In conclusion, the results of our study confirm the negative impact of PIK3CA mutations on the efficacy of the anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab that are used to treat patients with HER2+ breast cancer and support the clinical development of the alpha-selective PI3K inhibitor alpelisib to enhance their antitumor activity. Here, PIK3CD is linked to breast cancer.