Next-Generation Breast Cancer Treatments: New Oral Therapies for Metastatic Hormone-Positive Disease

Table of Contents

• Introduction: Understanding Endocrine Therapy for Breast Cancer
• How Breast Cancer Becomes Resistant to Treatment
• ESR1 Mutations: A Key Driver of Treatment Resistance
• New Hormonal Therapies and Clinical Opportunities
• Current Selective Estrogen Receptor Degraders (SERDs)
• Future Directions and Ongoing Research
• What This Means for Patients
• Study Limitations and Considerations
• Source Information

Introduction: Understanding Endocrine Therapy for Breast Cancer

Endocrine therapy (ET) is a fundamental treatment strategy for estrogen receptor-positive (ER+) breast cancer, which accounts for nearly 80% of all newly diagnosed breast cancers. These tumors express estrogen receptor alpha (ERα) and depend on estrogen-mediated growth signals to survive and proliferate. Approved classes of ET work through different mechanisms to block this estrogen signaling, either by reducing estrogen production or interfering with how estrogen binds to its receptor.

The main categories of endocrine therapy include aromatase inhibitors (AIs) like letrozole, anastrozole, and exemestane, which block the conversion of androgens to estrogens in non-ovarian tissues. For postmenopausal women, AIs effectively reduce systemic estrogen levels. Selective estrogen receptor modulators (SERMs) such as tamoxifen competitively bind the estrogen receptor (ER) and have tissue-dependent effects. Selective estrogen receptor degraders (SERDs) like fulvestrant both block ER activity and promote its degradation within cells.

These treatments can be used with or without ovarian suppression in premenopausal women. Ovarian suppression with luteinizing hormone releasing hormone agonists reduces circulating estrogen levels in younger women, enabling the use of AIs when they provide advantages over tamoxifen for added risk reduction. In high-risk early stage breast cancer, combining ovarian suppression with standard adjuvant therapy improves disease-free survival.

How Breast Cancer Becomes Resistant to Treatment

In metastatic breast cancer (MBC), ER+ tumors often respond initially to endocrine-directed therapy, but disease progression inevitably occurs due to developed resistance mechanisms. Response to ET depends on whether patients have intrinsic or acquired drivers of endocrine resistance. Acquired resistance emerges after an initial response to therapy (generally six or more months on treatment), while intrinsically resistant breast cancers may not respond at all (generally less than 6 months on treatment).

Researchers have identified two broad categories of resistance mechanisms: ER-mediated signaling and ER-independent oncogenic signaling. ER-mediated resistance involves ligand-independent signaling that promotes tumor proliferation even without estrogen present. ER-independent resistance occurs through oncogenic signaling pathways that bypass the normal endocrine-regulated transcription pathways entirely.

These resistance pathways don't operate in isolation—there's considerable intracellular communication between them that makes treatment resistance complex. While we separate these mechanisms for understanding, in reality, they interact extensively within cancer cells. Only about 10% of resistance cases involve complete loss of ER expression, meaning the estrogen receptor remains a viable therapeutic target in most patients even when resistance develops.

ESR1 Mutations: A Key Driver of Treatment Resistance

Mutations in the estrogen receptor 1 (ESR1) gene represent a particularly important acquired mechanism of endocrine resistance in ER+ metastatic breast cancer. These mutations are rare in primary breast cancer (found in less than 1% of de novo metastatic tumors) but become common after treatment. In cancers that recur after adjuvant AI treatment, ESR1 mutations appear in 4-8% of cases, and after receiving AI therapy in the metastatic setting, approximately 20-40% of tumors will acquire an ESR1 mutation.

The most common ESR1 mutations are Y537S (found in 14-21% of cases) and D538G (found in 32-36% of cases). Several other activating mutations with lower incidence rates have been implicated in resistance, including Y537C, E380Q, S463P, V534E, P535H, L536H, L536P, L536R, L536Q, and Y537N. Studies tracking serial circulating tumor DNA in metastatic breast cancer demonstrate a relatively frequent polyclonal mutation burden and high levels of genetic heterogeneity in these tumors.

