New Emerging Therapies Targeting PI3K/AKT/mTOR/PTEN Pathway in Hormonal Receptor-Positive and HER2-Negative Breast Cancer—Current State and Molecular Pathology Perspective

Abstract

Hormone receptor-positive, HER2-negative breast cancer is the most prevalent subtype of breast cancer, and also represents the majority of metastatic breast cancer cases. Dysregulation of the PI3K/AKT/mTOR pathway in breast cancer plays a critical role in resistance to standard therapies. In recent years, several inhibitors targeting the PI3K/AKT/mTOR pathway have been approved by the FDA to treat ER-positive, HER2-negative, high-risk and metastatic breast cancer, such as alpelisib (a PI3K inhibitor) and everolimus (an mTOR inhibitor), often combined with standard endocrine therapy like fulvestrant or aromatase inhibitors, particularly when a PIK3CA mutation is present in the tumor; AKT inhibitors like capivasertib may also be considered in some cases depending on the specific genetic profile of the tumor. However, clinicians face growing challenges in understanding the mechanism behind the genome events associated with this pathway and selecting the most effective therapy. This review focuses on the current state of the novel therapeutic options targeting the PI3K/AKT/mTOR/PTEN pathway and discusses the molecular mechanism and genomic testing interpretation from a molecular pathology perspective.