Ongoing clinical trials are evaluating selective PI3K/Akt/mTOR inhibitors in combination with HER2 inhibitors, including alpelisib combined with trastuzumab for the treatment of patients with HER2+ BC bearing PIK3CA mutations, previously treated with HER2 inhibitors (ALPHABET, NCT05063786), and inavolisib in combination with trastuzumab–pertuzumab as maintenance therapy after a chemotherapy regime with docetaxel plus trastuzumab and pertuzumab in patients with HER2+mBC harboring PI3KCA mutations (INAVO122 trial, NCT05894239) [9]. The gene discussed is PIK3CA; the disease is breast cancer.