandt, R.E.; Thornton, A.D.; Deavers, M.T.; Silva, E.G.; Gershenson, D.M. Significantly Greater Expression of ER, PR, and ECAD in Advanced-Stage Low-Grade Ovarian Serous Carcinoma as Revealed by Immunohistochemical Analysis. Int. J. Gynecol. Pathol. 2007, 26, 404–409. [Google Scholar] [CrossRef]
  8. Harbeck, N.; Gnant, M. Breast Cancer. Lancet 2017, 389, 1134–1150. [Google Scholar] [CrossRef]
  9. Lei, J.T.; Anurag, M.; Haricharan, S.; Gou, X.; Ellis, M.J. Endocrine Therapy Resistance: New Insights. Breast 2019, 48, S26. [Google Scholar] [CrossRef]
  10. Cardoso, F.; Senkus, E.; Costa, A.; Papadopoulos, E.; Aapro, M.; André, F.; Harbeck, N.; Aguilar Lopez, B.; Barrios, C.H.; Bergh, J.; et al. 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4). Ann. Oncol. 2018, 29, 1634–1657. [Google Scholar] [CrossRef]
  11. Clarke, R.; Tyson, J.J.; Dixon, J.M. Endocrine Resistance in Breast Cancer—An Overview and Update. Mol. Cell Endocrinol. 2015, 418, 220. [Google Scholar] [CrossRef]
  12. Gershenson, D.M.; Sun, C.C.; Iyer, R.B.; Malpica, A.L.; Kavanagh, J.J.; Bodurka, D.C.; Schmeler, K.; Deavers, M. Hormonal Therapy for Recurrent Low-Grade Serous Carcinoma of the Ovary or Peritoneum. Gynecol. Oncol. 2012, 125, 661–666. [Google Scholar] [CrossRef]
  13. Tang, M.; O’Connell, R.L.; Amant, F.; Beale, P.; McNally, O.; Sjoquist, K.M.; Grant, P.; Davis, A.; Sykes, P.; Mileshkin, L.; et al. PARAGON: A Phase II Study of Anastrozole in Patients with Estrogen Receptor-Positive Recurrent/Metastatic Low-Grade Ovarian Cancers and Serous Borderline Ovarian Tumors. Gynecol. Oncol. 2019, 154, 531–538. [Google Scholar] [CrossRef]
  14. Van Meurs, H.S.; Van Lonkhuijzen, L.R.C.W.; Limpens, J.; Van Der Velden, J.; Buist, M.R. Hormone Therapy in Ovarian Granulosa Cell Tumors: A Systematic Review. Gynecol. Oncol. 2014, 134, 196–205. [Google Scholar] [CrossRef]
  15. Langdon, S.P.; Herrington, C.S.; Hollis, R.L.; Gourley, C. Estrogen Signaling and Its Potential as a Target for Therapy in Ovarian Cancer. Cancers 2020, 12, 1647. [Google Scholar] [CrossRef]
  16. Clusan, L.; Ferrière, F.; Flouriot, G.; Pakdel, F. A Basic Review on Estrogen Receptor Signaling Pathways in Breast Cancer. Int. J. Mol. Sci. 2023, 24, 6834. [Google Scholar] [CrossRef]
  17. Kozieł, M.J.; Piastowska-Ciesielska, A.W. Estrogens, Estrogen Receptors and Tumor Microenvironment in Ovarian Cancer. Int. J. Mol. Sci. 2023, 24, 14673. [Google Scholar] [CrossRef]
  18. Belachew, E.B.; Sewasew, D.T. Molecular Mechanisms of Endocrine Resistance in Estrogen-Positive Breast Cancer. Front. Endocrinol. Lausanne 2021, 12, 599586. [Google Scholar] [CrossRef]
  19. McIntyre, J.B.; Rambau, P.F.; Chan, A.; Yap, S.; Morris, D.; Nelson, G.S.; Köbel, M. Molecular Alterations in Indolent, Aggressive and Recurrent Ovarian Low-Grade Serous Carcinoma. Histopathology 2017, 70, 347–358. [Google Scholar] [CrossRef]
  20. Toy, W.; Shen, Y.; Won, H.; Green, B.; Sakr, R.A.; Will, M.; Li, Z.; Gala, K.; Fanning, S.; King, T.A.; et al. ESR1 Ligand-Binding Domain Mutations in Hormone-Resistant Breast Cancer. Nat. Genet. 2013, 45, 1439–1445. [Google Scholar] [CrossRef]
  21. Brett, J.O.; Spring, L.M.; Bardia, A.; Wander, S.A. ESR1 Mutation as an Emerging Clinical Biomarker in Metastatic Hormone Receptor-Positive Breast Cancer. Breast Cancer Res. 2021, 23, 85. [Google Scholar] [CrossRef] [PubMed]
  22. Ahn, S.G.; Bae, S.J.; Kim, Y.; Ji, J.H.; Chu, C.; Kim, D.; Lee, J.; Cha, Y.J.; Lee, K.A.; Jeong, J. Primary Endocrine Resistance of ER+ Breast Cancer with ESR1 Mutations Interrogated by Droplet Digital PCR. NPJ Breast Cancer 2022, 8, 58. [Google Scholar] [CrossRef] [PubMed]
  23. Zundelevich, A.; Dadiani, M.; Kahana-Edwin, S.; Itay, A.; Sella, T.; Gadot, M.; Cesarkas, K.; Farage-Barhom, S.; Saar, E.G.; Eyal, E.; et al. ESR1 Mutations Are Frequent in Newly Diagnosed Metastatic and Loco-Regional Recurrence of Endocrine-Treated Breast Cancer and Carry Worse Prognosis. Breast Cancer Res. 2020, 22, 16. [Google Scholar] [CrossRef] [PubMed]
  24. Gaillard, S.L.; Andreano, K.J.; Gay, L.M.; Steiner, M.; Jorgensen, M.S.; Davidson, B.A.; Havrilesky, L.J.; Alvarez Secord, A.; Valea, F.A.; Colon-Otero, G.; et al. Constitutively Active ESR1 Mutations in Gynecologic Malignancies and Clinical Response to Estrogen-Receptor Directed Therapies. Gynecol. Oncol. 2019, 154, 199–206. [Google Scholar] [CrossRef] [PubMed]
  25. Stover, E.H.; Feltmate, C.; Berkowitz, R.S.; Lindeman, N.I.; Matulonis, U.A.; Konstantinopoulos, P.A. Targeted Next-Generation Sequencing Reveals Clinically Actionable BRAF and ESR1 Mutations in Low-Grade Serous Ovarian Carcinoma. JCO Precis. Oncol. 2018, 2018, 1–8. [Google Scholar] [CrossRef]
  26. Shiino, S.; Kinoshita, T.; Yoshida, M.; Jimbo, K.; Asaga, S.; Takayama, S.; Tsuda, H. Prognostic Impact of Discordance in Hormone Receptor Status Between Primary and Recurrent Sites in Patients with Recurrent Breast Cancer. Clin. Breast Cancer 2016, 16, e133–e140. [Google Scholar] [CrossRef] [PubMed]
