Hypoxia-inducible factor-1a (HIF-1a) is a transcription factor that is involved in tumour growth and metastasis by regulating genes involved in response to hypoxia. HIF-1a protein overexpression has been shown in a variety of human cancers, but only 2 studies have documented the prognostic relevance of HIF-1a expression in breast cancer. The aim of our study was to determine accurately the impact of HIF-1a expression on prognosis in a large series (n = 745) of unselected patients with invasive breast cancer in terms of overall survival, local recurrence and distant metastasis risk. HIF-1a expression was investigated using immunohistochemical assays on frozen sections, and correlated with patients' outcome (median follow-up = 13.5 years). Univariate (Kaplan-Meier) analysis showed that high levels of HIF-1a expression (cutoff = 10%) significantly correlated with poor overall survival ( p = 0.019). HIF-1a expression correlated with high metastasis risk among the whole group of patients ( p = 0.008). Multivariate analysis (Cox model) showed that the HIF-1a predictive value was independent of other current prognostic indicators. Moreover among node negative ones, HIF-1a expression was also significantly predictive of metastasis risk ( p = 0.03) and of relapse (p = 0.035). All the data suggest that HIF-1a is associated with a worse prognosis in patients with invasive breast carcinoma. Furthermore HIF-1a immunodetection may be considered as a potential indicator for selecting patients who could benefit from specific therapies interfering with HIF-1a pathway. ' 2005 Wiley-Liss, Inc.

Since the few data exploring a possible association between Epstein–Barr virus (EBV) and breast cancer are conflicting, we investigated this association together with the influences of geographical areas. 509 breast cancers were sampled from areas with varying risks of nasopharynx carcinoma (NPC) such as North Africa (Algeria and Tunisia, high-risk area); southern France (Marseille, intermediate-risk area); and northern Europe (northern France, the Netherlands and Denmark; low-risk areas). Polymerase chain reaction (PCR) of a subregion of EBV BamHIC encoding the EBERs demonstrated that 31.8% of the tumours contained the viral genome. No significant differences were observed among the geographical areas. However, positive samples showed higher loads of the EBV genome in the NPC high- and intermediate-risk areas than in the low-risk areas. EBV type 1 was the dominant strain. In situ hybridization studies using a 35 S-labelled riboprobe for EBER1 and a laser capture microdissection, combined with quantitative PCR, showed that EBV localization was restricted to some tumour epithelial cell clusters. EBV could not be detected in the stroma. Considering the whole population covered, the presence of the EBV genome was not correlated with age, menopausal status, tumour, size, nodal status or histological grade. © 2001 Cancer Research Campaign http://www. bjcancer.com

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Conservative surgery for patients with EOC could be considered in young patients with stage IA G1 disease. This procedure should not be performed in patients with FIGO stage > IA.

Some controversy remains about the clinical or pathological definition of the different types of inflammatory breast cancer (IBC) and especially the diagnostic and prognostic value of dermal lymphatic involvement. Our purpose was to classify the different types of IBC for which diagnosis was confirmed intraoperatively and ascertain features allowing reliable diagnosis. We studied clinical findings, biological data, and treatment outcome in a series of 144 successive patients. Our results suggest that there are 2 biologically different entities i.e., true IBC and pseudo-IBC. True IBC, whose course is currently fatal in all cases, can be divided into 2 sub-categories i.e., common true IBC (75.7% of cases), in which inflammatory signs occur primarily or secondarily, and occult true IBC (13.2% of cases). Dermal emboli have been observed in 61% of common true IBC, but their absence did not alter the rapidly unfavourable outcome. Extensive lymph-node involvement, other biological features and survival were the same in the 2 sub-categories. Pseudo-IBC (11.1% of cases) can easily be confused with common true IBC. The biological characteristics of pseudo-IBC differ from those of true IBC: no dermal lymphatic involvement and little or no lymph-node involvement. Despite large tumour size, outcome was particularly favourable. It is of great importance to differentiate true and pseudo-IBC, for which the treatments are different. Confirmation of true IBC requires pathological demonstration of dermal lymphatic emboli or extensive lymph-node involvement. Occult IBC must be identified for patients presenting rapidly growing tumours.

The relationship of age with prognostic factors and outcome of breast cancer has long been controversial due to numerous confounding factors. In order to clarify the prognostic value of age, we analyzed a homogeneous population of 1,266 patients treated for breast cancer at the same institution (mean follow-up: 62 months). Three groups were compared: patients under 35 years of age, non-menopausal patients over 35 years of age, and post-menopausal patients under the age of 70 years. A higher frequency of undifferentiated tumors, histoprognostic grade-3 cancer, microscopic lymph-node involvement and negative hormonal receptor status was observed in patients under 35 years. In addition, clinical but not anatomical tumor size was greater in young patients, suggesting higher stromal activity. Metastasis-free survival and overall survival were significantly poorer before 35 years. Differences were observed when patients were matched with regard to stage, anatomic size, histoprognostic grade, microscopic lymph-node involvement and receptor status. Multivariate analysis of both overall and metastasis-free survival demonstrated that age younger than 35 years was an independent risk factor. Younger women had a higher risk of local recurrence but, unlike older women, they did not experience any worsening of the already unfavorable outcome due to recurrence.

Purpose:Although a potential role of the Epstein-Barr virus (EBV) in the pathogenesis of breast cancer (BC) has been underlined, results remain conflicting. Particularly, the impact of EBV infection on biological markers of BC has received little investigation.Methods:In this study, we established the frequency of EBV-infected BC using real-time quantitative PCR (RT–PCR) in 196 BC specimens. Biological and pathological characteristics according to EBV status were evaluated.Results:EBV DNA was present in 65 of the 196 (33.2%) cases studied. EBV-positive BCs tended to be tumours with a more aggressive phenotype, more frequently oestrogen receptor negative (P=0.05) and with high histological grade (P=0.01). Overexpression of thymidine kinase activity was higher in EBV-infected BC (P=0.007). The presence of EBV was weakly associated with HER2 gene amplification (P=0.08).Conclusion:Our study provides evidence for EBV-associated BC undergoing distinct carcinogenic processes, with more aggressive features.

Neoangiogenesis in tumours contributes to the development of blood-borne metastases, and can be evaluated by markers of activated endothelial cells in preference to panendothelial markers. Our purpose was to document the prognostic significance of VEGF-R1, VEGF-R2, Tie-2/Tek and CD105 immunoexpression in breast carcinoma frozen samples (n ¼ 905, follow-up ¼ 11.7 years). We observed that: (i) CD105 (P ¼ 0.001) and Tie-2/Tek (P ¼ 0.025) (but not VEGF-R1 and VEGF-R2) overexpression correlated with a shorter survival, and were (Cox's model) independent histoprognostic indicators; (ii) only CD105 marked expression correlated (P ¼ 0.035) with a shorter survival of node-negative patients; (iii) three markers -CD105 (P ¼ 0.001), Tie-2/Tek (P ¼ 0.01), VEGF-R1 (P ¼ 0.001), but not VEGF-R2 -correlated with metastatic risk in node-negative patients in univariate analysis; and (iv) VEGF-R1 (P ¼ 0.01) expression correlated with high local recurrence risk. It is concluded that CD105 and to a lesser extent Tie-2/Tek and VEGF-R1, but not VEGF-R2 are endowed with prognostic significance that may be useful for patient monitoring, particularly CD105 expression for selecting node-negative patients for more aggressive postsurgery therapy.