Next Frontier in HER2+/HR+ Breast Cancer: Leveraging Cell Cycle Control with CDK4/6 Inhibitors

HER2-positive/hormone-receptor-positive breast cancer represents approximately 10% of all breast cancer cases and constitutes a distinct biological entity with unique therapeutic challenges. The complex crosstalk between HER2 and estrogen receptor signaling pathways contributes to both primary and acquired resistance to anti-HER2 therapies, and the convergence of these pathways on cell cycle regulation, particularly through the cyclin D1-CDK4/6-Rb axis, has provided a compelling rationale for combining CDK4/6 inhibitors with anti-HER2 therapy. This scoping review aimed to map preclinical and clinical evidence evaluating combinations of CDK4/6 inhibitors with HER2-targeted therapy in HER2+/HR+ disease. Eligible sources included preclinical models and clinical studies assessing CDK4/6 inhibitor-based combinations with anti-HER2 therapy, identified through searches of PubMed, Embase, Cochrane Library, Web of Science and ClinicalTrials.gov. Data were charted and synthesized descriptively according to PRISMA-ScR guidelines. Preclinical studies have demonstrated synergistic antitumor activity when CDK4/6 inhibitors are combined with trastuzumab, pertuzumab, or newer HER2-targeted agents across multiple HER2+ breast cancer models. In the metastatic setting, phase II trials including MonarcHER and PATRICIA II have shown encouraging efficacy signals, while the phase III PATINA trial demonstrated a clinically meaningful 15.2-month progression-free survival benefit with palbociclib plus anti-HER2 therapy and endocrine therapy. In the neoadjuvant setting, trials including NA-PHER2 and MUKDEN-01 demonstrated marked Ki67 suppression and promising pathologic responses, supporting the exploration of chemotherapy de-escalation strategies. Despite these advances, key challenges remain including the identification of predictive biomarkers, optimal treatment sequencing, and the integration of emerging HER2-targeted agents such as trastuzumab deruxtecan. Novel CDK4/6 inhibitors including dalpiciclib and next-generation agents are expanding therapeutic options, while combination strategies incorporating CDK7 inhibition represent future therapeutic frontiers. The evolving landscape of HER2+/HR+ breast cancer treatment increasingly emphasizes precision medicine approaches that leverage cell cycle control mechanisms to overcome resistance and improve patient outcomes across all disease stages.