Unmasking intratumoral heterogeneity: Postoperative revelation of subclonal divergence in <i>de novo</i> metastatic HR‑positive/HER2‑negative breast cancer: A case report

Intratumoral heterogeneity poses a significant challenge in the management of metastatic hormone receptor-positive (HR⁺), human epidermal growth factor receptor 2 (HER2)-negative (HER2^-) breast cancer (BC), as it may contribute to treatment resistance and disease progression. Two cases of <i>de novo</i> metastatic HR⁺/HER2^- BC with bone-only metastases were reported. Both patients responded well to first-line systemic therapy with CDK4/6 inhibitors and endocrine agents. Locoregional surgery was subsequently performed and revealed HER2-positive subclones in the primary tumors that were not detected in the initial core biopsies. In one patient, HER2-targeted therapy was initiated with sustained clinical benefit. In the second patient, CDK4/6 inhibitor therapy was initially continued, but the disease later progressed. Post-treatment pathology can uncover distinct subclones, reflecting the dynamic nature of tumor biology. These cases highlight the potential value of surgical reassessment in selected patients with metastatic BC to guide individualized treatment strategies.