Oral SERDs will change the landscape of hormone receptor-positive breast cancer treatment. Although estrogen receptor inhibition is an effective treatment for hormone receptor-positive breast cancer, traditional endocrine therapy has pharmacokinetic limitations and drug resistance problems (such as ligand-independent estrogen receptor signaling activation). At the 2024 Miami Breast Cancer Conference, Dr. Komal Jhaveri of Memorial Sloan Kettering Cancer Center proposed that a new generation of oral selective estrogen receptor degraders (SERDs) is expected to overcome these bottlenecks [1].
Treatment Evolution and the Importance of ESR1 Testing
Tumor Evolution and Drug Resistance Mechanisms
ESR1 mutations are a common adaptive change in tumors under endocrine therapy stress, leading to estrogen receptor-dependent but estrogen-independent growth.
These mutations occur in 40-50% of metastatic patients (plasma testing is superior to tissue biopsy), and the prognosis is poor [2].
Key Finding: Switching to SERDs (such as fulvestrant) in patients with ESR1 mutations can significantly prolong survival (12-month survival rate 80% vs. 62% for exemestane) [2].
Breakthrough in oral SERDs
First oral SERD: Elacestrant
The EMERALD trial showed that, compared with standard treatment, elacestrant was effective in CDK4/6 inhibitor-resistant patients:
Overall population: 30% reduction in progression-free survival (PFS) risk (HR=0.70).
More significant effect in the ESR1 mutation subgroup (HR=0.55), approved for use in this patient group[3].
Significant benefit in specific patient groups:
ESR1-mutant patients who had received CDK4/6 inhibitors for ≥12 months had a median PFS of 8.6 months (compared to <2 months in the control group)[4].
The median PFS was 5.5 months in patients with PIK3CA mutations and 9.0 months in patients with ESR1 mutations alone[5].
Potential of other oral SERDs
Imlunestrant:
The EMBER-3 trial showed that the combination with abemaciclib improved PFS to 9.4 months (compared to 5.5 months with monotherapy)[6].
When used in combination with the mTOR inhibitor everolimus, the median PFS reached 15.9 months[1].
Girdestrant:
In neoadjuvant therapy, the combination with palbociclib significantly reduced the tumor proliferation marker Ki67[6].
Combination Therapy Strategies and Future Directions
Later-Line Treatment Combinations
Targeted Pathway Inhibitors:
Combining PI3K inhibitors (alpelisib) or mTOR inhibitors (everolimus) can prolong PFS.
For example: imlunestrant + alpelisib had a median PFS of 9.2 months [1].
Clinical Trial Progress:
ELEVATE Trial: Exploring elacestrant in combination with CDK4/6 inhibitors or alpelisib.
pionERA Trial: Comparing giredestrant vs fulvestrant in combination with CDK4/6 inhibitors.
Moving to First-Line vs Early Treatment
Metastatic First-Line:
persevERA and SERENA-4 trials are evaluating the efficacy of SERD in combination with CDK4/6 inhibitors.
Early-Line Breast Cancer:
lidERA and EMBER-4 trials are evaluating SERD for adjuvant therapy, potentially changing the existing paradigm.
The SERENA-6 trial attempted to detect ESR1 mutations early through liquid biopsy and adjust treatment accordingly [1].
Clinical Application Recommendations:
Detection of ESR1 mutations: Dynamic monitoring of plasma ctDNA is superior to single tissue testing.
Monotherapy selection: For patients with ESR1 mutations and a history of long-term CDK4/6 inhibitor use, elacestrant may be considered first.
Combination therapy:
For later-line resistant patients, SERD combined with CDK4/6 inhibitors or pathway inhibitors (such as alpelisib) is recommended.
Monitor co-variants such as PIK3CA mutations to optimize combinations.
"Oral SERDs not only improve patient convenience but also overcome resistance bottlenecks through combination strategies, potentially reshaping the early to late-stage treatment pathway in the future."
— Komal Jhaveri, MD
Disclosure of Interests
Dr. Jhaveri has received consulting fees from several pharmaceutical companies (such as Novartis, Pfizer, Genentech, etc.).
References
Jhaveri K. 2024 Miami Breast Cancer Conference.
Turner NC, et al. Clin Cancer Res. 2020.
Bidard FC, et al. J Clin Oncol. 2022.
Kaklamani V, et al. SABCS 2022.
Bardia A, et al. SABCS 2023.
Hurvitz SA, et al. Lancet Oncol. 2023.
Source: https://ascopost.com/issues/june-25-2024/oral-serds-poised-to-impact-treatment-of-hormone-receptor-positive-breast-cancer/