Groundbreaking research presented at the 2024 San Antonio Breast Cancer Symposium is reshaping treatment paradigms for the most common form of breast cancer.
For the millions of people living with hormone receptor-positive (HR+) breast cancer, treatment has long revolved around a simple principle: block estrogen's ability to fuel cancer growth. This approach has saved countless lives, but it has limitations. Many cancers eventually develop resistance to traditional therapies, creating a critical need for more effective strategies.
At the latest San Antonio Breast Cancer Symposium (SABCS), researchers unveiled groundbreaking advances that are reshaping treatment paradigms for HR+ breast cancer. From powerful new oral medications that overcome treatment resistance to innovative approaches that help patients avoid unnecessary therapy, these developments offer new hope in the ongoing fight against the most common form of breast cancer.
of all breast cancers are HR+
develop ESR1 mutations after endocrine therapy
months PFS with imlunestrant + abemaciclib
Hormone receptor-positive breast cancer, which accounts for approximately 70% of all breast cancers, grows in response to estrogen and/or progesterone. For decades, the standard treatment approach has involved endocrine therapy - medications that either block estrogen receptors or reduce estrogen production in the body. While drugs like tamoxifen and aromatase inhibitors have been cornerstone treatments, the emergence of resistance has remained a significant challenge, particularly in advanced cases.
Occur in the estrogen receptor gene itself, leading to constitutive activation of estrogen signaling even in the presence of traditional endocrine therapy.
Alterations in this pathway create another escape route for cancer cells to bypass treatment and develop resistance.
Tamoxifen, aromatase inhibitors - block estrogen receptors or reduce estrogen production
Fulvestrant - requires monthly intramuscular injections
Palbociclib, abemaciclib, ribociclib - combined with endocrine therapy
Imlunestrant - oral medications that overcome resistance mechanisms
One of the most exciting developments presented at SABCS was the emergence of next-generation oral Selective Estrogen Receptor Degraders (SERDs). These medications represent a significant advance over older endocrine therapies because they not only block estrogen receptors but also trigger their degradation, making it harder for cancer cells to develop resistance.
The phase III EMBER-3 clinical trial took center stage at the symposium, evaluating the investigational oral SERD imlunestrant in patients with ER-positive, HER2-negative advanced breast cancer that had progressed on prior endocrine therapy.
This multicenter study enrolled 874 patients whose cancer had recurred or progressed during or after treatment with an aromatase inhibitor alone or in combination with a CDK4/6 inhibitor. Participants were randomly assigned to one of three treatment groups:
Unlike the first-generation SERD fulvestrant, which requires monthly intramuscular injections, imlunestrant is an oral medication with the added advantage of being able to penetrate the blood-brain barrier, potentially offering protection against central nervous system metastases.
The findings, presented by Dr. Komal Jhaveri of Memorial Sloan Kettering Cancer Center, were practice-changing:
| Treatment Group | Progression-Free Survival (Overall) | Progression-Free Survival (ESR1-Mutant) | Risk Reduction vs. Standard Therapy |
|---|---|---|---|
| Imlunestrant alone | Not significantly improved | Significantly improved | 38% in ESR1-mutant patients |
| Imlunestrant + abemaciclib | 9.4 months | Benefit observed regardless of ESR1 status | 43% vs. imlunestrant alone |
| Standard endocrine therapy | 5.5 months | Less effective in ESR1-mutant patients | Reference group |
The trial demonstrated that imlunestrant significantly improved progression-free survival in patients with ESR1 mutations, reducing the risk of progression or death by 38% compared to standard endocrine therapy. This is particularly significant given that ESR1 mutations occur in 40-50% of patients whose cancer progresses on endocrine therapy.