  27. Viedma-RodríGuez, R.; Baiza-Gutman, L.; Salamanca-Gómez, F.; Diaz-Zaragoza, M.; Martínez-Hernández, G.; Esparza-Garrido, R.R.; Velázquez-Flores, M.A.; Arenas-Aranda, D. Mechanisms Associated with Resistance to Tamoxifen in Estrogen Receptor-Positive Breast Cancer (Review). Oncol. Rep. 2014, 32, 3–15. [Google Scholar] [CrossRef] [PubMed]
  28. Martin, L.A.; Ribas, R.; Simigdala, N.; Schuster, E.; Pancholi, S.; Tenev, T.; Gellert, P.; Buluwela, L.; Harrod, A.; Thornhill, A.; et al. Discovery of Naturally Occurring ESR1 Mutations in Breast Cancer Cell Lines Modelling Endocrine Resistance. Nat. Commun. 2017, 8, 1865. [Google Scholar] [CrossRef] [PubMed]
  29. Razavi, P.; Chang, M.T.; Xu, G.; Bandlamudi, C.; Ross, D.S.; Vasan, N.; Cai, Y.; Bielski, C.M.; Donoghue, M.T.A.; Jonsson, P.; et al. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell 2018, 34, 427–438. [Google Scholar] [CrossRef] [PubMed]
  30. Jeselsohn, R.; Buchwalter, G.; De Angelis, C.; Brown, M.; Schiff, R. ESR1 Mutations—A Mechanism for Acquired Endocrine Resistance in Breast Cancer. Nat. Rev. Clin. Oncol. 2015, 12, 573–583. [Google Scholar] [CrossRef] [PubMed]
  31. Fader, A.N.; Bergstrom, J.; Jernigan, A.; Tanner, E.J.; Roche, K.L.; Stone, R.L.; Levinson, K.L.; Ricci, S.; Wethingon, S.; Wang, T.L.; et al. Primary Cytoreductive Surgery and Adjuvant Hormonal Monotherapy in Women with Advanced Low-Grade Serous Ovarian Carcinoma: Reducing Overtreatment without Compromising Survival? Gynecol. Oncol. 2017, 147, 85–91. [Google Scholar] [CrossRef]
  32. Stergiopoulou, D.; Markou, A.; Giannopoulou, L.; Buderath, P.; Balgkouranidou, I.; Xenidis, N.; Kakolyris, S.; Kasimir-Bauer, S.; Lianidou, E. Detection of ESR1 Mutations in Primary Tumors and Plasma Cell-Free DNA in High-Grade Serous Ovarian Carcinoma Patients. Cancers 2022, 14, 3790. [Google Scholar] [CrossRef] [PubMed]
  33. Li, X.; Lu, J.; Zhang, L.; Luo, Y.; Zhao, Z.; Li, M. Clinical Implications of Monitoring ESR1 Mutations by Circulating Tumor DNA in Estrogen Receptor Positive Metastatic Breast Cancer: A Pilot Study. Transl. Oncol. 2020, 13, 321. [Google Scholar] [CrossRef] [PubMed]
  34. Cargnello, M.; Roux, P.P. Activation and Function of the MAPKs and Their Substrates, the MAPK-Activated Protein Kinases. Microbiol. Mol. Biol. Rev. 2011, 75, 50. [Google Scholar] [CrossRef] [PubMed]
  35. Hunter, S.M.; Anglesio, M.S.; Ryland, G.L.; Sharma, R.; Chiew, Y.E.; Rowley, S.M.; Doyle, M.A.; Li, J.; Blake Gilks, C.; Moss, P.; et al. Molecular Profiling of Low Grade Serous Ovarian Tumours Identifies Novel Candidate Driver Genes. Oncotarget 2015, 6, 37663. [Google Scholar] [CrossRef] [PubMed]
  36. Anglesio, M.S.; Arnold, J.M.; George, J.; Tinker, A.V.; Tothill, R.; Waddell, N.; Simms, L.; Locandro, B.; Fereday, S.; Traficante, N.; et al. Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors. Mol Cancer Res. 2008, 6, 1678–1690. [Google Scholar] [CrossRef] [PubMed]
  37. Raheem, F.; Karikalan, S.A.; Batalini, F.; El Masry, A.; Mina, L. Metastatic ER+ Breast Cancer: Mechanisms of Resistance and Future Therapeutic Approaches. Int. J. Mol. Sci. 2023, 24, 16198. [Google Scholar] [CrossRef]
  38. Hanker, A.B.; Sudhan, D.R.; Arteaga, C.L. Overcoming Endocrine Resistance in Breast Cancer. Cancer Cell 2020, 37, 496. [Google Scholar] [CrossRef]
  39. Gershenson, D.M.; Sun, C.C.; Westin, S.N.; Eyada, M.; Cobb, L.P.; Nathan, L.C.; Sood, A.K.; Malpica, A.; Hillman, R.T.; Wong, K.K. The Genomic Landscape of Low-Grade Serous Ovarian/Peritoneal Carcinoma and Its Impact on Clinical Outcomes. Gynecol. Oncol. 2022, 165, 560–567. [Google Scholar] [CrossRef]
  40. Dong, C.; Wu, J.; Chen, Y.; Nie, J.; Chen, C. Activation of PI3K/AKT/MTOR Pathway Causes Drug Resistance in Breast Cancer. Front. Pharmacol. 2021, 12, 628690. [Google Scholar] [CrossRef] [PubMed]
  41. Miller, T.W. Endocrine Resistance: What Do We Know? Am. Soc. Clin. Oncol. Educ. Book 2013, 33, e37–e42. [Google Scholar] [CrossRef]
  42. Miller, T.W.; Hennessy, B.T.; González-Angulo, A.M.; Fox, E.M.; Mills, G.B.; Chen, H.; Higham, C.; García-Echeverría, C.; Shyr, Y.; Arteaga, C.L. Hyperactivation of Phosphatidylinositol-3 Kinase Promotes Escape from Hormone Dependence in Estrogen Receptor–Positive Human Breast Cancer. J. Clin. Investig. 2010, 120, 2406. [Google Scholar] [CrossRef]
  43. Beltrame, L.; Di Marino, M.; Fruscio, R.; Calura, E.; Chapman, B.; Clivio, L.; Sina, F.; Mele, C.; Iatropoulos, P.; Grassi, T.; et al. Profiling Cancer Gene Mutations in Longitudinal Epithelial Ovarian Cancer Biopsies by Targeted Next-Generation Sequencing: A Retrospective Study. Ann. Oncol. 2015, 26, 1363–1371. [Google Scholar] [CrossRef]
  44. Jones, S.; Wang, T.L.; Kurman, R.J.; Nakayama, K.; Velculescu, V.E.; Vogelstein, B.; Kinzler, K.W.; Papadopoulos, N.; Shih, I.M. Low-Grade Serous Carcinomas of the Ovary Contain Very Few Point Mutations. J. Pathol. 2012, 226, 413. [Google Scholar] [CrossRef]
