In this rationale-building pre-clinical study, we examine the efficacy of amcenestrant alone and in combination with the HER2-targeting TKIs lapatinib, tucatinib and neratinib, the mAb trastuzumab and the ADC T-DM1 in a panel of HER2+/ER+ breast cancer cell lines. The gene discussed is ESR1; the disease is breast cancer.