title: Claudin-2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences.
abstract: BACKGROUND
  Predicting any future metastatic site of early-stage breast cancer is important as it significantly influences the prognosis of advanced disease. This study aimed at investigating the potential of claudin-2, over-expressed in breast cancer liver metastases, as a biomarker for predicting liver metastatic propensity in primary breast cancer.
  
  
  METHODS
  Claudin-2 expression was analyzed in two independent cohorts. Cohort 1 included 304 women with metastatic breast cancer diagnosed between 2002 and 2007, while cohort 2 included 237 premenopausal women with early-stage node-negative breast cancer diagnosed between 1991 and 1994. Global transcriptional profiling of fine-needle aspirates from metastases was performed, followed by immunohistochemical analyses in archival primary tumor tissue. Associations between claudin-2 expression and relapse site were assessed by univariable and multivariable Cox regression models including conventional prognostic factors. Two-sided statistical tests were used.
  
  
  RESULTS
  CLDN2 was significantly up-regulated (P < 0.001) in liver metastases compared to other metastatic sites. Claudin-2 protein was more frequently expressed in primary tumors from patients who subsequently developed liver metastases (P = 0.02) and high expression was associated with a shorter metastasis-free interval (cohort 1, HR = 1.4, 95% CI = 1.0-1.9; cohort 2, HR = 2.2, 95% CI = 1.3-3.5). Specifically, a significantly shorter interval between primary tumor diagnosis and liver-specific recurrence was observed among patients with high levels of claudin-2 expression in the primary tumor (cohort 1, HR = 2.3, 95% CI = 1.3-3.9).
  
  
  CONCLUSIONS
  These results suggest a novel role for claudin-2 as a prognostic biomarker with the ability to predict not only the likelihood of a breast cancer recurrence, but more interestingly, the liver metastatic potential of the primary tumor.
authors.affiliation: Division of Oncology, Department of Clinical Sciences, Lund, Lund University, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Siker
authors.initials: S
authors.lastname: Kimbung
authors.affiliation: Department of Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Anikó
authors.initials: A
authors.lastname: Kovács
authors.affiliation: Division of Oncology, Department of Clinical Sciences, Lund, Lund University, Sweden.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: Division of Oncology, Department of Clinical Sciences, Lund, Lund University, Sweden; Skåne Department of Oncology, Skåne University Hospital, Lund, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Malmström
authors.affiliation: Division of Oncology, Department of Clinical Sciences, Lund, Lund University, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hatschek
authors.affiliation: Division of Oncology, Department of Clinical Sciences, Lund, Lund University, Sweden; CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden. Electronic address: Ingrid.Hedenfalk@med.lu.se.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hedenfalk
mesh_terms: D001940:Breast / Q000378:metabolism / Q000473:pathology*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology*; D062446:Claudin-2 / Q000032:analysis* / Q000235:genetics; D015331:Cohort Studies; D005260:Female; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis / Q000235:genetics / Q000473:pathology / Q000556:secondary*; D011379:Prognosis; D059467:Transcriptome; D015854:Up-Regulation
chemical_list: D062446:Claudin-2
keywords: BCSS; Breast cancer; CI; CLDN2; Claudin-2; ER; HR; IHC; LNM; LiMFS; Liver metastasis; OR; PR; Prognostic biomarker; RFS; TMA; breast cancer specific survival; claudin-2 mRNA; confidence interval; estrogen receptor; hazard ratio; immunohistochemistry; liver metastasis-free survival; lymph node metastasis; odds ratio; progesterone receptor; relapse-free survival; tissue microarray