Breast Cancer Update HR-Positive Metastatic Breast Cancer — An Interview with Dr Erika Hamilton on the Potential Role of PROTAC Estrogen Receptor Degraders
Nov 20, 2025
Dr. Erika Hamilton, a medical oncologist at Sarah Cannon Research Institute, dives into the cutting-edge world of PROTAC estrogen receptor degraders for HR-positive metastatic breast cancer. She breaks down the differences between PROTACs and traditional therapies like SERDs, detailing their unique mechanisms and resistance advantages. The conversation highlights clinical trial data, tolerability issues, and the importance of precise biomarker testing. Erika also shares insights on future applications and the evolving landscape of treatment strategies for this challenging disease.
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Different ER Degradation Mechanisms Matter
- PROTACs and SERDs all reduce ER signaling but use distinct degradation mechanisms that can matter for resistance.
- PROTACs recruit E3 ligases to ubiquitinate ER, potentially overcoming binding-site resistance.
PROTACs May Work After Oral SERDs
- Erika Hamilton observed responses to a PROTAC after prior oral SERD exposure in phase 1 patients.
- This suggests PROTACs may work where some oral SERDs fail due to different resistance biology.
Endocrine Therapy Can Suppress ER Detection
- Fulvestrant and oral SERDs can lower measurable ER on biopsy, sometimes causing temporary ER-negativity.
- ER expression typically returns after stopping therapy, so timing of biopsy influences receptor assessment.