Alpelisib therapy: from theory to practice

Abstract

Before the development and implementation of the first PI3K inhibitor (alpelisib), the presence of a mutation in the PIK3CA gene had only prognostic value: it determined the unfavorable course of luminal HER2-negative metastatic breast cancer (testing for mutations was not part of routine screening methods). Achievements in the treatment of HR+HER2- mBC are primarily associated with the use of CDK4/6 inhibitors, which allowed not only a significant increase in the median progression-free survival while maintaining high quality of life, but also significantly increased overall survival of patients with luminal HER2-negative metastatic breast cancer. However, subgroup analyses demonstrate that the presence of the PIK3CA mutation is an independent factor in decreasing progression-free time and overall survival, even in patients treated with CDK4/6 inhibitors. Mutations of the PIK3CA gene are diagnosed in 30-40% of luminal metastatic breast cancer patients, they are associated with an increased risk of relapse and disease progression, are associated with a significant reduction in survival rates and treatment effectiveness, and determine the development of primary and secondary resistance to endocrine therapy. Standard endocrine therapy with fulvestrant combined with alpelisib has significantly improved treatment outcomes in patients with HR+HER2-metastatic breast cancer with the PIK3CA mutation who previously received treatment for advanced disease or had progression during adjuvant therapy. This combination is now included in all major international guidelines and is a priority therapy option. Testing for PIK3CA mutations is the current diagnostic standard in luminal HER2-negative mBC. The review presents an update of the main clinical trials with alpelisib, treatment results from real clinical practice, and also considers aspects of use in pretreated patients with different medical history. The article outlines the main recommendations for the prevention and correction of adverse events, and presents our own experience of using alpelisib in a patient with a classic course of breast cancer with a PIK3CA mutation.