PIK3CA Mutation Assessment in HR+/HER2− Metastatic Breast Cancer: Overview for Oncology Clinical Practice

Activation of the PI3K–AKT–mTOR pathway occurs in several human cancers, including hormone receptor (HR)-positive breast cancer (BC) where is associated with resistance to endocrine therapy and disease progression. In BC, the most common PI3K–AKT–mTOR pathway alteration is represented by PIK3CA oncogenic mutations. These mutations can occur throughout several domains of the p110α catalytic subunit, but the majority are found in the helical and kinase domains (exon 9 and 20) that represent the “hotspots”. Considering the central role of the PI3K–AKT–mTOR pathway in HR-positive BC, several inhibitors (both pan-PI3K and isoform-specific) have been developed and tested in clinical trials. Recently, the PI3Kα-selective inhibitor alpelisib was the first PI3K inhibitor approved for clinical use in HR-positive metastatic BC based on the results of the phase III SOLAR-1 trial. Several methods to assess PIK3CA mutational status in tumor samples have been developed and validated, including real-time polymerase chain reaction (PCR), digital droplet PCR (ddPCR), BEAMing assays, Sanger sequencing, and next-generation sequencing (NGS) panels. Several new challenges will be expected once alpelisib is widely available in a clinical setting, including the harmonization of testing procedures for the detection of PI3K–AKT–mTOR pathway alterations. Herein, we provide an overview on PI3K–AKT–mTOR pathway alterations in HR-positive BC, discuss their role in determining prognosis and resistance to endocrine therapy and highlight practical considerations about diagnostic methods for the detection of PI3K–AKT–mTOR pathway activation status.