Risk factors for non-sentinel lymph node metastasis in breast cancer: a meta-analysis

Objective To systematically evaluate risk factors associated with non-sentinel lymph node (NSLN) metastasis in patients with sentinel lymph node (SLN)-positive breast cancer. Methods A comprehensive literature search was performed in PubMed, Embase, Web of Science, and the Cochrane Library from database inception to November 12, 2025. Studies reporting multivariable analyses of risk factors for NSLN metastasis were included. Study quality was independently assessed by two reviewers using the Newcastle–Ottawa Scale (NOS). Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using a random-effects model. Heterogeneity, sensitivity analyses, and publication bias were also evaluated. All statistical analyses were conducted using Stata version 15.0. Results A total of 37 studies involving 13,304 patients were included. The meta-analysis demonstrated that SLN macrometastasis (OR = 6.07, 95% CI: 2.21–16.7), abnormal preoperative AUS findings (OR = 3.51, 95% CI: 2.25–5.47), extranodal extension of SLN (OR = 2.67, 95% CI: 2.07 -3.44), lymphovascular invasion (OR = 2.68, 95% CI: 2.18–3.29), perineural invasion (OR = 2.37, 95% CI: 1.18–4.76), tumor diameter > 2 cm (OR = 2.06, 95% CI: 1.52–2.78), clinical T stage ≥ T2 (OR = 2.44, 95% CI: 2.02–2.95), histologic grade ≥ 3 (OR = 1.76, 95% CI: 1.44–2.16), number of positive SLNs (OR = 2.32, 95% CI: 1.53–3.53), SLN positivity ratio ≥ 50% (OR = 2.17, 95% CI: 1.74–2.70), multifocality (OR = 2.68, 95% CI: 1.98–3.63), HER2 positivity (OR = 2.22, 95% CI: 1.63–3.01), and a high Ki-67 index (OR = 2.20, 95% CI: 1.13–4.25) were associated with an increased risk of NSLN metastasis. Conclusion SLN tumor burden, abnormal preoperative axillary ultrasound findings, tumor aggressiveness, and intrinsic biological characteristics (e.g., HER2 status and Ki-67 index) are key predictors of NSLN metastasis. Given the limitations in the quality and quantity of the included studies, further high-quality, large-scale prospective studies are warranted to validate these findings and provide more robust evidence for individualized axillary management in breast cancer. Systematic Review Registration https://www.crd.york.ac.uk/PROSPERO/ , identifier CRD420261301905.