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The aim of this study was to identify a prognostic immunohistochemical signature indicative of risk of early metastasis in node-negative breast carcinomas that would also be relevant to the development of new tailored therapy. Quantitative measurements of the immunohistochemical expression of 64 markers (selected from literature data) using high-throughput densitometry (as a continuous variable) of digitised microscopic micro-array images were correlated with clinical outcome in 667 node-negative breast carcinomas (mean follow-up 102 months). Multivariable fractional polynomials model of logistic regression allowed the selection of the best combination of markers (in terms of sensitivity and specificity) to predict patient outcome without any categorisation using predefined cut-points for individual marker measurements. A highly predictive ten-marker (out of 64) signature was identified comprising PI3K, pmTOR, pMAPKAPK-2, SHARP-2, P21, HIF-1alpha, Moesin, p4EBP-1, pAKT and P27 that well classified 91.4% of node-negative patients (specificity 90.9%, sensitivity 93.7%, area under ROC curve 0.958) independently of estrogen receptors (ER), and progesterone receptors (PR) and HER-2 status (91.6% well classified patients when ER, PR, HER-2 excluded). It is concluded that quantitative immunoprofiling of node-negative breast carcinomas is helpful in selecting patients who should not receive aggressive adjuvant chemotherapy and provides data for the development of tailored therapy.

The aim of this study is to estimate the accuracy and reliability of intraoperative frozen section of nonpalpable breast lesions. In fact, frozen section of palpable breast lesions has proven to be valid, but its use in breast infraclinic lesions has been discussed recently, with the publication of European recommendations. Diagnosis on frozen section was routinely performed in a serie of 791 patients with nonpalpable mammographically detected abnormalities breast lesions from January 1990 through July 2000. The initial frozen section diagnoses with known mammographic pattern were compared with the diagnoses obtained on permanent paraffin sections to estimate the accuracy of frozen sections. Frozen section diagnosis was delayed until final diagnosis assessed on permanent paraffin sections in only 8 cases (1%). Frozen section diagnoses were accurate in 744 of 783 cases (95%). The diagnosis was modified on the basis of permanent sections in 39 cases; consisting of 39 false negative. No false positive diagnosis was noted. Sensitivity and specificity of frozen section diagnoses were 87,69 and 100, respectively. When the comparison between frozen and permanent section was analyzed according to the mammographic pattern, the sensitivity among patients with microcalcifications was lower (75,23) than among patients with opacities (93,86). When frozen section and permanent section diagnoses were related according to the mammographic size ( 10 mm) the sensitivity among patients with opacities measuring less than 10 mm was lower (91,75) than among patients with opacities larger than 10 mm (95,65) and the sensitivity among patients with microcalcifications larger than 10 mm was greater (77,14) than among patients with microcalcifications size less than 10 mm (74,28). This results are similar to those obtained on palpable breast lesions, and show that frozen section is a feasible and reliable procedure in nonpalpable breast lesions, particularly more relevant in mammographic opacities than in microcalcifications, whatever the lesion size.

The purpose of this study was to evaluate the efficacy of concurrent chemotherapy and irradiation in inflammatory breast cancer (IBC). Between January 1990 and December 1998, forty-eight non-metastatic patients with clinical or occult IBC were treated with chemotherapy and irradiation. The induction chemotherapy consisted of epirubicin, cyclophosphamide and vindesin, in association with split-course bi-fractionated irradiation to a total dose of 65 Gy with concomitant cisplatin and fluorouracil. Maintenance chemotherapy consisted of high-dose methotrexate and 6 cycles of epirubicin, cyclophosphamide and fluorouracil Hormonal treatment was given routinely but mastectomies were not routinely performed. A high rate of locoregional control was obtained in 47 evaluable patients of whom 93.6 % achieved a complete clinical response. Three patients had locoregional relapses, always with concomitant metastatic dissemination. In 47 patients, 21 developed metastatic dissemination with a median delay of 23 months. Median disease-free survival (DFS) was 45 months. Median overall survival (OS) has not yet been reached after a median follow-up of 44.5 months. The 3-year DFS rate was 53 % and the 3-year OS rate was 71 %. Toxicity was mainly hematological. During the induction therapy, grade 3 or 4 neutropenia occurred in 54 % of patients, grade 3 or 4 thrombocytopenia in 23 % and grade 3 or 4 anemia in 8 %. The administration of induction chemotherapy and concomitant irradiation is feasible in patients with IBC. The hematological toxicity of this treatment approach is significant but nevertheless, the treatment achieves a high degree of locoregional control and improved survivaL

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., (Copyright 2001 Cancer Research Campaign.)