  45. Van Nieuwenhuysen, E.; Busschaert, P.; Laenen, A.; Moerman, P.; Han, S.N.; Neven, P.; Lambrechts, D.; Vergote, I. Loss of 1p36.33 Frequent in Low-Grade Serous Ovarian Cancer. Neoplasia 2019, 21, 582–590. [Google Scholar] [CrossRef]
  46. Arend, R.C.; Davis, A.M.; Chimiczewski, P.; O’Malley, D.M.; Provencher, D.; Vergote, I.; Ghamande, S.; Birrer, M.J. EMR 20006-012: A Phase II Randomized Double-Blind Placebo Controlled Trial Comparing the Combination of Pimasertib (MEK Inhibitor) with SAR245409 (PI3K Inhibitor) to Pimasertib Alone in Patients with Previously Treated Unresectable Borderline or Low Grade Ovarian Cancer. Gynecol. Oncol. 2020, 156, 301–307. [Google Scholar] [CrossRef]
  47. Garcia-Martinez, L.; Zhang, Y.; Nakata, Y.; Chan, H.L.; Morey, L. Epigenetic Mechanisms in Breast Cancer Therapy and Resistance. Nat. Commun. 2021, 12, 1786. [Google Scholar] [CrossRef]
  48. Dimitrakopoulos, F.I.; Kottorou, A.; Tzezou, A. Endocrine Resistance and Epigenetic Reprogramming in Estrogen Receptor Positive Breast Cancer. Cancer Lett. 2021, 517, 55–65. [Google Scholar] [CrossRef]
  49. Soleimani Dodaran, M.; Borgoni, S.; Sofyall, E.; Verschure, P.J.; Wiemann, S.; Moerland, P.D.; Van Kampen, A.H.C. Candidate Methylation Sites Associated with Endocrine Therapy Resistance in ER+/HER2- Breast Cancer. BMC Cancer 2020, 20, 676. [Google Scholar] [CrossRef]
  50. Lin, X.; Li, J.; Yin, G.; Zhao, Q.; Elias, D.; Lykkesfeldt, A.E.; Stenvang, J.; Brünner, N.; Wang, J.; Yang, H.; et al. Integrative Analyses of Gene Expression and DNA Methylation Profiles in Breast Cancer Cell Line Models of Tamoxifen-Resistance Indicate a Potential Role of Cells with Stem-like Properties. Breast Cancer Res. 2013, 15, R119. [Google Scholar] [CrossRef]
  51. Stone, A.; Zotenko, E.; Locke, W.J.; Korbie, D.; Millar, E.K.A.; Pidsley, R.; Stirzaker, C.; Graham, P.; Trau, M.; Musgrove, E.A.; et al. DNA Methylation of Oestrogen-Regulated Enhancers Defines Endocrine Sensitivity in Breast Cancer. Nat. Commun. 2015, 6, 7758. [Google Scholar] [CrossRef] [PubMed]
  52. Zhang, F.; Cui, Y. Dysregulation of DNA Methylation Patterns May Identify Patients with Breast Cancer Resistant to Endocrine Therapy: A Predictive Classifier Based on Differentially Methylated Regions. Oncol. Lett. 2019, 18, 1287–1303. [Google Scholar] [CrossRef] [PubMed]
  53. Muluhngwi, P.; Klinge, C.M. Roles for MiRNAs in Endocrine Resistance in Breast Cancer. Endocr. Relat. Cancer 2015, 22, R279. [Google Scholar] [CrossRef] [PubMed]
  54. Muluhngwi, P.; Klinge, C.M. Identification of MiRNAs as Biomarkers for Acquired Endocrine Resistance in Breast Cancer. Mol. Cell Endocrinol. 2017, 456, 76–86. [Google Scholar] [CrossRef] [PubMed]
  55. Patel, R.; Klein, P.; Tiersten, A.; Sparano, J.A. An Emerging Generation of Endocrine Therapies in Breast Cancer: A Clinical Perspective. npj Breast Cancer 2023, 9, 20. [Google Scholar] [CrossRef] [PubMed]
  56. Ma, C.X.; Reinert, T.; Chmielewska, I.; Ellis, M.J. Mechanisms of Aromatase Inhibitor Resistance. Nat. Rev. Cancer 2015, 15, 261–275. [Google Scholar] [CrossRef] [PubMed]
  57. Wang, Y.; Minden, A. Current Molecular Combination Therapies Used for the Treatment of Breast Cancer. Int. J. Mol. Sci. 2022, 23, 11046. [Google Scholar] [CrossRef] [PubMed]
  58. Gadducci, A.; Cosio, S. Therapeutic Approach to Low-Grade Serous Ovarian Carcinoma: State of Art and Perspectives of Clinical Research. Cancers 2020, 12, 1336. [Google Scholar] [CrossRef] [PubMed]
  59. Johnston, S.; Martin, M.; Di Leo, A.; Im, S.A.; Awada, A.; Forrester, T.; Frenzel, M.; Hardebeck, M.C.; Cox, J.; Barriga, S.; et al. MONARCH 3 Final PFS: A Randomized Study of Abemaciclib as Initial Therapy for Advanced Breast Cancer. NPJ Breast Cancer 2019, 5, 5. [Google Scholar] [CrossRef] [PubMed]
  60. Sledge, G.W.; Toi, M.; Neven, P.; Sohn, J.; Inoue, K.; Pivot, X.; Burdaeva, O.; Okera, M.; Masuda, N.; Kaufman, P.A.; et al. MONARCH 2: Abemaciclib in Combination with Fulvestrant in Women with HR+/HER2-Advanced Breast Cancer Who Had Progressed While Receiving Endocrine Therapy. J. Clin. Oncol. 2017, 35, 2875–2884. [Google Scholar] [CrossRef] [PubMed]
  61. Dickler, M.N.; Tolaney, S.M.; Rugo, H.S.; Cortes, J.; Dieras, V.; Patt, D.; Wildiers, H.; Hudis, C.A.; O’Shaughnessy, J.; Zamora, E.; et al. MONARCH 1, A Phase II Study of Abemaciclib, a CDK4 and CDK6 Inhibitor, as a Single Agent, in Patients with Refractory HR+/HER2- Metastatic Breast Cancer. Clin. Cancer Res. 2017, 23, 5218–5224. [Google Scholar] [CrossRef] [PubMed]
  62. Turner, N.C.; Slamon, D.J.; Ro, J.; Bondarenko, I.; Im, S.-A.; Masuda, N.; Colleoni, M.; DeMichele, A.; Loi, S.; Verma, S.; et al. Overall Survival with Palbociclib and Fulvestrant in Advanced Breast Cancer. N. Engl. J. Med. 2018, 379, 1926–1936. [Google Scholar] [CrossRef]
