CDK4/6 Inhibitors in HER2-positive Metastatic Breast Cancer.

HR +/HER2 + breast cancer (BC) represents a unique clinical entity distinct from HR-/HER2 + BC, with specific molecular characteristics and resistance mechanisms. The interaction between estrogen receptor (ER) and HER2 signaling pathways promotes tumor growth and therapeutic resistance, highlighting the need for tailored approaches. This review focuses on the clinical and molecular features of HR + /HER2 + metastatic BC, with an emphasis on recent data exploring the integration of CDK4/6 inhibitors (CDK4/6i) into anti-HER2 therapeutic strategies. Key findings from metastatic trials are summarized. HR + /HER2 + metastatic BC is characterized by a predominance of luminal molecular subtypes, associated with distinct patterns of metastatic spread and prolonged progression-free survival compared to nonluminal subtypes. Despite the efficacy of dual HER2 blockade, resistance remains a challenge, driven by crosstalk between ER and HER2 pathways. CDK4/6i disrupt the cell cycle at the G1/S checkpoint and have shown promise in overcoming resistance, inducing sustained senescence, and improving outcomes in luminal subtypes. Recent trials suggest that CDK4/6i may play a key role in maintenance therapy and chemotherapy-free regimens for selected patients with HR + /HER2 + metastatic BC. The integration of CDK4/6 inhibitors into anti-HER2 treatment strategies represents a promising approach to address the unique biology of HR + /HER2 + BC. Molecular profiling and personalized treatment strategies are essential to optimize patient outcomes and reduce unnecessary toxicity.