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The Humoral Immune System Has a Key Prognostic Impact in Node-Negative Breast Cancer

¹ Department of Obstetrics and Gynecology, Medical School, Johannes Gutenberg University, Mainz, Germany; ² Siemens Medical Solutions Diagnostics GmbH, Cologne, Germany; ³ Department of Obstetrics and Gynecology, and ⁴ Center for Toxicology, Institute of Legal Medicine and Rudolf-Boehm Institute of Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany; and ⁵ Department of Pathology, University of Lausanne, Lausanne, Switzerland

Requests for reprints: Mathias Gehrmann, Siemens Medical Solutions Diagnostics, Nattermann Allee 1, Cologne 50829, Germany. Phone: 49-221-576-3603; Fax: 49-221-576-3621; E-mail: mathias.gehrmann{at}siemens.com.

Key Words: Breast cancer • molecular diagnosis and prognosis • humoral immune system • gene expression analysis

Estrogen receptor (ER) expression and proliferative activity are established prognostic factors in breast cancer. In a search for additional prognostic motifs, we analyzed the gene expression patterns of 200 tumors of patients who were not treated by systemic therapy after surgery using a discovery approach. After performing hierarchical cluster analysis, we identified coregulated genes related to the biological process of proliferation, steroid hormone receptor expression, as well as B-cell and T-cell infiltration. We calculated metagenes as a surrogate for all genes contained within a particular cluster and visualized the relative expression in relation to time to metastasis with principal component analysis. Distinct patterns led to the hypothesis of a prognostic role of the immune system in tumors with high expression of proliferation-associated genes. In multivariate Cox regression analysis, the proliferation metagene showed a significant association with metastasis-free survival of the whole discovery cohort [hazard ratio (HR), 2.20; 95% confidence interval (95% CI), 1.40–3.46]. The B-cell metagene showed additional independent prognostic information in carcinomas with high proliferative activity (HR, 0.66; 95% CI, 0.46–0.97). A prognostic influence of the B-cell metagene was independently confirmed by multivariate analysis in a first validation cohort enriched for high-grade tumors (n = 286; HR, 0.78; 95% CI, 0.62–0.98) and a second validation cohort enriched for younger patients (n = 302; HR, 0.83; 95% CI, 0.7–0.97). Thus, we could show in three cohorts of untreated, node-negative breast cancer patients that the humoral immune system plays a pivotal role in metastasis-free survival of carcinomas of the breast. [Cancer Res 2008;68(13):5405–13]

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