One way in which secondary resistance can appear during treatment is through epigenetic alterations that result in significant chromatin reprogramming,[96] altered cell lineage fidelity,[97] and activation of alternative signaling pathways.[98, 99] In estrogen receptor (ER) positive breast cancer, acquired resistance to endocrine therapy is associated with cancer spread, frequently following a period of tumor dormancy, with the appearance of metastasis eventually leading to death. This evidence concerns the gene ESR1 and breast cancer.