Whether suboptimal drug exposure due to toxicities or a small sample size may have influenced the results of the MK-2206 phase I trial in advanced HR-positive/HER2-negative BC patients (Ma et al., 2016), the crosstalk between the estrogen receptor and PI3K signaling is the most likely cause for the lack of additional benefit from capivasertib observed in the PI3K/AKT/PTEN altered population of the FAKTION study (Jones et al., 2020). Here, PIK3CA is linked to breast cancer.