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Clinical implications of recent studies using mTOR inhibitors to treat advanced hormone receptor-positive breast
1Clinical Research Alliance, Lake Success, New York, NY, USA.
Abstract:
Breast cancer is a leading cause of cancer-related death worldwide. Approximately 75% of breast cancer is hormone receptor-positive (HR(+)) and is managed with endocrine therapies. However, relapse or disease progression caused by primary or acquired endocrine resistance is frequent. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)-mediated signaling is one of the molecular mechanisms leading to endocrine resistance. mTOR inhibitors that target the PI3K/Akt/mTOR pathway are the first of the targeted therapies to be evaluated in clinical trials to overcome endocrine resistance. Although the clinical trial with temsirolimus, an mTOR inhibitor, did not show any benefit when compared with endocrine therapy alone, a Phase II clinical trial with sirolimus has been promising. Recently, everolimus was approved in combination with exemestane by the US Food and Drug Administration for treating postmenopausal women with advanced HR(+) breast cancer, based on the results of a Phase III trial. Therefore, everolimus represents the first and only targeted agent approved for combating endocrine resistance.
Insights
mTOR inhibitors show promise in overcoming endocrine resistance in hormone receptor-positive breast cancer. Everolimus is now approved for advanced cases, offering a new targeted therapy option.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Breast cancer is a major global health concern, with 75% of cases being hormone receptor-positive (HR(+)).
- Endocrine therapies are standard for HR(+) breast cancer, but resistance frequently leads to relapse or progression.
- The phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is implicated in endocrine resistance.
Purpose of the Study:
- To evaluate mTOR inhibitors as targeted therapies to overcome endocrine resistance in HR(+) breast cancer.
- To review the clinical efficacy of mTOR inhibitors in combating endocrine resistance.
Main Methods:
- Clinical trials were conducted to assess mTOR inhibitors, including temsirolimus and sirolimus.
- A Phase III trial evaluated everolimus in combination with exemestane for advanced HR(+) breast cancer.
- US Food and Drug Administration (FDA) approval was based on Phase III trial results.
Main Results:
- Temsirolimus did not demonstrate added benefit over endocrine therapy alone.
- Sirolimus showed promising results in a Phase II clinical trial.
- Everolimus in combination with exemestane demonstrated efficacy in postmenopausal women with advanced HR(+) breast cancer.
Conclusions:
- Everolimus is the first targeted agent approved for treating advanced HR(+) breast cancer with endocrine resistance.
- Targeting the PI3K/Akt/mTOR pathway with agents like everolimus represents a significant advancement in managing endocrine-resistant breast cancer.
