Precision Treatments for HR-Positive Metastatic Breast Cancer: A Guide to Emerging Therapies

Table of Contents

• Key Points
• Why This Research Matters
• The Role of Oestrogen in HR+ Breast Cancer
• Standard Endocrine Therapies
• How Resistance to Endocrine Therapy Develops
• A New Treatment in Practice: Elacestrant
• Emerging Therapies in Late-Stage Trials
• What This Means for Patients
• Limitations of Current Research
• Recommendations for Patients
• Frequently Asked Questions
• Source Information

Key Points

• HR+ breast cancer is the most common subtype, and estrogen drives its growth.
• Anti-estrogen therapy plus CDK4/6 inhibitors is standard first-line for metastatic disease.
• ESR1 mutations arise in 20–40% of patients during aromatase inhibitor treatment.
• Elacestrant, an oral SERD, improved progression-free survival in ESR1-mutant metastatic breast cancer.
• Genomic testing for ESR1 and PIK3CA mutations helps guide personalized endocrine therapy.

Why This Research Matters

Breast cancer is the most commonly diagnosed cancer in women worldwide. Despite major advances in detection and treatment, it remains a leading cause of illness and death. Breast cancers are traditionally divided into three subtypes based on which receptors they express: hormone receptor-positive (HR+, about 7 out of 10 breast cancers), HER2-positive (HER2+, about 2 out of 10), and triple-negative (about 1 in 10).

HR+ breast cancer cells rely on oestrogen to grow. This makes understanding how oestrogen drives tumour growth essential for developing better treatments. Modern molecular profiling has enabled doctors to look deeper into the genes that control cancer cell growth, survival, and movement. The goal is to move beyond one-size-fits-all treatment toward truly personalised medicine.

The therapeutic approach for HR+ breast cancer now prioritises endocrine therapy (hormone-blocking treatment) and targeted therapies. These strategies aim to shut down oestrogen signals while avoiding the harsh side effects of chemotherapy. For patients with metastatic disease, the standard first-line approach combines an aromatase inhibitor (AI) with a CDK4/6 inhibitor. These combinations have improved progression-free survival (PFS, the time a patient lives without the cancer growing), although their effect on overall survival (OS) varies between trials.

This review from doctors at Beth Israel Deaconess Medical Center, Memorial Sloan Kettering, Winship Cancer Institute, UCLA Health, and Massachusetts General Hospital describes how the field is evolving. The authors highlight new therapies that have entered clinical practice, promising drugs in late-stage trials, and the crucial role of genomic testing in guiding treatment decisions.

The Role of Oestrogen in HR+ Breast Cancer

Oestrogen drives HR+ breast cancer through a specific biological chain of events. In premenopausal women, the ovaries produce oestrogen. In postmenopausal women, the body converts androgens (male-type hormones) into oestrogen using enzymes called aromatases, which are found in fat tissue. Breast cancer cells that express the oestrogen receptor (ER) depend on oestrogen to switch on genes that promote tumour growth and survival.

Three main classes of anti-oestrogen drugs have been used for decades. Each works differently to interrupt this process:

• Selective oestrogen receptor modulators (SERMs) — such as tamoxifen, which binds to the ER and blocks its activity in breast tissue.
• Aromatase inhibitors (AIs) — such as letrozole, anastrozole, and exemestane, which stop androgens from being converted into oestrogen.
• Selective oestrogen receptor degraders (SERDs) — such as fulvestrant, which bind to the ER, block it, and cause the cell to destroy the receptor entirely.

These agents have been the backbone of HR+ breast cancer treatment since the 1970s. They all work by disrupting oestrogen receptor signalling, but each has a different mechanism and side-effect profile.

Standard Endocrine Therapies

Tamoxifen is a SERM that acts in a tissue-specific way. In breast tissue it works as an anti-oestrogen, suppressing tumour growth. In other tissues it can act as an oestrogen agonist (activator), which explains some of its effects. Tamoxifen is generally well tolerated. Common side effects include hot flashes and vaginal discharge. A small but important risk exists: less than a 1% increase in the chance of blood clots (venous thromboembolism) and cancer of the uterine lining (endometrial malignancy).

