Precision diagnosis and treatment of PI3K/AKT/PTEN signaling pathway in HR-positive advanced breast cancer: perspectives from Chinese experts.

Abstract

For hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (BC), the combinations of endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are considered the standard first-line treatment. However, the unfortunate reality is that most patients will eventually develop drug resistance, necessitating the exploration of effective treatment strategies. Multiple treatment options exist, including phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) inhibitors, histone deacetylase (HDAC) inhibitors, oral selective estrogen receptor degraders (SERDs), and antibody-drug conjugates (ADCs), yet no optimal treatment sequence has been established. The activation of the PI3K/AKT/phosphatase and tensin homolog (PTEN) signaling pathway is significantly associated with resistance to ET and CDK4/6i in patients with HR+/HER2- BC, highlighting the need for targeted interventions. In light of this, antitumor therapies targeting key molecules within this pathway have become a hot spot in current BC research. With the rapid development of precision diagnosis and treatment of BC, the importance of detecting mutant genes in the PI3K/AKT/PTEN signaling pathway is increasingly coming to the fore, especially concerning test timing, sample selection, and detection methods. This article aims to discuss in depth the treatment landscape of HR+/HER2- advanced BC, the development of PI3K/AKT/PTEN signaling pathway inhibitors, and underscore the importance of mutation detection in promoting the precision diagnosis and treatment of HR+/HER2- BC. Understanding these aspects is critical to developing more effective personalized treatment strategies that can overcome CDK4/6i resistance and improve outcomes for patients with this challenging disease.