Almost 30% of patients with HER2+ breast cancer have a mutation in the PIK3CA gene, which encodes for PI3K protein; this protein facilitates HER2 activity and it has been observed that gene mutations may induce PI3K to turn active, thus promoting uncontrolled tumor growth. Therefore, in some cases PIK3CA mutations have been associated with reduced efficacy of anti-HER2 therapies or to allow resistance to anti-HER2 drugs.

The ALPHABET study is an ongoing clinical trial being carried out in 110 centers in 6 European countries, designed to address the clinical need of patients with HER2+ breast cancer and a mutation in the PIK3CA gene, who may develop resistance to anti-HER2-therapies: the study will assess the combination of alpelisib, an alpha-selective PI3K inhibitor, and trastuzumab or alpesilib, trastuzumab and fulvestrant, in patients expressing hormone receptors, compared with a standard treatment of investigator’s choice, with the aim of overcoming anti-HER2 drug resistances that can be induced by PIK3CA mutation. The combination represents a precision therapy aimed at multiple therapeutic targets and the goal of the study is to demonstrate a clinical benefit in disease control, avoiding the side effects associated with chemotherapy, thus improving the patients’ quality of life. The study, conducted in collaboration with GEICAM, BIG, IBSCG and Michelangelo Foundation, is ongoing at the IEO in Milan and will soon be active in other Italian centers; those interested in participating or in receiving further information can contact division.svilupponuovifarmaci@ieo.it.