The cycline-D kinase 4/6 inhibitors palbociclib, abemaciclib, and ribociclib have revolutionized the management of metastatic estrogen receptor (ER)-positive breast cancer and enabled chemotherapy-free early line treatment regimens for patients without significant organ impairments due to their metastases, with comparable disease-related outcomes [41,42]. This evidence concerns the gene ESR1 and breast carcinoma.