T-DM1 was effective against brain metastases from HER2-amplified breast cancer independent of the PIK3CA mutation status.4 We investigated the effects of adding macitentan to T-DM1 on its efficacy against MDA-MB-361-Gluc BM, which are HER2-amplified but also harbor an activating PIK3CA mutation (E545K). The gene discussed is PIK3CA; the disease is breast cancer.