The phosphatidylinositol-3-kinase (PI3K) pathway is frequently dysregulated in human breast cancer. Approximately
30%of all patients with breast cancer will carry mutations of the PIK3CA gene, which encodes the PI3K catalytic subunit
isoform p110a. Mutations in PIK3CA have been associated with resistance to endocrine therapy, HER2-directed
therapy, and cytotoxic therapy. Early trials of pan-PI3K inhibitors showed little treatment benefit as monotherapy
owing to disease resistance arising through enhanced estrogen receptor pathway signaling. Combining PI3K inhibition
with endocrine therapy can help overcome resistance. Clinical trials of pan-PI3K inhibitors combined with endocrine
therapy demonstrated modest clinical benefits but challenging toxicity profiles, facilitating the development of more
selective PI3K-targeting agents. More recent trials of isoform-specific PI3K inhibitors in patients with PIK3CA mutations
have shown promising clinical efficacy with a predictable, manageable safety profile. In the present review, we discuss
the clinical relevance of mutations of PIK3CA and their potential use as a biomarker to guide treatment choices in
patients with HRþ HER2 advanced breast cancer.


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