Palbociclib (PD0332991) is the first highly selective inhibitor of CDK4/6 to be tested and approved in humans for use in combination with letrozole for the treatment of postmenopausal women with estrogen receptor (ER)-positive human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer as an initial endocrine-based therapy for metastatic disease. This evidence concerns the gene ESR1 and metastatic neoplasm.