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Axillary lymph node nanometastases are prognostic factors for metastatic relapse in breast cancer patients

S. Alberti, P. Querzoli, M. Pedriali, R. Rinaldi, E. Biganzoli, P. Boracchi, M. Piantelli, S. Iacobelli, E. Marubini and I. Nenci University of Chieti, Chieti Scalo, Italy; University of Ferrara, Ferrara, Italy; National Cancer Institute, Milano, Italy; University of Milano, Milano, Italy

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Background: Early breast cancer presents with a remarkable and largely unaccounted for 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 analysed their prognostic impact. Methods: Seven hundred and two single institution, consecutive patients with 8 years of median follow-up were studied. To maximize the chances of detecting micro and nanometastases, whole-axilla dissections were analysed. pN0 cases were systematically reevaluated by step sectioning and anti-cytokeratin immunohistochemical analysis of 6676 corresponding dissected lymph nodes. 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. Crude cumulative incidence (CCI) curves were used to estimate the cumulative probability of occurrence of adverse events. CCI curves were compared by the Gray’s test. A proportional sub distribution hazard (SDH) regression model was utilized to assess the difference among CCI curves of pN0(i+) versus pN0(i-), and of pN1mi versus pN0(i+). Competing risks were accounted for and regression models were adjusted for established breast cancer prognostic factors, i.e. grading, pathological T stage and age. Proportional SDH assumptions were checked using Schoenfeld-type residuals. Results: A pN0(i+) status was shown to be a strong risk factor for event-free survival (P<0.0005) and for metastatic relapse in both univariate and multivariate analyses accounting for competing risks and adjusted for grading, pathological T stage and age. Conclusions: Our findings demonstrate that nanometastases are an important risk factor in breast cancer. These results support the inclusion of procedures for nanometastasis detection in TNM pathological staging.

No significant financial relationships to disclose.