Unlocking the potential of oral SERDs in HER2+/ER+ breast cancer

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Reference: August 2025 | Issue 8 | Vol 11 | Page 40

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In Ireland, breast cancer accounts for 30 per cent of all female cancer incidence and is the second most common invasive cancer cause of death.¹ Despite the high incidence, prognosis for many breast cancer cases is increasing year-on-year, with the latest Irish data reporting a five-year survival rate of 88 per cent.¹ A critical challenge still exists in the treatment of breast cancer recurrence and metastasis, both of which are closely linked to treatment resistance.

Pathological examination of receptor expression allows for breast cancer to be generally classified into: Oestrogen receptor-positive (ER+) (with/without progesterone receptor [PR+], can also be termed hormonal-positive [HR+]); human epidermal growth factor receptor 2 -positive (HER2+); or triple negative (TNBC) subtypes.

Along with staging parameters, the subtype dictates the appropriate treatment strategy. Breast cancer that expresses both hormonal receptors (ER ± PR) and HER2 (HER2+/ER+ breast cancer) may represent a distinct subtype of its own, with unique characteristics in terms of prognosis, metastasis, and treatment response.

Cohort studies estimate that the majority of HER2+ breast tumours also express ER. Overall, HER2+/ER+ breast cancer accounts for approximately 10 per cent of diagnoses.² The dual expression of both HER2 and ER can elicit a lack of clarity in treatment choice, whether to target HER2, ER or both, which of the numerous approved agents to use, as well as the timing of these regimes.

According to a review on the treatment landscape of hormonal positive/HER2+ breast cancer, treatment pathways vary between endocrine therapy alone, targeted anti-HER2 therapy, and chemotherapy combined with later endocrine therapy (ET) or primary endocrine therapy followed later by targeted anti-HER2 therapy and chemotherapy.²

At a molecular level, HER2 and ER signalling pathways are closely interlinked, with both in vitro and clinical studies showing evidence of compensatory cross-talk between the receptors, which can drive treatment resistance.

HER2+/ER+ tumours confer a worse prognosis than ER+/HER2- cases.³ In ER+ breast cancer, resistance to ET can develop due to activating mutations in HER2.⁴ HER2+/ER+ breast cancer is less responsive to both anti-HER2 therapy and chemotherapy, compared to HER2+/ER- cases.⁵

Furthermore, in the metastatic setting, ET is less effective in HER2+ positive tumours.⁶ Pre-clinical and clinical studies have suggested that dual targeting of both HER2 and ER is optimal in the treatment of HER2+/ER+ breast cancer, as reviewed in a comprehensive article by Pegram et al in 2023.⁵ Dual-receptor-targeting combinations have shown improvement over chemotherapy-containing regimes, offering another benefit in the potential reduction of adverse effects and improvement in patient quality of life.⁷

Despite the wealth of evidence supporting the benefits of dual-receptor-targeting in HER2+/ER+ breast cancer, this treatment strategy is often underutilised.⁵ One reason for this may be due to the sheer number of approved drug compounds to target these receptors and understanding the best combination thereof. Therapies targeting HER2 and ER are numerous, with new approvals being added to an oncologist’s repertoire each year.

As a result, clinical trials in HER2+/ER+ breast cancer are extremely heterogeneous, making it difficult to conduct head-to-head analysis of different combinations and the advantage of including ET.⁸ Targeted therapy for HER2+ breast cancer includes the monoclonal antibody therapies trastuzumab and pertuzumab, and has advanced in recent years to the antibody-drug conjugates trastuzumab-emtansine (T-DM1) and trastuzumab-deruxtecan (T-DXd), which have shown efficacy as later line treatments for advanced breast cancer.

TABLE 1: Selection of orally available selective oestrogen receptor degradation inhibitors that have reached clinical trial.
Source: www.clinicaltrials.gov/

Further treatment options exist in the form of small molecule tyrosine kinase inhibitors (TKIs) of HER2 including tucatinib, neratinib, and lapatinib. ET for hormonal positive breast cancer also come in many forms, targeting the action of ER, including selective oestrogen receptor modulators (SERMs), eg, tamoxifen, aromatase inhibitors (AI), eg, anastrozole and letrozole), gonadotropin-releasing hormone agonists (GnRH), eg, goserelin), and selective oestrogen receptor degraders (SERDs), eg, fulvestrant.

SERDs are an important class of ET, as they can be used following acquisition of resistance to prior ETs. Early line ET such as SERMs prevent the activation of ER by preventing oestrogen interacting with its receptor. Resistance can occur when ER develops ligand-independent signalling or an activating ESR1 mutation, at which point SERDs, which degrade the ER itself, must be used.

For over 20 years, fulvestrant was the only approved SERD.⁹ Although showing efficacy, due to its poor bioavailability fulvestrant must be administered via high-dose intramuscular injection, limiting its practicality and impacting on patient compliance and comfort.

The recent development of orally available SERDs offers a breakthrough in this drug class, combining the efficacy of SERDs in advanced breast cancer with the convenience of oral administration. Over 12 oral SERDs are in clinical development by a range of pharmaceutical backers, with several in phase 2/3 trials and showing promising results of efficacy in both early and late-stage ER+ breast cancer (Table 1).

