In patients with estrogen receptor–positive (ER+) breast cancer, mortality from anti-estrogen–resistant tumors, in part due to aberrant intracellular signal transduction events as a consequence of constitutive activation of the HER2 kinase in HER2+ disease, accounts for a disproportionate fraction of breast cancer mortality each year, despite initial efficacy with selective ER modulators, selective ER downregulators, or estrogen suppressive therapies23. The gene discussed is ESR1; the disease is breast cancer.