Introducing cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) has changed therapeutic paradigms in HR+/HER2- breast cancer, as their synergistic use with endocrine therapy significantly prolongs progression-free survival (PFS) and effectively mitigates clinically relevant endocrine resistance in this patient population compared to ET alone. The gene discussed is ERBB2; the disease is breast cancer.