Advances in the intrinsic signaling pathway interactions and clinical translation of HR+/HER2+ breast cancer.

Hormone receptor-positive (HR +) and HER2-positive (HER2+) breast cancers represent a biologically unique subset of breast malignancies characterized by the co-expression of estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptor 2 (HER2). These cancers exhibit distinct molecular features, often leading to aggressive growth and higher recurrence rates. HR+/HER2+ breast cancer cells can utilize estrogen and HER2-driven signaling pathways to promote proliferation, survival, and metastatic potential, presenting unique challenges and opportunities for treatment. The current therapeutic strategies focus on a combination of endocrine therapies, such as selective estrogen receptor modulators (e.g., tamoxifen) or aromatase inhibitors, with HER2-targeted therapies like trastuzumab, pertuzumab, or tyrosine kinase inhibitors, to concurrently inhibit both hormone and HER2-driven pathways. Despite initial treatment efficacy, resistance often develops through various mechanisms, including mutations in the PIK3CA gene, cross-talk between ER and HER2 signaling, and activation of alternative growth pathways. Ongoing research aims to improve patient outcomes by exploring novel combination therapies, including CDK4/6 inhibitors and PI3K/AKT/mTOR pathway inhibitors, and by targeting resistance pathways. This review highlights the molecular basis, treatment approaches, and emerging therapeutic strategies in HR+/HER2+ breast cancer, emphasizing the need for personalized and adaptive treatment strategies in managing this complex disease subtype.