  63. Hortobagyi, G.N.; Stemmer, S.M.; Burris, H.A.; Yap, Y.-S.; Sonke, G.S.; Hart, L.; Campone, M.; Petrakova, K.; Winer, E.P.; Janni, W.; et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N. Engl. J. Med. 2022, 386, 942–950. [Google Scholar] [CrossRef] [PubMed]
  64. Konecny, G.E.; Winterhoff, B.; Kolarova, T.; Qi, J.; Manivong, K.; Dering, J.; Yang, G.; Chalukya, M.; Wang, H.J.; Anderson, L.; et al. Expression of P16 and Retinoblastoma Determines Response to CDK4/6 Inhibition in Ovarian Cancer. Clin. Cancer Res. 2011, 17, 1591–1602. [Google Scholar] [CrossRef] [PubMed]
  65. Dall’acqua, A.; Bartoletti, M.; Masoudi-Khoram, N.; Sorio, R.; Puglisi, F.; Belletti, B.; Baldassarre, G. Inhibition of CDK4/6 as Therapeutic Approach for Ovarian Cancer Patients: Current Evidences and Future Perspectives. Cancers 2021, 13, 3035. [Google Scholar] [CrossRef] [PubMed]
  66. Konecny, G.E.; Hendrickson, A.E.W.; Jatoi, A.; Burton, J.K.; Paroly, J.; Glaspy, J.A.; Dowdy, S.C.; Slamon, D.J. A Multicenter Open-Label Phase II Study of the Efficacy and Safety of Palbociclib a Cyclin-Dependent Kinases 4 and 6 Inhibitor in Patients with Recurrent Ovarian Cancer. J. Clin. Oncol. 2016, 34, 5557. [Google Scholar] [CrossRef]
  67. Colon-Otero, G.; Zanfagnin, V.; Hou, X.; Foster, N.R.; Asmus, E.J.; Wahner Hendrickson, A.; Jatoi, A.; Block, M.S.; Langstraat, C.L.; Glaser, G.E.; et al. Phase II Trial of Ribociclib and Letrozole in Patients with Relapsed Oestrogen Receptor-Positive Ovarian or Endometrial Cancers. ESMO Open 2020, 5, e000926. [Google Scholar] [CrossRef] [PubMed]
  68. Ottenbourgs, T.; Van Gorp, T.; Kridelka, F.; Baert, T.; Denys, H.; Selle, F.; Baas, I.; Van Rompuy, A.-S.; Lambrechts, D.; Van Nieuwenhuysen, E.; et al. A Phase II, Multicenter, Open-Label Study of Abemaciclib and Letrozole in Patients with Estrogen Receptor-Positive Rare Ovarian Cancer: ALEPRO Trial. Int. J. Gynecol. Cancer 2024, 34, 627–630. [Google Scholar] [CrossRef] [PubMed]
  69. Gershenson, D.M.; Miller, A.; Brady, W.E.; Paul, J.; Carty, K.; Rodgers, W.; Millan, D.; Coleman, R.L.; Moore, K.N.; Banerjee, S.; et al. Trametinib versus Standard of Care in Patients with Recurrent Low-Grade Serous Ovarian Cancer (GOG 281/LOGS): An International, Randomised, Open-Label, Multicentre, Phase 2/3 Trial. Lancet 2022, 399, 541–553. [Google Scholar] [CrossRef]
  70. Tholander, B.; Koliadi, A.; Botling, J.; Dahlstrand, H.; Von Heideman, A.; Ahlström, H.; Öberg, K.; Ullenhag, G.J. Complete Response with Combined BRAF and MEK Inhibition in BRAF Mutated Advanced Low-Grade Serous Ovarian Carcinoma. Ups J. Med. Sci. 2020, 125, 325. [Google Scholar] [CrossRef] [PubMed]
  71. Bussies, P.L.; Schlumbrecht, M. Dual Fulvestrant-Trametinib Therapy in Recurrent Low-Grade Serous Ovarian Cancer. Oncologist 2020, 25, e1124–e1126. [Google Scholar] [CrossRef] [PubMed]
  72. Zaman, K.; Winterhalder, R.; Mamot, C.; Hasler-Strub, U.; Rochlitz, C.; Mueller, A.; Berset, C.; Wiliders, H.; Perey, L.; Rudolf, C.B.; et al. Fulvestrant with or without Selumetinib, a MEK 1/2 Inhibitor, in Breast Cancer Progressing after Aromatase Inhibitor Therapy: A Multicentre Randomised Placebo-Controlled Double-Blind Phase II Trial, SAKK 21/08. Eur. J. Cancer 2015, 51, 1212–1220. [Google Scholar] [CrossRef] [PubMed]
  73. Hou, J.Y.; Rodriguez-Gabin, A.; Samaweera, L.; Hazan, R.; Goldberg, G.L.; Horwitz, S.B.; McDaid, H.M. Exploiting MEK Inhibitor-Mediated Activation of ERα for Therapeutic Intervention in ER-Positive Ovarian Carcinoma. PLoS ONE 2013, 8, e54103. [Google Scholar] [CrossRef] [PubMed]
  74. Bedard, P.L.; Tabernero, J.; Janku, F.; Wainberg, Z.A.; Paz-Ares, L.; Vansteenkiste, J.; Van Cutsem, E.; Pérez-García, J.; Stathis, A.; Britten, C.D.; et al. A Phase Ib Dose-Escalation Study of the Oral Pan-PI3K Inhibitor Buparlisib (BKM120) in Combination with the Oral MEK1/2 Inhibitor Trametinib (GSK1120212) in Patients with Selected Advanced Solid Tumors. Clin. Cancer Res. 2015, 21, 730–738. [Google Scholar] [CrossRef] [PubMed]
  75. Skolariki, A.; D’Costa, J.; Little, M.; Lord, S. Role of PI3K/Akt/MTOR Pathway in Mediating Endocrine Resistance: Concept to Clinic. Explor. Target Antitumor. Ther. 2022, 3, 172. [Google Scholar] [CrossRef] [PubMed]
  76. André, F.; Ciruelos, E.; Rubovszky, G.; Campone, M.; Loibl, S.; Rugo, H.S.; Iwata, H.; Conte, P.; Mayer, I.A.; Kaufman, B.; et al. Alpelisib for PIK3CA-Mutated, Hormone Receptor-Positive Advanced Breast Cancer. N. Engl. J. Med. 2019, 380, 1929–1940. [Google Scholar] [CrossRef] [PubMed]
  77. Turner, N.C.; Kingston, B.; Kilburn, L.S.; Kernaghan, S.; Wardley, A.M.; Macpherson, I.R.; Baird, R.D.; Roylance, R.; Stephens, P.; Oikonomidou, O.; et al. Circulating Tumour DNA Analysis to Direct Therapy in Advanced Breast Cancer (PlasmaMATCH): A Multicentre, Multicohort, Phase 2a, Platform Trial. Lancet Oncol. 2020, 21, 1296–1308. [Google Scholar] [CrossRef] [PubMed]