Aromatase inhibitors — letrozole, anastrozole, and exemestane — block the aromatase enzyme from converting androgens into oestrogen. They are used in postmenopausal patients, or in premenopausal patients who also receive ovarian suppression with a luteinizing hormone-releasing hormone modulator. Clinical studies have shown that patients taking AIs have better outcomes than those taking tamoxifen. However, AIs have their own side effects, including hot flashes, joint pain (arthralgias), vaginal dryness, and loss of bone density.

Fulvestrant was the first SERD approved for advanced-stage endocrine-sensitive breast cancer. It is given by injection, either alone in postmenopausal women or combined with ovarian suppression in premenopausal women. Fulvestrant binds to the ER and triggers its degradation through the cell's ubiquitin system, effectively eliminating the receptor. It is generally safe, but it has a key drawback: it is not orally bioavailable, meaning it cannot be taken as a pill.

How Resistance to Endocrine Therapy Develops

In the metastatic setting, prolonged treatment with anti-oestrogen therapies inevitably leads to drug resistance. The authors categorise resistance into two broad types: ER-dependent and ER-independent.

ER-dependent resistance occurs when cancer cells become resistant to anti-oestrogen drugs while still depending on ER signalling for survival. The most common cause is an acquired mutation in ESR1, the gene that encodes the oestrogen receptor itself. These mutations typically occur in the ligand-binding domain — the part of the receptor where oestrogen attaches. Two well-known mutations, Y537S and D538G, cause the ER to become constitutively active, meaning it fires signals even without oestrogen present. These mutations also reduce the ability of drugs to bind to the receptor.

ESR1 mutations are rarely present when a patient is first diagnosed with metastatic disease. However, they arise during treatment in about 20% to 40% of patients with HR+ metastatic breast cancer (2 to 4 out of every 10 patients). This happens because ongoing use of aromatase inhibitors creates selective pressure that favors the growth of mutated cancer cells. Research shows that ESR1 mutations are linked to poorer responses to AIs. Interestingly, fulvestrant generally remains effective in this setting, although one specific mutation (ESR1 Y537S) has been reported to reduce its anti-tumour activity.

ER-independent resistance develops when cancer cells find alternative ways to survive without relying on ER signalling. This involves the activation of "bypass" pathways that promote cancer cell growth. Key alterations include:

• Receptor tyrosine kinase genes: FGFR, EGFR, and ERBB2
• AKT signalling pathway genes: PIK3CA, PTEN, and AKT1
• RAS–MAPK pathway genes: NF1 and KRAS
• Transcription factor genes, such as MYC

These mutations reduce the effectiveness of anti-oestrogens. Still, tumours harbouring these alterations often continue to rely on ER signalling due to complex crosstalk between pathways. This insight has led to a powerful strategy: inhibiting the bypass pathway can restore the tumour's dependence on oestrogen, effectively reversing the endocrine-resistant phenotype.

This approach has already produced approved drugs. The PI3K inhibitor alpelisib is approved for patients with PIK3CA-mutant advanced breast cancer. The AKT inhibitor capivasertib is approved for those with AKT pathway-altered disease. Both are given alongside endocrine therapy.

Resistance to CDK4/6 inhibitor combinations follows a different pattern. Mutations in FGFR, KRAS, and AKT1 appear to drive resistance to both anti-oestrogen therapy and CDK4/6 inhibitors. By contrast, ESR1 and PIK3CA mutations do not correlate with resistance to these combinations. Loss of the RB1 gene, which encodes a key cell cycle regulatory protein, can be sufficient to cause resistance to CDK4/6 inhibitors even in tumours that remain sensitive to endocrine therapy.

