Due to the limited efficacy of trastuzumab and pertuzumab in the HR-positive HER2-positive breast cancer subgroup, our study explored the activity and safety of the combinational therapy with oral HER2 tyrosine kinase inhibitor of pyrotinib, letrozole, and CDK4/6 inhibitor dalpiciclib in patients with stage II–III TPBC. This evidence concerns the gene CDK4 and breast carcinoma.