  78. Lloyd, M.R.; Wander, S.A.; Hamilton, E.; Razavi, P.; Bardia, A. Next-Generation Selective Estrogen Receptor Degraders and Other Novel Endocrine Therapies for Management of Metastatic Hormone Receptor-Positive Breast Cancer: Current and Emerging Role. Ther. Adv. Med. Oncol. 2022, 14, 17588359221113694. [Google Scholar] [CrossRef]
  79. Goetz, M.P.; Bagegni, N.A.; Batist, G.; Brufsky, A.; Cristofanilli, M.A.; Damodaran, S.; Daniel, B.R.; Fleming, G.F.; Gradishar, W.J.; Graff, S.L.; et al. Lasofoxifene versus Fulvestrant for ER+/HER2- Metastatic Breast Cancer with an ESR1 Mutation: Results from the Randomized, Phase II ELAINE 1 Trial. Ann. Oncol. 2023, 34, 1141–1151. [Google Scholar] [CrossRef]
  80. Bidard, F.C.; Kaklamani, V.G.; Neven, P.; Streich, G.; Montero, A.J.; Forget, F.; Mouret-Reynier, M.A.; Sohn, J.H.; Taylor, D.; Harnden, K.K.; et al. Elacestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results from the Randomized Phase III EMERALD Trial. J. Clin. Oncol. 2022, 40, 3246–3256. [Google Scholar] [CrossRef] [PubMed]
  81. Tolaney, S.M.; Chan, A.; Petrakova, K.; Delaloge, S.; Campone, M.; Iwata, H.; Peddi, P.F.; Kaufman, P.A.; De Kermadec, E.; Liu, Q.; et al. AMEERA-3: Randomized Phase II Study of Amcenestrant (Oral Selective Estrogen Receptor Degrader) Versus Standard Endocrine Monotherapy in Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer. J. Clin. Oncol. 2023, 41, 4014–4024. [Google Scholar] [CrossRef] [PubMed]
  82. Martin, M.; Lim, E.; Gregor, M.C.M.; Shivhare, M.; Ross, G.; Patre, M.; Roncoroni, L.; Louka, M.; Sohn, J. AcelERA Breast Cancer (BC): Phase II Study Evaluating Efficacy and Safety of Giredestrant (GDC-9545) versus Physician’s Choice of Endocrine Monotherapy in Patients (Pts) with Estrogen Receptor-Positive, HER2-Negative (ER+/HER2-) Locally Advanced or Metastatic Breast Cancer (LA/MBC). J. Clin. Oncol. 2021, 39, TPS1100. [Google Scholar] [CrossRef]
  83. Martin Jimenez, M.; Lim, E.; Chavez Mac Gregor, M.; Bardia, A.; Wu, J.; Zhang, Q.; Nowecki, Z.; Cruz, F.; Safin, R.; Kim, S.-B.; et al. 211MO Giredestrant (GDC-9545) vs Physician Choice of Endocrine Monotherapy (PCET) in Patients (Pts) with ER+, HER2– Locally Advanced/Metastatic Breast Cancer (LA/MBC): Primary Analysis of the Phase II, Randomised, Open-Label AcelERA BC Study. Ann. Oncol. 2022, 33, S633–S634. [Google Scholar] [CrossRef]
  84. Lawson, M.; Cureton, N.; Ros, S.; Cheraghchi-Bashi-Astaneh, A.; Urosevic, J.; D’Arcy, S.; Delpuech, O.; DuPont, M.; Fisher, D.I.; Gangl, E.T.; et al. The Next-Generation Oral Selective Estrogen Receptor Degrader Camizestrant (AZD9833) Suppresses ER+ Breast Cancer Growth and Overcomes Endocrine and CDK4/6 Inhibitor Resistance. Cancer Res. 2023, 83, 3989–4004. [Google Scholar] [CrossRef] [PubMed]
  85. Oliveira, M.; Pominchuck, D.; Nowecki, Z.; Hamilton, E.; Kulyaba, Y.; Andabekov, T.; Hotko, Y.; Melkadze, T.; Nemsadze, G.; Neven, P.; et al. Abstract GS3-02: GS3-02 Camizestrant, a next Generation Oral SERD vs Fulvestrant in Post-Menopausal Women with Advanced ER-Positive HER2-Negative Breast Cancer: Results of the Randomized, Multi-Dose Phase 2 SERENA-2 Trial. Cancer Res. 2023, 83, GS3-02. [Google Scholar] [CrossRef]
  86. Hamilton, E.P.; Schott, A.F.; Nanda, R.; Lu, H.; Keung, C.F.; Gedrich, R.; Parameswaran, J.; Han, H.S.; Hurvitz, S.A. ARV-471, an Estrogen Receptor (ER) PROTAC Degrader, Combined with Palbociclib in Advanced ER+/Human Epidermal Growth Factor Receptor 2–Negative (HER2-) Breast Cancer: Phase 1b Cohort (Part C) of a Phase 1/2 Study. J. Clin. Oncol. 2022, 40, TPS1120. [Google Scholar] [CrossRef]
  87. Johnston, S.R.D.; Pluard, T.J.; Wang, J.S.; Hamilton, E.P.; Juric, D.; Scholz, C.R.; Hnitecki, E.; Gao, L.; Cantagallo, L.; Korpal, M.; et al. Phase 1b Study of H3B-6545 in Combination with Palbociclib in Women with Metastatic Estrogen Receptor–Positive (ER+), Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Breast Cancer. J. Clin. Oncol. 2021, 39, e13025. [Google Scholar] [CrossRef]
  88. Hamilton, E.; Meisel, J.; Alemany, C.; Virginia, B.; Lin, N.; Wesolowski, R.; Mathauda-Sahota, G.; Makower, D.; Lawrence, J.; Faltaos, D.; et al. Phase 1b Results from OP-1250-001, a Dose Escalation and Dose Expansion Study of OP-1250, an Oral CERAN, in Subjects with Advanced and/or Metastatic Estrogen Receptor (ER)-Positive, HER2-Negative Breast Cancer (NCT04505826). Eur. J. Cancer 2022, 174, S36. [Google Scholar] [CrossRef]
  89. Turner, N.C.; Jhaveri, K.L.; Bardia, A.; Niikura, N.; Dieras, V.; Barrios, C.H.; Im, S.-A.; Mueller, V.; Bellet, M.; Chang, C.-W.; et al. PersevERA Breast Cancer (BC): Phase III Study Evaluating the Efficacy and Safety of Giredestrant (GDC-9545) + Palbociclib versus Letrozole + Palbociclib in Patients (Pts) with Estrogen-Receptor-Positive, HER2-Negative Locally Advanced or Metastatic BC (ER+/HER2–LA/MBC). J. Clin. Oncol. 2021, 39, TPS1103. [Google Scholar] [CrossRef]
