Objective: To determine factors important in local-regional recurrence (LRR) in patients with negative sentinel lymph nodes (SLNs) by hematoxylin and eosin (H&E) staining.

Background: Z0010 was a prospective multicenter trial initiated in 1999 by the American College of Surgeons Oncology Group to evaluate occult disease in SLNs and bone marrow of early-stage breast cancer patients. Participants included women with biopsy-proven T1-2 breast cancer with clinically negative nodes, planned for lumpectomy and whole breast irradiation.

Methods: Women with clinical T1-2,N0,M0 disease underwent lumpectomy and SLN dissection. There was no axillary-specific treatment for H&E-negative SLNs, and clinicians were blinded to immunohistochemistry results. Systemic therapy was based on primary tumor factors. Univariable and multivariable analyses were performed to determine clinicopathologic factors associated with LRR.

Results: Of 5119 patients, 3904 (76.3%) had H&E-negative SLNs. Median age was 57 years (range 23-95). At median follow-up of 8.4 years, there were 127 local, 20 regional, and 134 distant recurrences. Factors associated with local-regional recurrence were hormone receptor-negative disease (P = 0.0004) and younger age (P = 0.047). In competing risk-regression models, hormone receptor-positive disease and use of chemotherapy were associated with reduction in local-regional recurrence. When local recurrence was included in the model as a time-dependent variable, older age, T2 disease, high tumor grade, and local recurrence were associated with reduced overall survival.

Conclusions: Local-regional recurrences are rare in early-stage breast cancer patients with H&E-negative SLNs. Younger age and hormone receptor-negative disease are associated with higher event rates, and local recurrence is associated with reduced overall survival.