title: A gene signature for late distant metastasis in breast cancer identifies a potential mechanism of late recurrences.
abstract: BACKGROUND
  Breast cancer risk of recurrence is known to span 20 years, yet existing prognostic signatures are best at predicting early recurrences (≤ 5 years). There is a critical need to identify those patients at risk of late-relapse (>5 years), in order to select potential candidates for further treatment and to identify molecular targets for such treatment.
  
  
  METHODS
  A total of 252 breast primary tumors were selected at the Netherlands Cancer Institute from a retrospective series of ER+, HER2- breast cancer patients with a follow-up of at least 10 years. Gene expression analysis was performed using Agilent 4x44K microarrays. Patients were classified in 3 groups: no relapse (M0); relapse before 5 years (M0-5) or after 5 years (M5-15). We assessed the correlation of clinico-pathological variables with late Distant Metastases (DM). We divided the patient series into a training set of untreated patients (n = 140) and a test set of treated patients (n = 112), to investigate whether a gene-signature or single genes could be identified for predicting late DM. Pathway level late DM correlates were identified using PARADIGM and DAVID.
  
  
  RESULTS
  Of the clinico-pathologic variables tested, only lymph node status associated with late DM. A 241-gene signature developed on the NKI training set was able to classify M5-15 patients in the test set with a sensitivity of 77% and a specificity of 33% (AUC 0.654). This signature showed enrichment in genes involved in immune response and extracellular matrix. An alternative analysis of individual genes identified CH25H as an independent predictor of distant metastasis in our patient series.
  
  
  CONCLUSIONS
  We identified a gene signature for late metastasis in breast cancer. Our data are consistent with a model in which suppressed anti-tumoral immunity enables dormant tumor cells to re-enter the cell cycle to form metastases in response to extrinsic events in the microenvironment.
authors.affiliation: The Netherlands Cancer Institute, Division of Molecular Carcinogenesis, Amsterdam, The Netherlands.
authors.forename: Lorenza
authors.initials: L
authors.lastname: Mittempergher
authors.forename: Mahasti
authors.initials: M
authors.lastname: Saghatchian
authors.forename: Denise M
authors.initials: DM
authors.lastname: Wolf
authors.forename: Stefan
authors.initials: S
authors.lastname: Michiels
authors.forename: Sander
authors.initials: S
authors.lastname: Canisius
authors.forename: Philippe
authors.initials: P
authors.lastname: Dessen
authors.forename: Suzette
authors.initials: S
authors.lastname: Delaloge
authors.forename: Vladimir
authors.initials: V
authors.lastname: Lazar
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Benz
authors.forename: Thomas
authors.initials: T
authors.lastname: Tursz
authors.forename: René
authors.initials: R
authors.lastname: Bernards
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van't Veer
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics*
keywords: Breast cancer; CH25H gene; Gene expression profiling; Late distant metastasis; MammaPrint; Microenvironment; PARADIGM; Prognostic
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