  90. Im, S.-A.; Hamilton, E.P.; Cussac, A.L.; Baird, R.D.; Ettl, J.; Goetz, M.P.; Iwata, H.; Joy, A.A.; Neven, P.; Haddad, V.; et al. SERENA-4: A Phase 3 Comparison of AZD9833 (Camizestrant) plus Palbociclib, versus Anastrozole plus Palbociclib, for Patients with ER-Positive, HER2-Negative Advanced Breast Cancer Who Have Not Previously Received Systemic Treatment for Advanced Disease. J. Clin. Oncol. 2021, 39, TPS1101. [Google Scholar] [CrossRef]
  91. Mayer, E.L.; Tolaney, S.; Brufsky, A.M.; Gradishar, W.; Jhaveri, K.; Martín, M.; Moscetti, L.; Vidal, G.; Cortazar, P.; Feldman, M.; et al. Abstract OT2-01-07: EvERA Breast Cancer: A Phase III Study of Giredestrant (GDC-9545) + Everolimus vs Exemestane + Everolimus in Patients with Estrogen Receptor+, HER2– Locally Advanced or Metastatic Breast Cancer. Cancer Res. 2023, 83, OT2-01. [Google Scholar] [CrossRef]
  92. Oliveira, M.; Sonnenblick, A.; Rugo, H.S.; Jung, K.H.; Yam, E.G.; Hurvitz, S.A.; Hernando, C.; Im, S.-A.; Breton, V.; Collier, A.; et al. Interim Analyses (IA) of the Giredestrant (G), G + Abemaciclib (A), and G + Ribociclib (R) Arms in MORPHEUS Breast Cancer (BC): A Phase I/II Study of G Treatment (Tx) Combinations in Patients (Pts) with Estrogen Receptor-Positive, HER2-Negative Locally Advanced/Metastatic BC (ER+, HER2–LA/MBC). J. Clin. Oncol. 2023, 41, 1061. [Google Scholar] [CrossRef]
  93. Turner, N.; Huang-Bartlett, C.; Kalinsky, K.; Cristofanilli, M.; Bianchini, G.; Chia, S.; Iwata, H.; Janni, W.; Ma, C.X.; Mayer, E.L.; et al. Design of SERENA-6, a Phase III Switching Trial of Camizestrant in ESR1-Mutant Breast Cancer during First-Line Treatment. Future Oncol. 2023, 19, 559–573. [Google Scholar] [CrossRef]
  94. Jhaveri, K.; Harbeck, N.; Aftimos, P.; Kim, S.-B.; Pivot, X.; Saura, C.; Curigliano, G.; Casalnuovo, M.; Wang, X.A.; Young, S.R.L.; et al. Abstract OT2-11-01: EMBER-3: A Randomized Phase 3 Study of LY3484356, a Novel, Oral Selective Estrogen Receptor Degrader vs Investigator’s Choice of Endocrine Therapy of Either Fulvestrant or Exemestane, in Patients with Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative, Locally Advanced or Metastatic Breast Cancer Previously Treated with Endocrine-Based Therapy. Cancer Res. 2022, 82, OT2-11. [Google Scholar] [CrossRef]
  95. Andreano, K.J.; Wardell, S.E.; Baker, J.G.; Desautels, T.K.; Baldi, R.; Chao, C.A.; Heetderks, K.A.; Bae, Y.; Xiong, R.; Tonetti, D.A.; et al. G1T48, an Oral Selective Estrogen Receptor Degrader, and the CDK4/6 Inhibitor Lerociclib Inhibit Tumor Growth in Animal Models of Endocrine-Resistant Breast Cancer. Breast Cancer Res. Treat 2020, 180, 635–646. [Google Scholar] [CrossRef] [PubMed]
  96. Keogh, G.P.; Papish, S.; Piskorski, W.; Ulanska, M.; Jackson, B.; Suster, M.; Ptaszynski, M.; Mina, L. 564TiP A Phase Ib Dose-Escalation Study of ZN-C5, an Oral Selective Estrogen Receptor Degrader (SERD), in Combination with Abemaciclib in Patients with Advanced Estrogen Receptor (ER)+/HER2- Breast Cancer. Ann. Oncol. 2021, 32, S618–S619. [Google Scholar] [CrossRef]
  97. Abramson, V.; Linden, H.M.; Crew, K.; Mortimer, J.; Alidzanovic, J.; Nangia, J.; Layman, R.; Vranjes, Z.J.; Andric, Z.; Milovic-Kovacevic, M.; et al. 565TiP A Phase I/II Dose-Escalation and Expansion Study of ZN-C5, an Oral Selective Estrogen Receptor Degrader (SERD), as Monotherapy and in Combination with Palbociclib in Patients with Advanced Estrogen Receptor (ER)+/HER2- Breast Cancer. Ann. Oncol. 2021, 32, S619. [Google Scholar] [CrossRef]
  98. Osborne, C.; Richards, D.A.; Wilks, S.T.; Diab, S.; Juric, D.; Lathrop, K.; Silber, A.; Edenfield, W.; Aulakh, A.; Cho, B.; et al. Abstract PS11-26: A Phase 1 Study of D-0502, an Orally Bioavailable SERD, for Advanced or Metastatic HR-Positive and HER2-Negative Breast Cancer. Cancer Res. 2021, 81, PS11-26. [Google Scholar] [CrossRef]
  99. Maenhoudt, N.; Defraye, C.; Boretto, M.; Jan, Z.; Heremans, R.; Boeckx, B.; Hermans, F.; Arijs, I.; Cox, B.; Van Nieuwenhuysen, E.; et al. Developing Organoids from Ovarian Cancer as Experimental and Preclinical Models. Stem Cell Rep. 2020, 14, 717–729. [Google Scholar] [CrossRef] [PubMed]
  100. Dumont, S.; Jan, Z.; Heremans, R.; Van Gorp, T.; Vergote, I.; Timmerman, D. Organoids of Epithelial Ovarian Cancer as an Emerging Preclinical in Vitro Tool: A Review. J. Ovarian Res. 2019, 12, 105. [Google Scholar] [CrossRef]
Cancers 16 01862 g001
Figure 1. Schematic representation of the estrogen receptor-α (ERα), including the most common LBD point mutations. The structural domains of ERα are shown, including the transcription activation function domains (AF1 and AF2), the DNA-binding domain, the receptor dimerization and nuclear localization (hinge) domain, and the ligand-binding domain. Abbreviations: AF1, activation function 1 domain; AF2, activation function domain 2; DBD, DNA-binding domain; LBD, the ligand-binding domain. Created with BioRender.com.
