Advances in Targeted Therapy for Breast Cancer Treatment - Episode 5

PI3K Inhibition in Breast Cancer

The alpha isoform of PI3K is commonly mutated in breast cancer, particularly in estrogen receptor (ER)-positive disease, says Ian E. Krop, MD. Activation of the PI3K pathway can interfere with the sensitivity of inhibitors to the ER pathway. As a result, investigational PI3K inhibitors are mainly being evaluated in combination with hormonal therapy in ER-positive breast cancer.

In the phase II FERGI study, the PI3K inhibitor pictilisib was combined with the ER antagonist fulvestrant in patients with prior exposure to an aromatase inhibitor. In ER-positive disease progression-free survival was not improved with the addition of pictilisib. Additionally, pictilisib was associated with a significant amount of toxicity, notes Krop.

While pictilisib targets the alpha and beta isoforms of PI3K, the next generation of PI3K inhibitors are more specific for the alpha isoform that is mutated in breast cancer. Phase I data of the alpha-specific PI3K inhibitors taselisib and alpelisib have shown compelling degrees of activity in PIK3CA-mutated breast cancer, comments Krop. These alpha-specific agents appear to have better toxicity profiles, adds Hope S. Rugo, MD.

PI3K inhibition is also being explored in HER2-positive disease, since PI3K is downstream of HER2. Recent data have suggested that mTOR inhibitors may also have activity in helping patients overcome resistance to HER2-targeted therapies, notes Rugo. Similarly, drugs are in development that inhibit Akt, which is also a component of the PI3K pathway.