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Updated: Dec 1, 2025
Optimization of a Multiplex RNA-based Expression Assay Using Breast Cancer Archival Material
Published on: August 1, 2018
ESR1 genetic alterations and their association with clinicopathologic characteristics in advanced breast cancer: a
C Eric Freitag1, Ping Mei2, Lai Wei3
1Department of Pathology, The Ohio State University, Wexner Medical Center, Columbus, OH, USA.
Abstract:
Estrogen receptor (ER) alpha, a ligand-dependent nuclear transcription factor encoded by the ESR1 gene, is expressed in 70% of breast carcinomas (BCs) and is used as a target for endocrine-based therapies. However, some patients develop resistance to endocrine-based therapies due to ESR1 mutation, which leads to constitutive activation in the absence of ligand. We retrospectively analyzed 223 clinically advanced BCs using the FoundationOne CDX assay and found 13.9% (31/223) of cases had ESR1 genetic alterations (26 mutations and 5 amplifications). All ESR1 mutations occurred within the ligand binding domain, with the most prevalent being Y537S (42.3%) and D538G (38.5%), and all ESR1-mutated cases had a history of aromatase inhibitor use. No significant difference in clinicopathologic features was identified between ESR1-mutated and ESR1-amplified cases except higher frequency of HER2 positivity and TP53 mutations in ESR1-amplified cases. The prevalence of ESR1 mutations in ER-positive BCs was 19.1% (26/136). In comparison to ESR1-nonmutated ER-positive cases, ESR1-mutated cases demonstrated significantly higher percentage of tumor cells with ER and progesterone receptor expression, an increased tendency for overall distant metastasis and liver metastasis, higher frequency of FGF3/4/19 mutations, lower frequency of TP53 mutation, but no difference in overall survival and metastatic/recurrent intervals. In conclusion, our findings suggest that development of ESR1 mutations are selected for under the influence of estrogen deprivation, and a positive correlation between ESR1 mutations and ER protein expression may exist.
Insights
Estrogen receptor 1 (ESR1) mutations are found in 13.9% of advanced breast cancers and are linked to endocrine therapy resistance. These ESR1 mutations may correlate with higher ER protein expression and increased metastasis.
Area of Science:
- Oncology
- Genetics
- Endocrinology
Background:
- Estrogen receptor (ER) alpha, encoded by ESR1, is crucial in 70% of breast carcinomas (BCs) and a target for endocrine therapy.
- ESR1 mutations can cause resistance to endocrine therapies by leading to ligand-independent receptor activation.
- Understanding ESR1 alterations is vital for optimizing breast cancer treatment strategies.
Purpose of the Study:
- To investigate the prevalence and clinical significance of ESR1 genetic alterations in advanced breast cancer.
- To identify specific ESR1 mutations and amplifications and their association with clinicopathologic features.
- To explore the relationship between ESR1 mutations and treatment response, particularly to aromatase inhibitors.
Main Methods:
- Retrospective analysis of 223 advanced breast cancer cases.
- Utilized the FoundationOne CDX assay for comprehensive genomic profiling.
- Examined ESR1 genetic alterations (mutations and amplifications) and correlated them with clinical data.
Main Results:
- 13.9% of cases exhibited ESR1 genetic alterations (26 mutations, 5 amplifications).
- Prevalent mutations included Y537S (42.3%) and D538G (38.5%), all within the ligand-binding domain.
- ESR1-mutated cases showed higher ER/progesterone receptor expression, increased metastasis (especially liver), and altered co-occurring mutations (FGF3/4/19, TP53).
- All ESR1-mutated patients had prior aromatase inhibitor use.
Conclusions:
- ESR1 mutations are selected for under estrogen deprivation, suggesting a role in endocrine resistance.
- A potential positive correlation exists between ESR1 mutations and ER protein expression.
- Findings highlight the importance of detecting ESR1 alterations for guiding breast cancer therapy.
