We present two cases of estrogen receptor-positive/progesterone receptor-positive/human epidermal growth factor receptor 2-positive (ER+/PR+/HER2+) breast cancer patients, treated with a non-anthracycline, non-alkylating regimen of trastuzumab, carboplatin, docetaxel, and pertuzumab (TCHP), who developed therapy-related acute myeloid leukemia (t-AML) within 30 months of the completion of treatment. The gene discussed is ESR1; the disease is breast cancer.