Figure 1. Schematic representation of the estrogen receptor-α (ERα), including the most common LBD point mutations. The structural domains of ERα are shown, including the transcription activation function domains (AF1 and AF2), the DNA-binding domain, the receptor dimerization and nuclear localization (hinge) domain, and the ligand-binding domain. Abbreviations: AF1, activation function 1 domain; AF2, activation function domain 2; DBD, DNA-binding domain; LBD, the ligand-binding domain. Created with BioRender.com.
Cancers 16 01862 g001
Cancers 16 01862 g002
Figure 2. Activation of alternative pathways. (a) Normal estrogen signaling; (b) crosstalk between growth factor receptor pathways (MEK and PI3K/mTOR pathways) and the estrogen pathway. The estrogen pathway is activated in the absence of estrogen as a mechanism of endocrine resistance. Created with BioRender.com. Abbreviation: ERE; estrogen response element.
Figure 2. Activation of alternative pathways. (a) Normal estrogen signaling; (b) crosstalk between growth factor receptor pathways (MEK and PI3K/mTOR pathways) and the estrogen pathway. The estrogen pathway is activated in the absence of estrogen as a mechanism of endocrine resistance. Created with BioRender.com. Abbreviation: ERE; estrogen response element.
Cancers 16 01862 g002
Cancers 16 01862 g003
Figure 3. Mechanisms of action of different endocrine therapies. (a) Estrogens bind to the ER, promoting receptor dimerization and translocation to the nucleus. The estrogen-bound ER dimer regulates gene transcription, resulting in gene expression and cancer cell growth and survival; (b) aromatase inhibitors block the aromatase enzyme, preventing the conversion from androgens into estrogen and leading to the inhibition of gene transcription; (c) SERMs competitively bind to the ER, leading to the inhibition of ER-dependent gene transcription by recruiting transcriptional co-repressors; (d) SERDs bind to the ER, inhibiting its translocation to the nucleus, and promoting its destabilization and degradation; (e) PROTACs mediate an interaction between the ER and the E3 ubiquitin-ligase complex, facilitating ubiquitination of the ER and subsequently its degradation; (f) SERCAs covalently bind to the C530 residue of both wild-type and mutant ERs, leading to the inactivation of these receptors; (g) CERANs bind the ER, leading to the inactivation of AF1 and AF2 of both wild-type and mutant ERs, consequently inhibiting gene transcription. Created with BioRender.com. Abbreviations: AF1, activation function 1; AF2, activation function 2; CERAN, complete estrogen receptor antagonists; ER, estrogen receptor; ERE, estrogen response element; PROTAC, proteolysis targeting chimera; SERCA, selective estrogen receptor covalent antagonist; SERD, selective estrogen receptor modulator; SERM, selective estrogen receptor modulator.
Figure 3. Mechanisms of action of different endocrine therapies. (a) Estrogens bind to the ER, promoting receptor dimerization and translocation to the nucleus. The estrogen-bound ER dimer regulates gene transcription, resulting in gene expression and cancer cell growth and survival; (b) aromatase inhibitors block the aromatase enzyme, preventing the conversion from androgens into estrogen and leading to the inhibition of gene transcription; (c) SERMs competitively bind to the ER, leading to the inhibition of ER-dependent gene transcription by recruiting transcriptional co-repressors; (d) SERDs bind to the ER, inhibiting its translocation to the nucleus, and promoting its destabilization and degradation; (e) PROTACs mediate an interaction between the ER and the E3 ubiquitin-ligase complex, facilitating ubiquitination of the ER and subsequently its degradation; (f) SERCAs covalently bind to the C530 residue of both wild-type and mutant ERs, leading to the inactivation of these receptors; (g) CERANs bind the ER, leading to the inactivation of AF1 and AF2 of both wild-type and mutant ERs, consequently inhibiting gene transcription. Created with BioRender.com. Abbreviations: AF1, activation function 1; AF2, activation function 2; CERAN, complete estrogen receptor antagonists; ER, estrogen receptor; ERE, estrogen response element; PROTAC, proteolysis targeting chimera; SERCA, selective estrogen receptor covalent antagonist; SERD, selective estrogen receptor modulator; SERM, selective estrogen receptor modulator.
Cancers 16 01862 g003
Table 1. Ongoing and upcoming clinical trials with combination therapies for LGSOC.
Table 1. Ongoing and upcoming clinical trials with combination therapies for LGSOC.
