To address the question whether HER2/neu and CDK4/6 inhibition has a sustainable therapeutic effect in advanced HER2-positive breast cancer, we employed the MMTV-neu202Mul transgenic mouse bearing late-stage mammary tumor (volume > 500 mm3) and examined their response to a continuous anti-HER2/neu antibody (Ab) plus CDK4/6 inhibitor Palbociclib (Pal) treatment. Here, CDK4 is linked to breast cancer.