Claudin‐2 is an independent negative prognostic factor in breast cancer and specifically predicts early liver recurrences

Abstract

Keywords:Breast cancer Liver metastasis Claudin-2 Prognostic biomarker A B S T R A C TBackground: 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 ¼ 0.02) and high expression was associated with a shorter metastasis-free interval (cohort 1, HR ¼ 1.4, 95% CI ¼ 1.0e1.9; cohort 2, HR ¼ 2.2, 95% CI ¼ 1.3e3.5). 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 ¼ 2.3, 95% CI ¼ 1.3e3.9). Conclusion: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.ª 2013 Federation of European Biochemical Societies.Published by Elsevier B.V. All rights reserved.Abbreviations: BCSS, breast cancer specific survival; CI, confidence interval; CLDN2, claudin-2 mRNA; ER, estrogen receptor; HR, hazard ratio; IHC, immunohistochemistry; LiMFS, liver metastasis-free survival; LNM, lymph node metastasis; OR, odds ratio; PR, progesterone receptor; RFS, relapse-free survival; TMA, tissue microarray.

Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis–Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer

“…By using experimental mouse models and a limited series of clinical metastatic biopsies, genes associated with the propensity of breast cancer relapse to the bone (16), lung (17,18), and brain (19) have been published. Furthermore, we (7) and others (20,21) have shown an association between claudin-2 expression and liver recurrence. However, because experimental mouse models incompletely capture the relevant genetic complexity of tumor progression within the human host, studies using patientderived biopsies from metastases may reveal additional clinically relevant site-specific attributes to complement and/or validate these preliminary reports.…”

“…Because liver relapse is indicative of inferior postrecurrence survival, there is a need for more specific and independent biomarkers to identify patients at risk. Recently, we demonstrated that CLDN2, which is significantly upregulated in liver metastases, is an independent prognostic factor for early liver recurrence in breast cancer (7). Here, we show that downregulation of various genes involved in cell adhesion is characteristic of liver metastases.…”

“…After diagnosing metastatic breast cancer (MBC), the site of recurrence is an important feature for estimating the patient's prognosis. Liver metastasis is associated with the poorest survival relative to locoregional, bone, and lung colonization (2)(3)(4)(5)(6)(7). Noteworthy, the diagnosis of liver metastases is on the rise (8,9), suggesting that available adjuvant therapies may have limited efficacy in preventing liver colonization compared with metastases at other sites.…”

A 39-gene signature is associated with early occurrence of distant metastasis in primary lymph-node negative breast cancers

“…Four previously published microarray datasets were used in our study. GSE46141 dataset was used to identify distant metastasis-specific genes, it is derived from fine-needle aspiration biopsies of breast cancer metastases from different anatomical sites including 23 distant metastases (18 liver, 4 bone, 1 ascite) and 67 local metastases (breast, regional lymph node or skin) [7]. The expression, annotation and clinical data of GSE46141 were downloaded from Gene Expression Omnibus (GEO) database.…”

Can We Predict and Prevent Specific Sites of Metastases in Breast Cancer Patients?

“…Claudin-2 plays a key role in mediating the interaction between hepatocytes and cancer cells promoting the activation of metastatic signaling pathways. Indeed, Claudin-2 expression is considered a poor prognosis factor that mediates breast cancer relapse to the liver [24,25].…”