The initial step of cancer invasion and metastasis is the escape of tumour cells from the primary site, involving disruption of normal cell-cell adhesion and E-cadherin (E-cad) and beta-catenin (beta-cat) down-regulation, as shown in various types of human malignancies including breast carcinomas. Medullary carcinomas are high grade and poorly differentiated tumours with syncytial typical pattern, and prognosis unexpectedly better than that in high grade breast carcinomas. In a series of 55 breast typical medullary carcinomas diagnosed according to the strict use of Ridolfi et al (Cancer 40: 1365-1385, 1977) criteria, E-cad and beta-cat were investigated using quantitative (SAMBA 2005 system) immunocytochemical assays on frozen sections. Results were compared to that obtained on paraffin sections and in a series (n=55) of grade 3 ductal carcinomas. It was shown that medullary carcinomas significantly (p<0.001) expressed more E-cad and beta-cat than grade 3 ductal carcinomas. E-cad and beta-cat correlated with high expression of P53, of c-erbB, and of Ki-67 antigens, and with lack of hormone receptors antigenic sites (p<0.001). It was concluded that favourable prognosis and syncytial pattern of typical breast medullary carcinomas likely results, at least partly, from a particular expression of cell-cell adhesion molecules, significantly limiting tumour growth and efficiently mastering the tumour cell dissemination, opposing to high proliferative activity (grade 3).

Objective: Conservative treatment for ductal carcinoma in situ of the breast exposes patients to the risk of infiltrating recurrence which can lead to metastasis. The primary purposes of this retrospective study were to evaluate diagnostic and therapeutic methods over a 10-year period and to validate prognostic factors. This information should greatly improve patient selection for conservative treatment or mastectomy., Study Design: A multi-institutional data base including 575 patients treated between 1983 and 1993 was established by combining data from 16 French institutions. Survival at 5 and 7 years was studied as a function of various prognostic factors., Results: Recurrence-free survival at 7 years was 0.96 after modified radical mastectomy and 0.83 after breast-conserving treatment and radiotherapy (P=0.003). Metastasis-free survival at 7 years was 0.99 after modified radical mastectomy and 0.94 after breast-conserving treatment and radiotherapy (not significant). No factor was predictive of local recurrence after mastectomy. Clinical stage was the only factor significantly correlated with metastasis after mastectomy. Recurrence-free survival after breast-conserving treatment with radiotherapy was significantly lower for patients with comedo carcinoma, multifocal lesions, or unclear resection margins, regardless of whether the histological type was comedo or non-comedo carcinoma. Metastasis-free survival was significantly lower for patients with multifocal lesions and for patients with unclear margins after excision of comedo carcinoma., Conclusions: Breast-conserving treatment with radiotherapy is a valid alternative to mastectomy. Patients must be selected carefully on the basis of morphological criteria. Swift gains in therapeutic outcome can be obtained by stressing quality control at each stage of diagnosis and treatment.

Hormone-replacement therapy (HRT) is widely used by post-menopausal women. Although this treatment may slightly increase the incidence of breast cancer, more and more cases are diagnosed while women are taking HRT. The purpose of this study was to ascertain the influence of HRT on prognostic factors and outcome of breast cancer. Data on all breast-cancer patients, including precise information on HRT, was prospectively and systematically recorded in a data base. From 1985 to 1995, 1379 post-menopausal women fulfilled the eligibility criteria for this study. All were treated by us (P.B. and L.P.) in our ward of a large public hospital of Marseilles, France. The clinical features, laboratory findings and survival rates in 142 HRT users who developed breast cancer while being treated were compared with those of 284 matched never user breast-cancer patients. Patients who developed breast cancer during HRT had fewer locally advanced cancers and smaller and better-differentiated cancers. Lymph-node involvement was significantly less frequent in the user group than in the non-user group (non-significant). Estradiol receptivity was both qualitatively and quantitatively lower in users. There was no significant difference with regard to recurrence and metastasis-free survival and overall survival. We conclude that HRT does not affect the prognosis of breast cancer. Regular surveillance during HRT allows early detection of smaller lesions. The higher number of well-differentiated cancers and the distribution of hormone receptivity may reflect interaction between neoplastic tissue and exogenous hormones.

Immunocytochemical assays of cathepsin D were assessed in a series of breast carcinomas (n = 257) using monoclonal M1G8 anti-total cathepsin D and the avidin-biotin-peroxidase complex. Cathepsin immunoreactivity was compared in frozen and paraffin sections. All tumours were anti-cathepsin-positive. Positive staining was observed in carcinoma and stromal cells and in the extracellular matrix. The amount of immunodetectable cathepsin in tissue was measured by computer-assisted image analysis (SAMBA 2005). Both the percentage of immunostained tumour surface and the mean optical densities were processed as continuous variables for statistical analysis and correlated with prognostic factors. It was shown that cathepsin D was independent of the tumour size, the lymph node status, hormone receptors, and pHER-2/neu overexpression. Cathepsin was significantly correlated with anti-EGFR (P = 0.012) and Ki67 (P = 0.002) immunoreactivity, tumour grade (P = 0.032), vascular invasion (P = 0.0081), proliferation index (P = 0.0045), and, to a lesser extent with AgNORs (P = 0.0504) and the degree of hyperploidy (P = 0.057). Tissue fixation and paraffin embedding significantly decreased cathepsin immunoreactivity. These results show that cathepsin D is not a totally independent prognostic factor in breast carcinomas.