ESR1 and neoplasm: 4OH-Tam insensitive tumors often still express the ERα, with some of them being resistant at the time of the diagnosis (i.e., de novo resistant), while others acquire 4OH-Tam insensitivity during prolonged 4OH-Tam treatment through various mechanisms, including the selection of tumor cells that express a mutated constitutively active ERα variant (e.g., mutation of the receptor tyrosine (Y) 537 into serine (S)) [2,3,4,5,6].