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Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With
Mariana Chavez-MacGregor1, Jieling Miao2, Lajos Pusztai3
1The University of Texas MD Anderson Cancer Center, Houston, TX.
Purpose:
Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy.
Methods:
Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC.
Results:
One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%).
Conclusion:
One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.
Insights
Adjuvant everolimus did not improve outcomes for most patients with early-stage breast cancer. However, it showed survival benefits for premenopausal women when combined with endocrine therapy.
Area of Science:
- Oncology
- Pharmacology
- Clinical Trials
Background:
- Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (mTOR) pathway dysregulation is implicated in endocrine resistance in breast cancer.
- Everolimus, an mTOR inhibitor, has demonstrated efficacy in metastatic breast cancer when combined with endocrine therapy (ET).
Purpose of the Study:
- To evaluate the efficacy of adjuvant everolimus plus ET in high-risk, hormone receptor-positive, HER2-negative early-stage breast cancer patients post-chemotherapy.
- To assess the impact on invasive disease-free survival (IDFS) and overall survival (OS).
Main Methods:
- Phase III randomized, placebo-controlled trial involving 1,939 patients.
- Patients received physician's choice ET plus either everolimus (10 mg daily) or placebo for one year.
- Primary endpoint: IDFS; Secondary endpoints: OS and safety; Stratified analyses by risk group, menopausal status, and age.
Main Results:
- Overall, everolimus did not significantly improve IDFS (HR, 0.94) or OS (HR, 0.97) in the overall study population.
- No benefit was observed in postmenopausal patients.
- Premenopausal patients demonstrated improved IDFS (HR, 0.64) and OS (HR, 0.49) with everolimus.
- Lower treatment completion rates and higher rates of severe adverse events were noted in the everolimus arm.
Conclusions:
- Adjuvant everolimus combined with ET did not enhance overall outcomes in early-stage, high-risk breast cancer.
- Subset analysis indicates that mTOR inhibition may be a potential therapeutic target for premenopausal patients who remain premenopausal after chemotherapy.
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