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Updated: Jun 13, 2025
Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Estrogen-Receptor Loss and ESR1 Mutation in Estrogen-Receptor-Positive Metastatic Breast Cancer and the Effect on
Pieter J Westenend1, Claudia J C Meurs2, Bertie de Leeuw1
1Laboratory of Pathology, 3318 AL Dordrecht, The Netherlands.
Abstract:
In patients with metastatic estrogen-receptor (ER)-positive HER2-negative breast cancer, the loss of ER expression and the mutation of ESR1-the gene encoding the ER receptor-are mechanisms for resistance to endocrine therapy. We aimed to determine the frequency of these mechanisms and their interaction. Metastases were retrieved from our pathology files. ESR1 hotspot mutations resulting in p.(D538G), p.(Y537S), and p.(L536H) were determined by means of pyrosequencing. Clinical data were retrieved from electronic medical records. A total of 136 metastases were available for analysis. ER loss was found in 23 metastases (17%). ESR1 mutations were found in 18 metastases (13%), including p.(D538G) in 9, p.(Y537S) in 7, and p.(L536H) in 2. ESR1 mutation and ER loss were mutually exclusive (p = 0.042), and ESR1 mutation was associated with endocrine therapy (p = 0.002). ESR1 mutation was found in two primary breast cancers. ESR1 mutations are rare in primary breast cancer and develop in metastases during endocrine therapy. Furthermore, ER loss had a statistically significant negative effect on overall survival when compared to patients without ER loss, with a rate ratio of 3.21 (confidence interval 1.95-5.26). No such effect was observed for ESR1 mutations, with a rate ratio of 1.15 (confidence interval 0.67-1.95). We conclude that ER loss and ESR1 mutation together account for 30% of the resistance to endocrine therapy.
Insights
Mechanisms of endocrine therapy resistance in metastatic breast cancer, including estrogen receptor (ER) loss and ESR1 mutations, were analyzed. ER loss significantly impacted survival, while ESR1 mutations developed during treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Metastatic estrogen-receptor (ER)-positive, HER2-negative breast cancer often develops resistance to endocrine therapy.
- Estrogen receptor (ER) loss and ESR1 gene mutations are key mechanisms driving this resistance.
Purpose of the Study:
- To determine the frequency of ER loss and ESR1 mutations in metastatic breast cancer.
- To investigate the interaction between ER loss and ESR1 mutations as resistance mechanisms.
- To assess the clinical impact of these mechanisms on patient survival.
Main Methods:
- Analysis of 136 metastatic breast cancer samples retrieved from pathology archives.
- Pyrosequencing to detect specific ESR1 hotspot mutations (p.D538G, p.Y537S, p.L536H).
- Review of clinical data from electronic medical records for survival analysis.
Main Results:
- ER loss was identified in 17% of metastases, and ESR1 mutations in 13%.
- ER loss and ESR1 mutations were found to be mutually exclusive.
- ESR1 mutations were associated with prior endocrine therapy exposure.
- ER loss significantly reduced overall survival (rate ratio 3.21), whereas ESR1 mutations did not show a significant survival impact.
Conclusions:
- ER loss and ESR1 mutations account for approximately 30% of endocrine therapy resistance in this patient group.
- ESR1 mutations are rare in primary tumors and emerge during metastatic disease and treatment.
- ER loss represents a significant negative prognostic factor in metastatic breast cancer.
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