Elacestrant is the only approval to date, showing benefit over fulvestrant and other ETs after progression on CDK4/6 inhibitors, and particularly in the population harbouring ESR1 mutations.¹⁰ Conversely, other oral SERDs have failed to live up to potential and reach successful trial endpoints, such as AZD9496 and amcenestrant. Despite a strong rationale for development and promising pre-clinical and early trial results, overall oral SERDs have not yet found their role in the armamentarium of anti-cancer therapies.

As mentioned, amcenestrant is an example of an oral SERD which showed strong promise but ultimately was dropped from development. Amcenestrant is a non-steroidal, orally available SERD which shows an equivalency to fulvestrant in vitro and efficacy in pre-clinical fulvestrant-resistant models.¹¹

The AMEERA-1 trial of amcenestrant in postmenopausal women with pre-treated HER2−/ER+ breast cancer reported a clinical benefit rate of 28.3 per cent and no adverse event-associated discontinuations.¹² Disappointingly, later trials comparing amcenestrant to current ETs, both as a monotherapy and in combination with CDK4/6 inhibitors, did not meet specified endpoints in ER+ breast cancer trials. Thus, the decision was made by investigators and Sanofi to discontinue development of amcenestrant in August 2022.^13-15

To date, leading oral SERDs in late-stage clinical development include camizestrant, giredestrant, and imlunestrant (Table 1). These are being investigated in ER+ breast cancer in a variety of patient cohorts and combinations. However, the discontinuation of amcenestrant throws doubt on the ability of these new oral SERDs to perform better than current ET choices, and to overcome resistance in pre-treated cohorts – characteristics needed for successful clinical approval. This raises the question of where this emerging class of oral SERDs might fit within current treatment algorithms.

Considering the questions over the role of novel oral SERDs and the optimal combination treatment strategies for HER2+/ER+ breast cancer, it has been postulated that the potential of these oral SERDs could lie in the combination with anti-HER2 compounds for the treatment of HER2+/ER+ breast cancer. The sheer number of therapeutic compounds and possible combinations means clinical investigations of all options is impossible. Thus, the research must rely on pre-clinical in vitro and in vivo models to narrow in on the most promising combination strategies.

Recent in vitro research has made the first steps in tackling this hypothesis. In the study titled Pre-Clinical Rationale for Amcenestrant Combinations in HER2+/ER+ Breast Cancer, published in the International Journal of Molecular Sciences in 2025, researchers Amira F Mahdi, Niall Ashfield, John Crown, and Denis M.Collins from the Cancer Biotherapeutics Group at Dublin City University, explored the efficacy of combining the oral SERD amcenestrant with various anti-HER2 therapies in HER2+/ER+ breast cancer laboratory models.¹⁶

This pre-clinical study assessed the anti-proliferative effects of amcenestrant in combination with various HER2-targeted agents, including lapatinib, tucatinib, neratinib, trastuzumab, and T-DM1. The researchers sought to determine whether these combinations could work synergistically together and enhance therapeutic efficacy in HER2+/ER+ breast cancer cell lines, including those resistant to anti-HER2 therapy alone.

Synergy between amcenestrant and anti-HER2 TKIs was noted in several HER2+/ER+ cell lines. Amcenestrant also increased the anti-proliferative effect of trastuzumab and T-DM1 in a trastuzumab-resistant cell line. It was noted that the additional benefit of amcenestrant inclusion was closely linked to the expression of ER in the cell models – suggesting that heterogeneity exists in the HER2+/ER+ classification, and quantification of receptor expression could be helpful in stratifying the scenarios in which an oral SERD/anti-HER2 therapy combination would be most beneficial.

Investigation of signalling mechanisms in the cells post-treatment showed that the combinations of amcenestrant and anti-HER2 TKIs elicited a greater decrease in the activation of pro-growth and pro-survival pathways and an increase in the apoptotic response of cells, compared to amcenestrant treatment alone.

These pre-clinical findings support the further investigation of combinations of oral SERDs and anti-HER2 therapy, like TKIs, for HER2+/ER+ breast cancer. The observed synergy and efficacy in resistant models should next be investigated in vivo to further validate the results, before potentially informing the design of clinical trials.

A number of oral SERDs, including amcenestrant, camizestrant, imlunestrant, and giredestrant, have demonstrated tolerance and safety in humans, and the anti-HER2 therapies investigated in this study are all approved for breast cancer treatment.^12,17-19

Thus, there is a strong rationale that an oral SERD/anti-HER2 combination would be tolerable and potentially efficacious in a cohort of HER2+/ER+ breast cancer patients who may have received several therapy lines. Future work plans to investigate other oral SERDs in the context of HER2+/ER+ breast cancer.

In summary, the research provides a pre-clinical rationale for the combined use of amcenestrant and HER2-targeted treatments. This highlights a promising avenue for overcoming resistance and improving outcomes in HER2+/ER+ breast cancer.

As results roll in from further phase 3 trials of oral SERDs, it is yet to be seen if they offer advantage over current ET choices in the monotherapy format and will be approved for use. Early pre-clinical evidence suggests the true potential of orally available SERDs may be unlocked in combination treatment regimes, such as those for HER2+/ER+ breast cancer.