ESR1 mutations affect the ligand binding domain of the estrogen receptor and stabilize it in an active conformation. This promotes binding of coactivators and upregulates ER signal transduction even in the absence of estrogen. The biochemical changes at the ligand binding domain confer decreased affinity for therapeutic ligands, including SERMs and SERDs, and greater stability against proteolytic degradation. Different mutations confer varying resistance patterns—Y537S conveys greater resistance to endocrine therapy while D538G carries greater metastatic potential.

ESR1 fusions (ESR1-fus) represent rare but notable alterations that eliminate the ligand binding domain entirely and drive endocrine therapy resistance through constitutive ER transcriptional activity. These fusion events likely make tumors resistant to most current and next-generation ETs that target the ligand binding domain, and they may be underappreciated since many breakpoints are intronic and not captured by conventional genetic testing.

New Hormonal Therapies and Clinical Opportunities

Because ER signaling continues to be regulated by oncogenic signal transduction in a ligand-independent manner, targeting the ER remains the cornerstone of managing ER+ breast cancer despite resistance development. This understanding has driven considerable interest in novel endocrine therapies, particularly those that will remain active despite ESR1 mutations. Multiple next-generation ET drugs are currently in clinical development, representing several different therapeutic approaches.

The development pipeline includes numerous oral selective estrogen receptor degraders (SERDs) that aim to overcome the pharmacological limitations of fulvestrant, which requires intramuscular injection. These include elacestrant (RAD1901), amcenestrant (SAR439859), camizestrant (AZD9833), giredestrant (GDC-9545), imlunestrant (LY3484356), rintodestrant (G1T48), borestrant (ZB-716), ZN-c5, and D-0502. These agents are in various phases of clinical trials for metastatic, adjuvant, and neoadjuvant settings.

Additional novel approaches include lasofoxifene (a SERM), bazedoxifene (a SERM/SERD hybrid), H3B-6545 (a selective estrogen receptor covalent antagonist), OP-1250 (a complete estrogen receptor antagonist), ARV-471 (a proteolysis targeting chimera), and AC682 (a chimeric ER degrader). This diverse pipeline represents multiple innovative strategies for overcoming endocrine resistance in advanced breast cancer.

Current Selective Estrogen Receptor Degraders (SERDs)

Fulvestrant was the first clinically impactful SERD, incorporated into standard treatment for ER+ metastatic breast cancer. It works by antagonizing ER transcriptional activity through inhibiting nuclear translocation, promoting turnover through the ubiquitin-proteasome pathway, and inducing conformational changes that downregulate ER signaling. In metastatic breast cancer exposed to prior endocrine therapy, clinical trials demonstrated that the 500 mg dose of monthly fulvestrant showed improved progression-free survival and overall survival compared to the 250 mg dose.

The FALCON trial revealed that in treatment-naïve advanced breast cancer, patients treated with fulvestrant had significantly longer progression-free survival compared to anastrozole (16.6 months versus 13.8 months), leading to its approval in the first-line setting. Since ESR1 mutations are a recognized mechanism of acquired resistance to aromatase inhibitors, and these patients may retain some clinical sensitivity to SERDs, the sequencing of endocrine therapy lines for metastatic breast cancer treatment is an important clinical consideration.

Research has shown conflicting results about how ESR1 mutations affect fulvestrant sensitivity. Laboratory studies indicate that ESR1-mutant breast cancer models demonstrate relative (dose-related) resistance to fulvestrant, requiring 10- to 50-fold greater drug concentrations to inhibit ER signaling and tumor growth. However, clinical studies have demonstrated variable results regarding fulvestrant's effectiveness against ESR1-mutant metastatic breast cancer.

