Second ipsilateral locoregional recurrence in patients with hormone receptor-positive, HER2-negative breast cancer: a cohort study

Background Evidence regarding outcomes in patients with hormone receptor (HR)-positive/HER2-negative breast cancer (BC) with a second consecutive ipsilateral locoregional recurrence (LRR) remains limited. Methods Single-center, cohort study including consecutive patients with HR-positive/HER2-negative BC who underwent surgery (study baseline) for a second consecutive, ipsilateral LRR, at the European Institute of Oncology (Milan) from January 2001 to September 2025. Endpoints included invasive breast cancer-free survival (IBCFS) and distant recurrence-free survival (DRFS). Findings 111 patients were included: median age at study baseline was 61 years. The second LRR occurred in the breast in 44% of patients, in locoregional lymph nodes in 23%, on the mastectomy scar or chest wall in 31%. Endocrine-resistant recurrence was observed in 69% of patients. Overall, 14% of patients received adjuvant chemotherapy and 5% a CDK4/6-inhibitor. At a median follow-up of 6.3 years (95% CI: 4.7–7.9), 57 IBCFS events and 40 DRFS events were reported. Median IBCFS was 6.8 years (95% CI: 4.8–7.6) and median DRFS was 9.6 years (95% CI: 6.9–Not Reached [NR]). Median IBCFS was longer in endocrine-sensitive compared to endocrine-resistant LRR (8.6 years [95% CI: 4.6–NR] vs. 5.3 years [95% CI: 4.0–6.9]), and in intraparenchymal LRR (6.8 years [95% CI: 4.8–NR]) compared to nodal (6.4 years [95% CI: 1.4–NR]) or chest wall (5.1 years [95% CI: 4.0–NR]) recurrence. Interpretation Among patients experiencing a second consecutive LRR, approximately 50% develop a subsequent IBCFS event within 7 years, supporting consideration of treatment intensification, particularly in endocrine-resistant disease or recurrence involving the chest wall or regional lymph nodes. Funding None.