Perhaps even more impressive were the results from the combination arm: imlunestrant plus abemaciclib reduced the risk of progression or death by 43% compared to imlunestrant alone, with benefits seen in all patient subgroups regardless of ESR1 or PI3K pathway mutation status.
| Treatment | Most Common Adverse Events | Discontinuation Rate | Patient-Reported Injection Site Issues |
|---|---|---|---|
| Imlunestrant monotherapy | Generally low-grade, manageable | Low | Not applicable (oral medication) |
| Imlunestrant + abemaciclib | Consistent with known abemaciclib profile | 6.3% | Not applicable (oral medication) |
| Standard therapy (fulvestrant) | Typical for endocrine therapy | Comparable to other regimens | 72% reported pain, swelling, or redness |
The safety profile was favorable, with generally low-grade and manageable adverse events. Importantly, as an oral medication, imlunestrant avoids the injection site pain, swelling, and redness reported by 72% of patients receiving fulvestrant.
Beyond the EMBER-3 trial, several other studies presented at the symposium are reshaping HR+ breast cancer treatment:
Evaluated adding palbociclib (Ibrance) to standard first-line treatment for metastatic triple-positive breast cancer (HR+/HER2+). Results showed the addition improved progression-free survival by more than 15 months compared to standard therapy alone 1 .
Updated results confirmed that Enhertu (T-DXd) is more effective than chemotherapy for patients with metastatic HR+ breast cancer that is HER2-low or HER2-ultralow and has progressed on endocrine therapy 1 .
With a median follow-up of 6.1 years, continued to show that adjuvant olaparib (Lynparza) improves survival by 35% compared to placebo in patients with BRCA-mutated, high-risk, HER2-negative early breast cancer 1 .
+15 months with palbociclib combination
35% survival improvement with olaparib
38% risk reduction with imlunestrant
43% risk reduction with imlunestrant + abemaciclib
Modern HR+ breast cancer research relies on sophisticated biomarkers and reagents that enable precision medicine approaches:
| Tool/Biomarker | Function/Application | Clinical Significance |
|---|---|---|
| ESR1 Mutation Testing | Identifies mutations in estrogen receptor gene | Predicts response to oral SERDs; detected in 40-50% of endocrine-resistant cases |
| Liquid Biopsy/ctDNA | Detects tumor DNA in blood samples | Monitors treatment response and emergence of resistance mutations |
| Next-Generation Sequencing (NGS) | Comprehensive genomic profiling | Identifies multiple potential therapeutic targets simultaneously |
| PD-L1 Staining | Measures immune checkpoint protein expression | Guides immunotherapy use in aggressive subtypes |
| PIK3CA Mutation Testing | Identifies mutations in PI3K pathway | Predicts response to PI3K inhibitors like inavolisib |
| BRCA Germline Testing | Detects inherited BRCA1/2 mutations | Identifies patients who may benefit from PARP inhibitors like olaparib |
These tools have become increasingly important as research moves beyond traditional histologic classification toward molecular subtyping and resistance mechanism identification.
Understanding the molecular diversity within HR+ breast cancer is crucial for treatment personalization.
The developments unveiled at the San Antonio Breast Cancer Symposium represent significant strides in the management of hormone receptor-positive breast cancer. The emergence of effective oral SERDs like imlunestrant, the strategic combination therapies that overcome resistance mechanisms, and the refined understanding of biomarker-driven treatment selection all point toward a more hopeful future for patients.
"We need much more education on understanding genomics and treating endocrine-resistant breast cancer based on biomarkers"
This sentiment captures the evolving nature of HR+ breast cancer care - one that increasingly prioritizes molecular understanding and personalized treatment approaches over blanket strategies.
While challenges remain, particularly in managing treatment sequencing and addressing diverse resistance mechanisms, the progress highlighted at SABCS 2024 provides tangible hope that HR+ breast cancer is becoming a more manageable condition, even in its advanced stages. As these new therapies continue through development and regulatory approval, they promise to transform the standard of care and offer patients more effective, tolerable, and convenient treatment options.
Oral SERDs and targeted combinations expand therapeutic arsenal
Biomarker-driven treatment selection improves outcomes
Oral medications and better side effect profiles enhance patient experience