A New Treatment in Practice: Elacestrant

In 2023, the FDA approved elacestrant, the first orally bioavailable SERD. This approval changed the treatment landscape for advanced-stage ER+ breast cancer. Unlike fulvestrant, which requires injections, elacestrant comes as a pill.

Preclinical studies showed that elacestrant works both as a single agent and in combination with CDK4/6 inhibitors or everolimus. Importantly, it retained anti-tumour activity in laboratory models of ESR1-mutant, CDK4/6 inhibitor-resistant cancer cells. Phase I trial results confirmed clinical activity in patients with ESR1 mutations, including those who had already received CDK4/6 inhibitors or SERDs, with a tolerable side-effect profile.

These findings led to the phase III EMERALD trial, which compared elacestrant with standard-of-care endocrine monotherapy. The study enrolled patients with advanced-stage ER+ breast cancer whose disease had progressed on a CDK4/6 inhibitor plus an AI or fulvestrant. The standard-of-care arm received the investigator's choice of fulvestrant or another AI. Researchers evaluated ESR1 mutational status using a blood test called circulating tumour DNA (ctDNA) analysis with the Guardant360 next-generation sequencing assay.

The results were striking:

• In all patients (unselected), elacestrant improved PFS with a hazard ratio (HR) of 0.70 (95% CI 0.55–0.88; P = 0.002). A hazard ratio below 1 means the drug reduced the risk of cancer progression; an HR of 0.70 translates to a 30% lower risk of progression.
• In patients with ESR1-mutant disease, the benefit was even greater: HR 0.55 (95% CI 0.39–0.77; P = 0.0005), a 45% reduction in progression risk.
• A subgroup analysis of patients who had previously received fulvestrant also showed continued benefit: HR 0.68 (95% CI 0.52–0.90; P = 0.0049).

These statistics are highly significant. A p-value of 0.002 means there is only a 0.2% chance the result occurred by random chance. For the ESR1-mutant subgroup, the p-value of 0.0005 means a 0.05% chance — extremely strong evidence.

The survival curves in the EMERALD trial revealed an interesting pattern. Both treatment arms showed a sharp initial drop in the first few months of therapy, reflecting a subgroup of patients with endocrine-resistant tumours in this later-line treatment setting. The curves then flattened and separated, reflecting patients with endocrine-sensitive disease who derived lasting benefit.

Duration of prior CDK4/6 inhibitor therapy may predict response to elacestrant. Patients with ESR1-mutant tumours who had received 12 months or more of prior CDK4/6 inhibitor treatment had a median PFS of 8.6 months on elacestrant versus 1.9 months on standard endocrine therapy (HR 0.41, 95% CI 0.26–0.63). The authors suggest that a longer duration of benefit from prior CDK4/6 inhibition may be a surrogate marker of endocrine-dependent disease.

Side effects were common in both treatment arms. The most frequent were fatigue, joint pain (arthralgias), nausea and vomiting (more common with elacestrant), and elevated liver enzymes (transaminitis). Overall survival data from EMERALD are not yet mature.

The EMERALD results led to the approval of elacestrant for patients with advanced-stage ER+, HER2-negative breast cancer harbouring ESR1 mutations, specifically those with disease progression after at least one prior line of endocrine therapy.

Emerging Therapies in Late-Stage Trials

Several other next-generation endocrine therapies are moving through clinical trials. Three notable agents are camizestrant, imlunestrant, and giredestrant. Each is a novel oral SERD designed to overcome resistance, particularly in ESR1-mutant disease.

Camizestrant

Camizestrant is an orally bioavailable SERD that both degrades and inhibits the ER. In laboratory studies, it showed anti-tumour activity in both ESR1-wild-type and ESR1-mutant cancer cells and in patient-derived xenograft (PDX) models — tumours grown in mice from patient tissue. It also showed activity in combination with CDK4/6 inhibitors and with drugs targeting the PI3K–AKT–mTOR pathway, including capivasertib, alpelisib, and everolimus.

