PI3K/AKT Pathway Biology, Capivasertib, and Biomarker Testing

Erica L. Mayer, MD, MPH, of Dana-Farber Cancer Institute, reviews the rationale for capivasertib in hormone receptor positive, human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer, noting phosphatidylinositol 3-kinase (PI3K)/AKT pathway alterations in nearly half of patients, activation through PIK3CA or AKT alterations or PTEN loss, and guideline recommendations for capivasertib plus fulvestrant in altered disease after endocrine progression. Seth A. Wander, MD, PhD, of Massachusetts General Hospital, walks through the signaling cascade from PI3K to AKT to mTOR, estimating activating PIK3CA mutations in roughly 40% of estrogen receptor positive metastatic disease and downstream activation in another 5% to 10%, and argues that the most important differences between targeting each node are toxicity patterns and emerging resistance mechanisms. Sarah L. Sammons, MD, of the University of Maryland Greenebaum Comprehensive Cancer Center, recommends next-generation sequencing at diagnosis, tissue first, and repeat circulating tumor DNA at progression on a cyclin-dependent kinase 4/6 inhibitor.