For tumors that are hormonal therapy naïve or first-line therapy, oral SERDs plus CDK4/6 inhibitors are being compared with AIs plus CDK4/6 inhibitors as in AMEERA-5 [87] (amcenestrant), SERENA 4 [88](camizestrant), or with physicians’ choice plus CDK4/6 inhibitors as in acelERA Breast Cancer [78] (giredestrant) and in tumors with ESR1 mutation, as in SERENA 6 [89] (camizestrant). Here, ESR1 is linked to breast cancer.