The phase I SERENA-1 trial established that camizestrant monotherapy has clinical benefit and a tolerable safety profile. The phase II SERENA-2 trial then compared camizestrant with fulvestrant. About half of participants had previously received a CDK4/6 inhibitor, and 36.7% (about 1 in 3) had a detectable ESR1 mutation.

Key results from SERENA-2:

• Camizestrant at 75 mg: median PFS 7.2 months versus 3.7 months with fulvestrant (HR 0.58, 90% CI 0.41–0.81; P = 0.012).
• Camizestrant at 150 mg: median PFS 7.7 months versus 3.7 months (HR 0.67, 90% CI 0.48–0.92; P = 0.016).
• The 300 mg dosing arm was stopped early by the sponsor for reasons other than safety concerns.

As with EMERALD, the benefit was greatest in patients with ESR1-altered tumours. Their median PFS was 6.3 months at the 75 mg dose and 9.2 months at the 150 mg dose, compared with 2.2 months with fulvestrant. The adjusted hazard ratios were 0.33 (90% CI 0.18–0.58) for the 75 mg dose and 0.55 (90% CI 0.33–0.89) for the 150 mg dose.

Patients without detectable ESR1 mutations did not have significantly different PFS with camizestrant compared with fulvestrant at either dose.

An exploratory analysis combining data from the 75 mg and 150 mg dose groups confirmed the benefit in ESR1-mutant disease: median PFS of 8 months versus 2.2 months with fulvestrant (HR 0.44, 90% CI 0.28–0.68).

The duration of response also depended on the tumour's mutation profile:

• Tumours with a single ESR1 mutation responded for a median of 12.9 months.
• Tumours with more than one ESR1 variant responded for a median of 4.7 months.

A subgroup analysis looked at specific ESR1 mutations. Among 33 patients with the ESR1 Y537C/D/N/S mutations, camizestrant produced a median PFS of 9.1 months versus 2.3 months with fulvestrant (HR 0.46, 90% CI 0.28–0.76). Among patients with ESR1 D538G, camizestrant produced a median PFS of 4.5 months versus 2.2 months (HR 0.61, 90% CI 0.36–1.03) — a favourable trend that did not reach statistical significance. The authors caution that these small sample sizes mean the results should be interpreted with care.

Side effects in SERENA-2 were manageable. The rate of grade 3 or higher adverse events was 12.2% with camizestrant 75 mg, 13.7% with fulvestrant, and 21.9% with camizestrant 150 mg. Notable adverse events with camizestrant included bradycardia (slow heart rate, 13.6%) and visual disturbances (18.4%). All of these events were grade 1 or 2 in severity.

Imlunestrant

Imlunestrant is another novel oral SERD. In preclinical models, single-agent imlunestrant showed anti-proliferative activity in both ESR1-mutant and ESR1-wild-type breast cancer cells and in PDX models. It also showed activity when combined with other clinically relevant agents.

A clinical trial is now testing imlunestrant, given either alone or with abemaciclib (a CDK4/6 inhibitor), against the investigator's choice of fulvestrant or exemestane. The trial enrols patients with advanced-stage HR+ breast cancer whose disease has progressed on prior anti-oestrogen therapy, with or without a CDK4/6 inhibitor.

Giredestrant

Giredestrant, another oral SERD, inhibited the growth of ER+ breast cancer cells and xenografts in laboratory studies. It showed additional activity in models of ESR1-mutant tumours, both alone and combined with CDK4/6 inhibitors.

The phase Ia/Ib GO39932 trial tested giredestrant monotherapy, with or without palbociclib and with or without ovarian function suppression. Participants had previously received endocrine therapy for locally advanced or metastatic ER+, HER2-negative breast cancer. About 20% had previously received fulvestrant, and about 65% had received a CDK4/6 inhibitor.

Key results from GO39932:

• Clinical benefit — defined as tumour response or stable disease for at least 6 months — was observed in 48.6% of the 111 participants in the single-agent cohort.
• The majority of patients (86.4%) received either 30 mg or 90–100 mg daily doses.
• About half of all patients had tumours with baseline ESR1 mutations.
• Among ESR1-mutant patients receiving the 30 mg dose, the clinical benefit rate was 61.9%.

