Abstract Background: Recently, perineural invasion (PNI) has emerged as a promising biomarker and a potential therapeutic target in cancer. PNI has been shown to provide prognostic value on locoregional recurrence and distant metastasis in the breast cancer. However, its role in the the progression of lymph node metastasis remains controversial. This study aims to explore the relationship between PNI and the extent of axillary lymph node metastasis (ALNM) in breast cancer. Methods: Patients with early-stage, operable invasive breast cancer who underwent surgery between June 2011 and June 2023 were enrolled. The patients were stratified into PNI-positive and PNI-negative groups based on postoperative pathology. To control for confounding factors and simulate a randomized controlled trial, we used propensity score matching (PSM), inverse probability of treatment weighting (IPTW), and overlap weighting (OW) methods between two groups. Multivariate logistic regression analysis was performed to evaluate the association between PNI and both ALNM and lymph node ratio (LNR). A meta-analysis was conducted to further validate the effect. Results: Among 4,156 early-stage operable breast cancer patients, 1,223 (29.4%) were PNI-positive. Multivariate logistic regression analysis revealed that PNI is independently associated with ALNM (P = 0.002) and a high-risk lymph node ratio (LNR 0.2) (P = 0.012). These associations remained consistent after sensitivity analyses using PSM, IPTW, and OW methods (all P 0.05). The meta-analysis included 16 eligible studies with 17,451 participants, further confirmed the significant association between PNI and ALNM (P 0.001). Additionally, the meta-analysis demonstrated that PNI is linked to worse disease-free survival (DFS) (P 0.001) and overall survival (OS) (P = 0.007) in patients with breast cancer. Conclusion: PNI is associated with a greater burden of ALNM in patients with early-stage operable invasive breast cancer, underscoring its potential value for risk stratification in the era of axillary surgery de-escalation. Citation Format: W. Cai, Y. Wang, Y. Qiu, S. Liu, Q. Cai, P. He, Y. Lin, M. Chen, L. Chen, F. Fu, C. Wang. Perineural invasion increases the risk of lymph node metastasis in early-stage operable breast cancer:a large-scale propensity-matched cohort study and meta-analysis abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-05-08.
Cai et al. (Tue,) studied this question.