Tumor markers in breast cancer - European Group on Tumor Markers recommendations

Recommendations are presented for the routine clinical use of serum and tissue-based markers in the diagnosis and management of patients with breast cancer. Their low sensitivity and specificity preclude the use of serum markers such as the MUC-1 mucin glycoproteins ( CA 15.3, BR 27.29) and carcinoembryonic antigen in the diagnosis of early breast cancer. However, serial measurement of these markers can result in the early detection of recurrent disease as well as indicate the efficacy of therapy. Of the tissue-based markers, measurement of estrogen and progesterone receptors is mandatory in the selection of patients for treatment with hormone therapy, while HER-2 is essential in selecting patients with advanced breast cancer for treatment with Herceptin ( trastuzumab). Urokinase plasminogen activator and plasminogen activator inhibitor 1 are recently validated prognostic markers for lymph node-negative breast cancer patients and thus may be of value in selecting node-negative patients that do not require adjuvant chemotherapy. Copyright (C) 2005 S. Karger AG, Basel

Cytoplasmic location of factor-inhibiting hypoxia-inducible factor is associated with an enhanced hypoxic response and a shorter survival in invasive breast cancer

INTRODUCTION: Hypoxia-inducible factor (HIF)-1alpha levels in invasive breast carcinoma have been shown to be an adverse prognostic indicator. Cellular HIF-1alpha activity is regulated by factor-inhibiting hypoxia-inducible factor 1 (FIH-1). In hypoxia, FIH-1 hydroxylation of Asn803 within the C-terminal transactivation domain does not occur and HIF-1alpha forms a fully active transcriptional complex. The present study investigates the role of FIH-1 in invasive breast carcinoma and its correlation with hypoxia. METHODS: Microarrayed tissue cores from 295 invasive carcinomas were stained for FIH-1, for HIF-1alpha and for carbonic anhydrase 9. FIH-1 expression was correlated with standard clinicopathological parameters and with the expression of the surrogate hypoxic markers HIF-1alpha and carbonic anhydrase 9. RESULTS: FIH-1 was positive in 239/295 (81%) tumours, 42/295 (14%) exclusively in the nucleus and 54/295 (18%) exclusively in the cytoplasm. Exclusive nuclear FIH-1 expression was significantly inversely associated with tumour grade (P = 0.02) and risk of recurrence (P = 0.04), whereas exclusive cytoplasmic FIH-1 was significantly positively associated with tumour grade (P = 0.004) and carbonic anhydrase 9 expression (P = 0.02). Patients with tumours that excluded FIH-1 from the nucleus had a significantly shorter survival compared with those with exclusive nuclear expression (P = 0.02). Cytoplasmic FIH-1 expression was also an independent poor prognostic factor for disease-free survival. CONCLUSION: FIH-1 is widely expressed in invasive breast carcinoma. As with other HIF regulators, its association between cellular compartmentalization and the hypoxic response and survival suggests that tumour regulation of FIH-1 is an additional important mechanism for HIF pathway activation

Androgen receptor expression in male breast carcinoma: lack of clinicopathological association

Androgen receptor (AR) expression was retrospectively analysed in 47 primary male breast carcinomas (MBCs) using a monoclonal antibody on formalin-fixed, paraffin-embedded tissues. AR immunopositivity was detected in 16 out of 47 (34%) cases. No association was found with patient age, tumour stage, progesterone receptor (PGR) or p53 protein expression. Well-differentiated MBCs tended to be AR positive more often than poorly differentiated ones (P= 0.08). A negative association was found between ARs and cell proliferative activity: MIB-1 scores were higher (25.4%) in AR-negative than in AR-positive cases (21.11%; P= 0.04). A strong positive association (P= 0.0001) was found between ARs and oestrogen receptors (ERs). In univariate analysis, ARs (as well as ERs and PGRs) were not correlated with overall survival; tumour histological grade (P= 0.02), size (P= 0.01), p53 expression (P= 0.0008) and MIB-1 scores (P= 0.0003) had strong prognostic value. In multivariate survival analysis, only p53 expression (P= 0.002) and histological grade (P= 0.02) retained independent prognostic significance. In conclusion, the lack of association between AR and most clinicopathological features and survival, together with the absence of prognostic value for ER/PGR status, suggest that MBCs are biologically different from female breast carcinomas and make it questionable to use antihormonal therapy for patients with MBC. © 1999 Cancer Research Campaig

Determination of c-myc amplification and overexpression in breast cancer patients: evaluation of its prognostic value against c-erbB-2, cathepsin-D and clinicopathological characteristics using univariate and multivariate analysis

C-myc and c-erbB-2 amplification and/or overexpression as well as total cathepsin-D (CD) concentration have been reported to be associated with poor prognosis in breast cancer. The prognostic significance, however, remains somewhat controversial, partly because of discrepancies among the different methodologies used. We determined the amplification and overexpression of c-myc oncogene in 152 breast cancer patients and examined its prognostic value in relation to c-erbB-2 amplification and overexpression, high concentration of CD (≥ 60 pmol mg–1 protein) and standard clinicopathological prognostic factors of the disease. High CD concentration, as well as c-myc amplification and overexpression, proved to be the best of the new variables examined for prediction of early relapse (ER; before 3 years). After multivariate analysis only CD remained significant, which suggests that the prognostic power of these variables is similar. Using univariate analysis we proved that c-myc amplification and overexpression were highly significant for disease-free survival (DFS) (P = 0.0016 and P = 0.0001 respectively) and overall survival (OS) (P < 0.0001 and P = 0.0095 respectively), although by multivariate analysis c-myc overexpression was statistically significant only for DFS (P = 0.0001) and c-myc amplification only for OS (P = 0.0006). With regard to c-erbB-2, only its overexpression appeared to be significant for DFS and OS, although after multivariate analysis its prognostic power was weaker (P = 0.030 and P = 0.024 respectively). c-myc amplification and overexpression exhibited a tendency for locoregional recurrence (LRR) (P = 0.0024 and P = 0.0075 respectively), however, their prognostic value was lower after multivariate analysis and only CD remained significant. © 1999 Cancer Research Campaig

Histochemical estrogen binding. An independent predictor of recurrence and survival in stage II breast cancer.

Cox\u27s proportional hazards regression model was used to analyze the prognostic significance of multiple variables affecting recurrence and survival in patients with Stage II breast cancer. Among the variables were biochemical estrogen (ER) and progesterone receptor (PgR) values and results of a histochemical estrogen-binding assay using a fluoresceinated bovine serum albumin-estradiol conjugate where carrier and label were bound at position 17. In 190 cases ER and PgR were not found to be significantly associated with either disease recurrence or patient survival. On the other hand, patients with tumors that were demonstrably rich in estradiol ligand conjugate binding by histochemistry experienced both a longer disease-free interval (P less than 0.03) and survival (P less than 0.02) than did patients whose tumors were poor in conjugate binding or showed a heterogeneous population of positively and negatively stained cells. A patient with a tumor rich in estrogen binding was five times more likely to survive than a patient with a neoplasm that was poor in estrogen binding by histochemistry. These results indicate that the histochemical technique used provides new and independent parameters for determination of prognosis in Stage II breast cancer