Side effects occurred in 72 patients (64.9%, about 2 out of 3). The most common were fatigue, joint pain, nausea, bradycardia, elevated liver enzymes (aspartate aminotransferase or alanine aminotransferase elevations), diarrhoea, and hot flashes. Four patients required dose reductions. All bradycardia events were grade 1–2 in severity and dose-dependent.

The phase II acelERA trial is evaluating 30 mg daily doses of giredestrant compared with the investigator's choice of endocrine therapy in a similar patient population.

What This Means for Patients

These findings point to a clear direction: treatment for HR+ metastatic breast cancer is becoming increasingly personalised. Genomic testing now plays a central role in matching patients to the right therapy.

For patients whose tumours harbour ESR1 mutations, the new oral SERDs — elacestrant (already approved), camizestrant, imlunestrant, and giredestrant — offer meaningful improvements in progression-free survival. The magnitude of benefit is substantial. In the EMERALD trial, ESR1-mutant patients had a 45% lower risk of progression with elacestrant than with standard endocrine therapy. In SERENA-2, ESR1-mutant patients on camizestrant experienced a median PFS of 8 to 9.2 months versus 2.2 months with fulvestrant.

For patients whose tumours have bypass pathway mutations like PIK3CA or AKT alterations, targeted inhibitors (alpelisib and capivasertib) are now approved options. The principle is notable: blocking the bypass pathway can restore the tumour's dependence on oestrogen, making endocrine therapy effective again.

For patients with endocrine-refractory disease, antibody–drug conjugates (ADCs) — drugs that deliver chemotherapy directly to cancer cells via targeting proteins such as HER2, HER3, and TROP2 — represent another emerging option, though discussed only briefly in the sections of this review.

The authors emphasise that drug development is occurring rapidly for the large and heterogeneous population of patients with HR+ breast cancer. Efforts are underway to identify the optimal combination strategies and the best approach to treatment sequencing.

Limitations of Current Research

Several important caveats apply to these findings. Overall survival data from the EMERALD trial are still immature, so it is not yet clear whether elacestrant extends life or only delays progression. The SERENA-2 results come from a phase II trial, with relatively small subgroups; the analyses of specific ESR1 mutations involved only 33 and 23 patients respectively, and the authors explicitly caution that these results should be interpreted carefully.

Patients without detectable ESR1 mutations did not benefit significantly from camizestrant compared with fulvestrant. This means mutation testing is essential — these drugs are not for everyone.

The duration of prior CDK4/6 inhibitor therapy as a predictor of response to elacestrant is an exploratory finding. It needs prospective validation before it can be used to guide clinical decisions. Similarly, the question of whether patients should receive these agents sequentially — for example, one CDK4/6 inhibitor after another, or a CDK2 inhibitor after a CDK4/6 inhibitor — remains an area of active investigation.

The review also notes that resistance to current and emerging agents will continue to develop. Ongoing research into the molecular and genomic mechanisms of resistance is expected to have an integral role in optimising treatment.

Recommendations for Patients

For patients living with HR+ metastatic breast cancer, this research suggests several practical takeaways:

1. Ask about genomic testing. Knowing whether your tumour carries an ESR1 mutation, a PIK3CA mutation, or other pathway alterations can directly influence which treatment is best for you. Testing can be done on a tumour biopsy or through a blood test for circulating tumour DNA.
2. Discuss oral SERD options with your oncologist. Elacestrant is now an approved option for ESR1-mutant disease after progression on endocrine therapy. Other oral SERDs such as camizestrant, imlunestrant, and giredestrant are in late-stage trials and may become available.
3. Understand the side-effect profiles. Each drug has different side effects. Elacestrant is associated with nausea and fatigue. Camizestrant can cause slow heart rate (bradycardia) and visual disturbances, although these were mild in trials. Knowing what to expect helps you and your care team manage symptoms early.
4. Ask about clinical trials. Several promising agents are actively enrolling patients, including trials of imlunestrant with or without abemaciclib, and the acelERA trial of giredestrant.
5. Monitor bone health. Aromatase inhibitors reduce bone density. Regular bone density scans and appropriate supplements or medications can help prevent fractures.