DrugMode of ActionStatusPhaseIndicationBiomarkers for Patient SelectionEnrolmentClinicaltrials.gov
Ribociclib
Letrozole		CDK4/6 inhibitor
Aromatase inhibitor		Active, not recruitingIIRecurrent LGSOCNA51 (actual)NCT03673124
Abemaciclib
Fulvestrant		CDK4/6 inhibitor
SERD		Active, not recruitingIIAdvanced LGSOC, first-line, neo-adjuvant treatmentNA18 (actual)NCT03531645
Abemaciclib
Letrozole		CDK4/6 inhibitor
Aromatase inhibitor		RecruitingIIRecurrent LGSOCER positivity100 (estimated)NCT05872204
Palbociclib
Binimetinib		CDK4/6 inhibitor
MEK inhibitor		RecruitingIIRAS-mutant cancers, including LGSOCKRAS/NRAS/HRAS or BRAF alterations, RAF mutations or RAF fusions199 (estimated)NCT05554367
Avutometinib (VS-6766) +/−
Defactinib (VS-6063)		Dual RAF/MEK inhibitor
FAK inhibitor		RecruitingIIRecurrent LGSOC with or without a KRAS mutationKRAS wild-type
KRAS mutation		225 (estimated)NCT04625270
Avutometinib (VS-6766) +
Defactinib (VS-6063)		Dual RAF/MEK inhibitor
FAK inhibitor		RecruitingIIIRecurrent LGSOCKRAS wild-type
KRAS mutation		270 (estimated)NCT06072781
Pimasertib
Voxtalisib (SAR245409)		MEK1/2 inhibitor
PI3K/mTOR inhibitor		CompletedIIRecurrent borderline/low malignant potential and LGSOCNA65 (actual)NCT01936363
[46]
Regorafenib
Fulvestrant		Multikinase inhibitor
SERD		RecruitingIIRecurrent LGSOCNA31 (estimated)NCT05113368
Letrozole
Alpelisib
OR
Letrozole
Ribociclib based on presence of PI3KCA mutation status		Aromatase inhibitor
PI3Ka-inhibitor
OR
Aromatase inhibitor
CDK4/6 inhibitor		RecruitingIIAdvanced gynecological cancers that express hormone receptorsER and/or PR positivity100 (actual)ACTRN12621000639820
Biomarker-driven therapy *AKT inhibitor
MEK inhibitor
Chemotherapy
CDK4/6 inhibitor
PI3K α inhibitor
SERD
Aromatase inhibitor
VEGF-A inhibitor
PARP inhibitor
PD-L1 inhibitor
Anti-HER2 antibody + cytotoxic agent		Prematurely terminatedIIRecurrent rare epithelial ovarian tumorsSee footnote of this table500 (estimated)NCT04931342
* BOUQUET trial: PIK3CA/AKT1/PTEN-altered tumors => Ipatasertib (AKT inhibitor) and Paclitaxel (chemotherapy); BRAF/NRAS/KRAS/NF1-altered tumors => Cobimetinib (MEK inhibitor); ERBB2-amplified/mutant tumors => Trastuzumab Emtansine (anti-HER2 antibody + cytotoxic agent); no specific mutation => Atezolizumab (PD-L1 inhibitor) with Bevacizumab (VEGF-A inhibitor); ER+ tumors => Giredestrant (SERD) + Abemaciclib (CDK4/6 inhibitor) + LHRH agonist if peri- or pre-menopausal; PIK3CA-altered tumors => Inavolisib (PI3K-α inhibitor) + Palbociclib (CDK4/6 inhibitor); ER+ and PIK3CA-altered tumors => Inavolisib + Palbociclib + Letrozole (aromatase inhibitor); no specific mutation => Inavolisib + Olaparib (PARP inhibitor); ER+ and PIK3CA-altered tumors => Inavolisib + Giredestrant; PIK3CA-altered tumors => Inavolisib + Bevacizumab; no specific mutation => Atezolizumab + Bevacizumab + Cyclophosphamide (chemotherapy). Abbreviations: AKT, protein kinase B; CDK4/6, cyclin-dependent kinase 4 and 6; ER, estrogen receptor; FAK, focal adhesion kinase; HER2, human epidermal growth factor receptor 2; mTOR, mammalian target of rapamycin; NA, not applicable; PARP, poly ADP-ribose polymerase; PD-L1, programmed death-ligand 1; PI3K, phosphoinositide 3-kinase; PR, progesterone receptor; SERD, selective estrogen receptor degrader; RAF, rapidly accelerated fibrosarcoma; VEGF-A, vascular epidermal growth factor A.
Table 2. Completed trials in advanced and metastatic ER+ breast cancer with new endocrine drug therapies to overcome endocrine resistance.
Table 2. Completed trials in advanced and metastatic ER+ breast cancer with new endocrine drug therapies to overcome endocrine resistance.
Drug(s)Mode of ActionClinical TrialPhaseIndicationTreatment ArmsOutcome Primary EndpointsReference
LasofoxifeneSERMELAINE I
NCT03781063		IIER+/HER2- advanced or metastatic breast cancer with an ESR1 mutationLasofoxifene vs. fulvestrant
  • Median PFS: 5.6 months (lasofoxifene) vs. 3.7 months (fulvestrant); p = 0.138
  • ORR was higher for lasofoxifene (14.3%) compared to fulvestrant (3.9%)
Goetz et al. [79]
ElacestrantSERD/
SERM		EMERALD
NCT03778931 		IIIER+/HER2- advanced or metastatic breast cancer with 1–2 previous lines of endocrine therapy, including a CDK4/6 inhibitorElacestrant vs. standard endocrine therapy (fulvestrant/AI)Median PFS: 2.8 months (elacestrant) vs. 1.9 months (standard endocrine therapy); HR: 0.664; p = 0.0019Bidard et al. [80]
AmcenestrantSERDAMEERA-3 NCT04059484IIER+/HER2- advanced or metastatic breast cancer that progressed after prior treatment with an AI and a CDK4/6 inhibitorAmcenestrant vs. physician’s choice of endocrine treatmentMedian PFS: 3.6 months (amcenestrant) vs. 3.7 months (physician’s choice of endocrine treatment); HR: 1.05, p = 0.64Tolaney et al. [81]
GiredestrantSERDacelERA NCT04576455IIER+/HER2- advanced or metastatic breast cancer that received 1 or 2 prior lines of systemic therapyGiredestrant vs. physician’s choice of endocrine treatmentMedian PFS: 5.6 months (giredestrant) vs. 5.4 months (physician’s choice of endocrine treatment); HR 0.81, p = 0.18Martin et al.
Martin Jimenez et al. [82,83]
CamizestrantSERDSERENA-2
NCT04214288		IIER+/HER2- advanced or metastatic breast cancerCamizestrant 75, 150 or 300 mg vs. FulvestrantMedian PFS: 7.2 months (camizestrant 75 mg) vs. 3.7 (fulvestrant); p = 0.0124
Median PFS: 7.7 months (camizestrant 150 mg) vs. 3.7 (fulvestrant); p = 0.0161		Lawson et al.
Oliveira et al. [84,85]
Abbreviations: ER+, estrogen receptor-positive; HER2-, human epidermal growth factor receptor 2-negative; HR, hazard ratio; PFS, progression-free survival; OS, overall survival; SERD, selective estrogen receptor degrader; SERM; selective estrogen receptor modulator.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Ottenbourgs, T.; Van Nieuwenhuysen, E. Novel Endocrine Therapeutic Opportunities for Estrogen Receptor-Positive Ovarian Cancer—What Can We Learn from Breast Cancer? Cancers 2024, 16, 1862. https://doi.org/10.3390/cancers16101862

AMA Style

Ottenbourgs T, Van Nieuwenhuysen E. Novel Endocrine Therapeutic Opportunities for Estrogen Receptor-Positive Ovarian Cancer—What Can We Learn from Breast Cancer? Cancers. 2024; 16(10):1862. https://doi.org/10.3390/cancers16101862

Chicago/Turabian Style

Ottenbourgs, Tine, and Els Van Nieuwenhuysen. 2024. "Novel Endocrine Therapeutic Opportunities for Estrogen Receptor-Positive Ovarian Cancer—What Can We Learn from Breast Cancer?" Cancers 16, no. 10: 1862. https://doi.org/10.3390/cancers16101862

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop