Abstract
E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case-case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, >2 cm, and HER2-negative. Loss of E-cadherin expression (score < 100) was associated with menopausal hormone use among ER-positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97–1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06–2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes.
Highlights
Many studies have identified heterogeneity in risk factor associations based on breast tumor subtypes defined by hormone receptor status (e.g. estrogen receptor (ER)-positive vs. ER-negative) or histology[11,12,13,14,15,16,17,18,19,20,21,22], limited data have examined whether E-cadherin may define important subgroups of tumors with distinct etiologies[23]
Data suggest that loss of E-cadherin expression may be associated with malignant progression, metastasis, and reduced survival in breast cancer patients[24,25,26,27,28]; most of these studies were based on small numbers and not all analyses were stratified by ER-status, a known important prognostic and predictive marker
We were interested in determining whether known risk/ protective factors for breast cancer differed by E-cadherin expression, in order to provide new insights into possible mechanisms for E-cadherin loss in breast carcinogenesis similar to analyses previously done for ER, progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) markers[23,30,31]
Summary
Many studies have identified heterogeneity in risk factor associations based on breast tumor subtypes defined by hormone receptor status (e.g. ER-positive vs ER-negative) or histology (lobular vs ductal)[11,12,13,14,15,16,17,18,19,20,21,22], limited data have examined whether E-cadherin may define important subgroups of tumors with distinct etiologies[23]. Using immunohistochemical (IHC) data for E-cadherin performed centrally using tumor tissue microarrays (TMAs), we performed a large pooled analysis of 12 studies participating in the Breast Cancer Association Consortium (BCAC), and examined whether established breast cancer risk factor associations and survival differed by low vs high E-cadherin tumor tissue expression, stratified by ER status and histology
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