title: Molecular signatures of lymph node status by intrinsic subtype: gene expression analysis of primary breast tumors from patients with and without metastatic lymph nodes.
abstract: BACKGROUND
  Identification of a gene expression signature in primary breast tumors that could classify patients by lymph node status would allow patients to avoid the morbidities of surgical disruption of the lymph nodes. Attempts to identify such a signature have, to date, been unsuccessful. Because breast tumor subtypes have unique molecular characteristics and different sites of metastasis, molecular signatures for lymph node involvement may vary by subtype.
  
  
  METHODS
  Gene expression data was generated from HG U133A 2.0 arrays for 135 node positive and 210 node negative primary breast tumors. Intrinsic subtype was assigned using the BreastPRS. Differential gene expression analysis was performed using one-way ANOVA using lymph node status as the variable with a False-discovery rate <0.05, to define significance.
  
  
  RESULTS
  Luminal A tumors were most common (51%) followed by basal-like (27%), HER2-enriched (14%) luminal B (7%) and normal-like (1%). Basal-like and luminal A tumors were less likely to have metastatic lymph nodes (35% and 37%, respectively) compared to luminal B or HER2-enriched (52% and 51%, respectively). No differentially expressed genes associated with lymph node status were detected when all tumors were considered together or within each subtype.
  
  
  CONCLUSIONS
  Gene expression patterns from the primary tumor are not able to stratify patients by lymph node status. Although the primary breast tumor may influence tumor cell dissemination, once metastatic cells enter the lymphatics, it is likely that characteristics of the lymph node microenvironment, such as establishment of a pre-metastatic niche and release of pro-survival factors, determine which cells are able to colonize. The inability to utilize molecular profiles from the primary tumor to determine lymph node status suggest that other avenues of investigation, such as how systemic factors including diminished immune response or genetic susceptibility contribute to metastasis, may be critical in the development of tools for non-surgical assessment of lymph node status with a corresponding reduction in downstream sequelae associated with disruption of the lymphatics.
authors.affiliation: Clinical Breast Care Project, Murtha Cancer Center, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD, 20889, USA. craig.d.shriver.mil@mail.mil.
authors.forename: Craig D
authors.initials: CD
authors.lastname: Shriver
authors.affiliation: Clinical Breast Care Project, Murtha Cancer Center, Walter Reed National Military Medical Center, 8901 Rockville Pike, Bethesda, MD, 20889, USA. Matthew.T.Hueman.mil@health.mil.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Hueman
authors.affiliation: Clinical Breast Care Project, Murtha Cancer Center, 620 Seventh Street, Windber, PA, 15963, USA. r.ellsworth@wriwindber.org.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Ellsworth
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics*