These include targetable outlier gains and modifications in NTRKs as well as a distinct population of ESR1-depleted recurrences that enrich themselves with genes generally expressed in basal breast cancers—such as PROM1 and NDRG1. Preclinical, mechanistic investigations into these temporally altered genes are warranted given they may uncover novel and targetable mechanisms of endocrine therapy resistance in advanced breast cancers. The gene discussed is ESR1; the disease is breast cancer.