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Systems Biology of Metabolic Regulation by Estrogen Receptor Signaling in Breast Cancer
Published on: March 17, 2016
Estradiol as a Targeted, Late-Line Therapy in Metastatic Breast Cancer with Estrogen Receptor Amplification
Karthik Kota1, Adam Brufsky2, Steffi Oesterreich3
1Internal Medicine, UPMC Presbyterian.
Abstract:
Estradiol is a major regulator of growth for the subset of breast cancers that express the estrogen receptor (ER, ESR1). Strategies to block ER action, via reduction of estradiol or direct inhibition of ER, have shown major success in the prevention and treatment of breast cancer. However, most ER-positive (ER+) metastatic breast cancers (MBC) eventually become resistant to these interventions. Interestingly, high dose estrogen can induce apoptosis in breast cancer cell lines, and high-dose estrogen has been used for over 50 years as therapy for ER+ breast cancer. The mechanism for growth control of MBC by high dose estrogen is unclear. We present a patient with metastatic breast cancer whose tumor was found to have amplification of ESR1 by tumor genome sequencing. This patient was treated with high dose estradiol and subsequently experienced a sustained partial response, which was predicted by prior experiments with patient-derived xenograft animal models containing breast cancers with ER amplification.
Insights
High-dose estradiol therapy can be effective for metastatic breast cancer (MBC) with estrogen receptor 1 (ESR1) amplification. This approach, supported by patient-derived xenograft models, offers a new treatment avenue for resistant ER+ MBC.
Area of Science:
- Oncology
- Genomics
- Endocrinology
Background:
- Estrogen receptor (ER) signaling drives ER-positive breast cancer growth.
- Standard therapies targeting ER are effective but often face eventual resistance in metastatic breast cancer (MBC).
- High-dose estrogen has a historical role in treating ER-positive breast cancer, but its mechanism remains unclear.
Observation:
- A patient with metastatic breast cancer exhibited amplification of the estrogen receptor 1 (ESR1) gene.
- Tumor genome sequencing identified this ESR1 amplification.
- Patient-derived xenograft (PDX) models with ER amplification predicted response to high-dose estradiol.
Findings:
- The patient with ESR1 amplification received high-dose estradiol therapy.
- This treatment resulted in a sustained partial response.
- The patient's response correlated with PDX model predictions.
Implications:
- ESR1 amplification may predict response to high-dose estradiol in ER+ MBC.
- High-dose estradiol represents a potential therapeutic strategy for specific subsets of treatment-resistant breast cancer.
- Further investigation into the mechanisms of high-dose estrogen action in ER-amplified breast cancer is warranted.
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