title: The humoral immune system has a key prognostic impact in node-negative breast cancer.
abstract: 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.
authors.affiliation: Department of Obstetrics and Gynecology, Medical School, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Schmidt
authors.forename: Daniel
authors.initials: D
authors.lastname: Böhm
authors.forename: Christian
authors.initials: C
authors.lastname: von Törne
authors.forename: Eric
authors.initials: E
authors.lastname: Steiner
authors.forename: Alexander
authors.initials: A
authors.lastname: Puhl
authors.forename: Henryk
authors.initials: H
authors.lastname: Pilch
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: Heinz
authors.initials: H
authors.lastname: Kölbl
authors.forename: Mathias
authors.initials: M
authors.lastname: Gehrmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000917:Antibody Formation / Q000502:physiology*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006801:Humans; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis