On the other hand, many resistance mechanisms for drug therapy in breast cancer have been reported as follows: loss of estrogen receptor, deregulation of cell cycle for endocrine therapy, incomplete blockade of HER receptors, activation of the PI3K pathway, over-expression of estrogen receptor for HER2 inhibitors, polyclonal RB1 mutations for CDK 4/6 inhibitors, and so on [25,26]. The gene discussed is ESR1; the disease is breast cancer.