Frequently Asked Questions

What does it mean if my breast cancer is hormone receptor-positive (HR+)?

HR+ breast cancer cells rely on estrogen to grow. About 7 out of 10 breast cancers are HR+. Treatment usually blocks estrogen signals, using drugs like tamoxifen, aromatase inhibitors, or fulvestrant. These are often combined with targeted therapies. This approach can delay cancer progression while avoiding chemotherapy side effects in many patients.

Why would my doctor test my tumor for an ESR1 mutation?

If you have HR+ metastatic breast cancer, an ESR1 mutation can develop during treatment, especially after aromatase inhibitors. This mutation makes cancer resistant to some anti-estrogen drugs. Knowing the mutation helps your doctor choose a treatment that still works, such as elacestrant or certain new oral SERDs, because these were shown to help patients with ESR1-mutant tumors.

What is elacestrant and who can take it?

Elacestrant is the first oral SERD pill approved in 2023. It treats advanced-stage ER+, HER2-negative breast cancer with an ESR1 mutation. It is for patients whose disease progressed after at least one line of endocrine therapy. In the EMERALD trial, ESR1-mutant patients taking elacestrant had a 45% lower risk of progression than those on standard endocrine therapy.

What are common side effects of elacestrant?

In the EMERALD trial, the most common side effects were fatigue, joint pain, nausea, vomiting, and elevated liver enzymes. Nausea was more common with elacestrant than with other endocrine treatments. Side effects were generally manageable. Discuss any symptoms with your care team, as early management can help you stay comfortable during treatment.

Are there other new oral SERD drugs besides elacestrant?

Yes, several oral SERDs are in late-stage trials, including camizestrant, imlunestrant, and giredestrant. Camizestrant was tested in the SERENA-2 trial, where ESR1-mutant patients had a median progression-free survival of about 8 to 9.2 months, compared with 2.2 months on fulvestrant. Imlunestrant and giredestrant are still being evaluated in clinical trials.

Can I have hormone therapy resistance if I have PIK3CA or AKT mutations?

Yes. Mutations in PIK3CA, AKT1, or PTEN can cause ER-independent resistance, meaning cancer cells find other pathways to grow. However, blocking these bypass pathways can restore sensitivity to endocrine therapy. The drug alpelisib is approved for PIK3CA-mutant advanced breast cancer, and capivasertib is approved for AKT pathway-altered disease. Both are taken with endocrine therapy.

What should I ask my oncologist about genomic testing?

You can ask whether your tumor should be tested for ESR1, PIK3CA, AKT, or other mutations. Testing can be done on a tumor biopsy or through a blood test for circulating tumor DNA. Results help determine if new targeted drugs like elacestrant, alpelisib, or capivasertib are appropriate for your specific breast cancer.

Can a second opinion change my treatment plan for HR-positive metastatic breast cancer with an ESR1 mutation?

In HR-positive metastatic breast cancer, treatment choice now depends heavily on genomic testing. If you have an ESR1 mutation, drugs like elacestrant have been shown in trials to reduce progression risk by 45% compared with standard endocrine therapy. Emerging oral SERDs such as camizestrant also appear more effective in ESR1-mutant disease, but they are not yet approved. A second opinion can help confirm that your tumour was properly tested and that your proposed treatment — approved drug, targeted inhibitor, or clinical trial — matches the latest evidence. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

Original article: "Precision therapeutics and emerging strategies for HR-positive metastatic breast cancer"

Published in: Nature Reviews Clinical Oncology, DOI: 10.1038/s41571-024-00935-6

This patient-friendly article is based on peer-reviewed research.