Data from Axillary Lymph Node Nanometastases Are Prognostic Factors for Disease-Free Survival and Metastatic Relapse in Breast Cancer Patients

Abstract
Purpose: Early breast cancer presents with a remarkable heterogeneity of outcomes. Undetected, microscopic lymph node tumor deposits may account for a significant fraction of this prognostic diversity. Thus, we systematically evaluated the presence of lymph node tumor cell deposits ≤0.2 mm in diameter [pN0(i+), nanometastases] and analyzed their prognostic effect.Experimental Design: Single-institution, consecutive patients with 8 years of median follow-up (n = 702) were studied. To maximize chances of detecting micrometastases and nanometastases, whole-axilla dissections were analyzed. pN0 cases (n = 377) were systematically reevaluated by lymph node (n = 6676) step-sectioning and anticytokeratin immunohistochemical analysis. The risk of first adverse events and of distant relapse of bona fide pN0 patients was compared with that of pN0(i+), pN1mi, and pN1 cases.Results: Minimal lymph node deposits were revealed in 13% of pN0 patients. The hazard ratio for all adverse events of pN0(i+) versus pN0(i−) was 2.51 (P = 0.00019). Hazards of pN1mi and pN0(i+) cases were not significantly different. A multivariate Cox model showed a hazard ratio of 2.16 for grouped pN0(i+)/pN1mi versus pN0(i−) (P = 0.0005). Crude cumulative incidence curves for metastatic relapse were also significantly different (Gray's test χ2 = 5.54, P = 0.019).Conclusion: Nanometastases are a strong risk factor for disease-free survival and for metastatic relapse. These findings support the inclusion of procedures for nanometastasis detection in tumor-node-metastasis staging.

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