Targeting the PI3K/Akt/mTOR pathway in estrogen-receptor positive HER2 negative advanced breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Advanced hormone receptor-positive breast cancer is a leading cause of cancer death in women.
• Endocrine therapy combined with CDK4/6 inhibitors is standard treatment when visceral crisis is absent.
• Resistance to endocrine therapy often involves hyperactivation of the phosphoinositide 3 kinase (PI3K)/Akt pathway.

Purpose of the Study:

• To review the role of the PI3K/Akt pathway in breast cancer.
• To discuss current and emerging therapeutic strategies targeting this pathway.
• To highlight challenges in the development of PI3K pathway inhibitors.

Main Methods:

• Literature review of clinical trials and research on PI3K/Akt pathway inhibitors in breast cancer.
• Analysis of mechanisms of resistance to endocrine therapy.
• Evaluation of efficacy and toxicity profiles of approved and investigational drugs.

Main Results:

• Aberrant PIK3CA mutations are common (approx. 40%) in advanced hormone receptor-positive breast cancer, leading to PI3K/Akt pathway hyperactivation.
• Everolimus (mTOR inhibitor) and alpelisib (PI3K inhibitor) have shown progression-free survival benefits in specific trials (BOLERO-2, SOLAR-1).
• Other PI3K pathway inhibitors show promise but face development hurdles due to toxicities like rash, diarrhea, and diabetes.

Conclusions:

• The PI3K/Akt pathway is a critical target in advanced hormone receptor-positive breast cancer.
• Targeted therapies like PI3K inhibitors offer new treatment avenues.
• Managing treatment-related toxicities is essential for optimizing patient outcomes and advancing drug development.