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A Phase II Open Label Study of Everolimus in Combination With Endocrine Therapy in Resistant Hormone
Denise A Yardley1, William Liggett1, Mark Mainwaring1
1Sarah Cannon Research Institute, Nashville, TN; Tennessee Oncology, PLLC, Nashville, TN.
Background:
Therapies targeting estrogen receptor signaling are standard for patients with hormone receptor (HR)-positive (HR+) metastatic breast cancer (MBC). Dysregulation of the phosphoinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is associated with treatment resistance. Addition of the mTOR inhibitor, everolimus, to exemestane doubled progression-free survival (PFS) in HR+/HER2- MBC patients whose disease had previously progressed during endocrine therapy. In this phase II study, we used everolimus in addition to the most recent endocrine therapy during which a patient's disease progressed, in an attempt to restore and extend the benefit of the antiestrogen therapy in patients with HR+/HER2- MBC.
Patients And Methods:
Patients with HR+ MBC who progressed on antiestrogen therapy received everolimus (10 mg orally daily) in combination with the antiestrogen therapy most recently administered. Treatment was administered in 4-week cycles and continued until disease progression or unacceptable toxicity. Blood and archival tumor specimens were collected for VeriStrat (Biodesix, Inc) and Foundation One (Foundation Medicine) assays, respectively. Accrual of 42 evaluable patients allowed detection of improvement in median PFS from 2.8 months (expected with hormonal treatment alone) to 5 months (power 80%, α = 5%).
Results:
Forty-seven patients were enrolled and treated. After a median follow-up of 22.2 months, median PFS was 6.6 months. Secondary efficacy end points included: overall response rate, 6%; clinical benefit rate, 40%; and median overall survival, 21.1 months. No unexpected toxicity was observed. Efficacy could not be correlated with PI3K/AKT/mTOR alterations or VeriStrat (Biodesix, Inc) prognostic signatures.
Conclusion:
After progression during antiestrogen therapy, the addition of everolimus, without changing the hormonal therapy, resulted in a median PFS of 6.6 months, suggesting efficacy in patients with HR+/HER2- MBC.
Insights
Adding everolimus to endocrine therapy improved progression-free survival (PFS) in hormone receptor-positive metastatic breast cancer (HR+ MBC) patients who progressed on prior treatment. This combination therapy offers a new option for extending treatment benefits in HR+ MBC.
Area of Science:
- Oncology
- Pharmacology
Background:
- Estrogen receptor (ER) signaling inhibitors are standard for ER-positive (ER+) metastatic breast cancer (MBC).
- Dysregulation of the PI3K/AKT/mTOR pathway contributes to resistance against endocrine therapies.
- The mTOR inhibitor everolimus, combined with exemestane, previously doubled PFS in a subset of HR+/HER2- MBC patients post-endocrine therapy.
Purpose of the Study:
- To evaluate the efficacy of adding everolimus to the most recent endocrine therapy in patients with HR+/HER2- MBC who experienced disease progression.
- To determine if everolimus can restore or extend the benefit of antiestrogen therapy in this patient population.
Main Methods:
- A phase II study enrolled 47 patients with HR+/HER2- MBC who progressed on antiestrogen therapy.
- Patients received everolimus (10 mg daily) concurrently with their last-received antiestrogen therapy for 4-week cycles.
- Blood and tumor samples were collected for molecular profiling (VeriStrat, Foundation One).
Main Results:
- Median progression-free survival (PFS) was 6.6 months in patients treated with everolimus plus endocrine therapy.
- The overall response rate was 6%, and the clinical benefit rate was 40%.
- Median overall survival reached 21.1 months, with no unexpected toxicities observed.
Conclusions:
- Adding everolimus to ongoing endocrine therapy demonstrated efficacy in HR+/HER2- MBC patients after disease progression.
- The combination therapy resulted in a median PFS of 6.6 months, suggesting a benefit beyond standard endocrine therapy alone.
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