Combined analysis of the SoFEA and EFECT trials compared fulvestrant versus exemestane in metastatic breast cancer after progression on an AI. The results demonstrated statistically significantly worse progression-free survival (2.4 months versus 4.8 months) and 1-year overall survival in patients with ESR1 mutations on the exemestane arm. However, ESR1-mutant and ESR1-wild-type metastatic breast cancer treated with fulvestrant had similar progression-free survival (3.9 months versus 4.1 months) and 1-year overall survival.

Future Directions and Ongoing Research

The most promising development in novel endocrine therapies comes from oral SERDs, which aim to overcome the pharmacological limitations of fulvestrant while maintaining efficacy against ESR1-mutant tumors. Recent results from the phase III EMERALD trial demonstrated improved outcomes with the oral SERD elacestrant compared to standard anti-estrogen therapies in ER+ metastatic breast cancer after prior progression on endocrine therapy.

This trial specifically showed benefit in patients with ESR1 mutations, highlighting the potential of these agents to address a major mechanism of treatment resistance. Other oral SERDs have shown promise in both laboratory studies and early-phase clinical trials, suggesting that this class of medications may significantly expand treatment options for patients with advanced hormone receptor-positive breast cancer.

As clinical data continue to mature on these next-generation endocrine therapies, important questions will emerge related to the optimal sequence of therapeutic options and how the genomic and molecular landscape of tumors influences response to these agents. Researchers are particularly interested in understanding which patients benefit most from specific therapies and how to best combine these novel agents with established targeted therapies like CDK4/6 inhibitors.

What This Means for Patients

For patients with metastatic hormone receptor-positive breast cancer, these developments represent significant hope for more effective treatment options, especially after developing resistance to conventional therapies. The recognition that ESR1 mutations drive resistance in many patients has led to targeted approaches that specifically address this mechanism.

Key implications for patients include:

• More treatment options: The pipeline of novel endocrine therapies means more potential options when current treatments stop working
• Oral medications: Many new agents are taken orally rather than by injection, improving convenience and quality of life
• Personalized approach: Understanding a tumor's mutation status (particularly ESR1) can help guide treatment selection
• Overcoming resistance: These new drugs are specifically designed to work even when traditional endocrine therapies fail

Patients should discuss with their oncologists whether genetic testing of their tumor (through biopsy or liquid biopsy) might help guide treatment decisions, particularly if they've received prior aromatase inhibitor therapy and experienced disease progression.

Study Limitations and Considerations

While the development of novel endocrine therapies represents significant progress, several limitations and considerations remain. The research on ESR1 mutations and treatment response has sometimes shown conflicting results between laboratory studies and clinical trials, suggesting that the relationship is complex and may depend on additional factors beyond the mere presence of mutations.

Additionally, the relatively recent recognition of ESR1 fusion events means that their full clinical significance isn't yet understood, and current genetic testing approaches may miss these alterations. The optimal sequencing of these novel agents with existing treatments like CDK4/6 inhibitors remains to be determined through additional clinical research.

Most of the newer agents discussed are still in clinical trials and not yet widely available. Patients interested in these treatments may need to seek out clinical trial opportunities or wait for regulatory approval and insurance coverage decisions. As with any cancer treatment, individual responses will vary, and not all patients will benefit equally from these novel approaches.

Source Information

Original Article Title: Next-generation selective estrogen receptor degraders and other novel endocrine therapies for management of metastatic hormone receptor-positive breast cancer: current and emerging role

Authors: Maxwell R. Lloyd, Seth A. Wander, Erika Hamilton, Pedram Razavi, Aditya Bardia

Publication: Therapeutic Advances in Medical Oncology, 2022, Vol. 14: 1–25

DOI: https://doi.org/10.1177/17588359221113694

This patient-friendly article is based on peer-reviewed research published in a scientific medical journal. It aims to translate complex scientific information into accessible language while preserving all key findings, data points, and clinical implications from the original research.