Abstract Background: Skip metastasis, defined as lymphatic spread that bypasses anatomically contiguous lymph nodes, is frequently observed in breast cancer. Previous studies have reported that skip metastasis occurs in approximately 2.6% of invasive breast cancer cases1. Lymphatic dissemination typically follows a sequential pattern, with axillary level I nodes being the most common initial site, followed by levels II, III, and occasionally other nodal basins2. However, the precise patterns and underlying mechanisms of lymphatic spread remain unclear and warrant further investigation. Methods: This retrospective study included adult patients with unilateral, invasive breast cancer who underwent axillary lymph node dissection at Renji Hospital, School of Medicine, Shanghai Jiao Tong University, between October 2013, and December 2023. Patients with de novo stage IV disease were excluded. We developed a novel classification system that stratified patients based on the involvement of axillary, interpectoral (Rotter’s), and infraclavicular lymph nodes. Patients were categorized into three groups, lymph node negative (LN-), lymph node sequentially positive (LNs+) and lymph node non-sequentially positive (LNns+). LN- represents no lymph node metastasis. LNs+ means lymph node metastases following a typical anatomic sequence, from proximal to distal. While LNns+ was defined as involvement of distal nodes without proximal node involvement. Kaplan-Meier analysis and Cox proportional hazards models were used to compare disease-free survival (DFS), the primary endpoint, and recurrence-free survival (RFS) and overall survival (OS) as secondary endpoints. Results: A total of 2,838 patients diagnosed with invasive breast cancer and treated with axillary lymph node dissection were included. Based on the classification, 1,833 patients were assigned to the LN- group, 858 to the LNs+ group, and 147 to the LNns+ group, among whom 9.5% patients presented with isolated Rotter’s lymph node metastasis, 6.8% patients had isolated infraclavicular lymph node involvement and 81.0% patients with axillary nodal metastasis, infraclavicular node metastasis occurred without Rotter’s node involvement. Additionally, 4 patients exhibited combined Rotter’s and infraclavicular lymph node metastases without axillary lymph node involvement. Compared with the other two groups, the LNns+ group showed significantly different characteristics in terms of age, pathological tumor stage, hormone receptor status, human epidermal growth factor receptor 2 (HER2) status, molecular subtype, and the number of infraclavicular lymph nodes dissected (P 0.05). In the univariate analysis, the LNns+ group consistently exhibited the poorest prognosis across DFS, RFS, and OS (P0.001). A similar trend was observed in the multivariate Cox regression analysis (P0.001). Conclusions: Non-sequential lymphatic metastasis may indicate more aggressive biological behavior than either the absence or sequential spread of nodal involvement. These patients may benefit from more potent treatmentsand closer surveillance during follow-up. References: 1. Chung HL, Sun J, Leung JWT. Breast Cancer Skip Metastases: Frequency, Associated Tumor Characteristics, and Role of Staging Nodal Ultrasound in Detection. AJR American Journal of Roentgenology 2021; 217(4): 835-44.2. Bitencourt A, Rossi Saccarelli C, Morris EA, et al. Regional Lymph Node Involvement Among Patients With De Novo Metastatic Breast Cancer. JAMA Network Open 2020; 3(10): e2018790. Citation Format: P. Zhu, L. Zhu, Y. Feng, Y. Ye, S. Xu, L. Zhou, Y. Lin, Y. Wang, Y. Du, J. Lu, W. Yin. Impact of non-sequential lymphatic spread on breast cancer prognosis 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 PS2-03-12.
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