Such adverse prognosis can in part be attributed to the lack of actionable cell surface targets like human epidermal growth factor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) as well as molecular characteristics of the primary tumor that promote the development of chemotherapy resistant clonal variants, namely, genome instability (GI), and replication stress that drive a high degree of cellular heterogeneity (Chavez et al., 2010; Harbeck and Gnant, 2017; Park et al., 2018). The gene discussed is ESR1; the disease is neoplasm.