Locally advanced/inflammatory breast cancers treated with intensive epirubicin-based neoadjuvant chemotherapy: are there molecular markers in the primary tumour that predict for 5-year clinical outcome?

BACKGROUND: Locally advanced and/or inflammatory breast cancer (LABC) is a heterogeneous disease. Molecular markers may help to understand this heterogeneity. This paper reports the results of a study assessing the potential prognostic or predictive value of HER-2, p53, cyclinD1, MIB1, ER and PgR expression by immunohistochemistry from patients included in an EORTC-NCIC-SAKK trial. PATIENTS AND METHODS: A total of 448 patients with a cytological or histological diagnosis of LABC were randomised into a trial comparing two anthracycline-based neoadjuvant regimens. Chemotherapy was followed by standard locoregional therapy. Survival was comparable in both arms. We collected and analysed centrally paraffin-embedded tumour specimens from 187 (72.5%) of 258 patients that had a histological diagnosis. RESULTS: Of the patients included in this molecular marker study 114 relapsed and 91 died. In the multivariate analysis p53 positivity was associated with a shorter progression-free survival [hazard ratio (HR) = 1.96; 95% CI 1.33-2.91; P = 0.0008) and a shorter overall survival (HR = 1.98; 95% CI 1.28-3.06; P = 0.002). PgR positivity predicted for a longer overall survival (HR = 0.54; 95% CI 0.35-0.83; P = 0.0045). CONCLUSIONS: p53 was an independent factor predicting for survival. In order to clarify whether p53 is a pure prognostic and/or a predictive factor, a phase III trial is being conducted (EORTC 10994/BIG 00-01 study) using functional assay in yeast from frozen tumour samples.

Detecting tumor-related alterations in plasma or serum DNA of patients diagnosed with breast cancer.

Chromosomal abnormalities are associated with the development of breast cancer, and widespread allelic loss or imbalance is frequently found in tumor tissues taken from patients with this disease. Using different markers, we studied a total of 61 patients (divided into three groups) for the presence of microsatellite instability and loss of heterozygosity (LOH) in plasma or serum DNA. Of the initial 27 patients, 35% of the tumor samples displayed LOH, whereas 15% had identical alterations in the corresponding plasma samples. In addition, the adjacent normal breast tissue of two patients also displayed LOH. In a second group of 11 patients, 45% of the tumors displayed LOH, and 27% displayed identical plasma DNA alterations; one case displayed an identical LOH in adjacent nontumor tissue. In a third series of 23 patients also studied with tetranucleotide repeats, 81% of the tumor samples displayed LOH, whereas 48% had LOH in the corresponding serum samples. The fact that small tumors (T1) of histoprognostic grade 1 or in situ carcinomas could present DNA alterations in the plasma/serum at an early stage, allied to the widely increased range of available microsatellite markers, suggests that plasma or serum DNA may become a useful diagnostic tool for early and potentially curable breast cancer.

Relation of smoking to breast cancer by estrogen receptor status.

It has been suggested that smoking is associated with estrogen-negative breast cancer but not with estrogen-positive breast cancer. A population-based case-control study was conducted in Geneva, Switzerland, to determine the relation of passive and active smoking to breast cancer when the referent unexposed category consisted of women unexposed to active and passive smoke. The 242 patients with breast cancer (cases), in whom estrogen receptor (ER) status was determined on biopsy material, were compared with 1,059 women free of breast cancer (controls). Lifetime history of active and passive smoking was recorded year by year, between age 10 and the date of interview. Prevalence rates of ER+ tumors were 74.7% in pre-menopausal women and 74.2% in post-menopausal women. Post-menopausal active smokers had a lower prevalence of ER+ tumors (70.0%, p = ns). Among pre-menopausal women, the age-adjusted ORs of breast cancer with having smoked an average of > or = 20 cigarettes per day (cpd) during lifetime were 2.7 for ER- tumors and 2.6 for ER+ tumors. Among post-menopausal women, corresponding ORs were 5.7 for ER- tumors and 2.4 for ER+ tumors. Smoking was related to both ER- and ER+ breast cancer in pre- and post-menopausal women, but the strength of the association appeared to be greater for ER- tumors among post-menopausal women.

Cytologic diagnosis of isolated pancreatic alveolar hydatid disease with immunologic and PCR analyses. A case report.

BACKGROUND: Alveolar hydatid disease (AHD) is a rare and severe parasitic infection caused by the larval stage of the fox tapeworm, Echinococcus multilocularis. AHD mainly involves the liver, and although it may extend progressively to the pancreas, isolated pancreatic localization has not been reported previously. CASE: A 68-year-old white female presented with a multicystic mass in the pancreas. Fine needle aspiration showed some protoscolices, free hooklets and fragments of laminated layer, which are pathognomonic features of echinococcosis. Serologic analyses by an enzyme-linked immunosorbent assay using Em2plus antigen showed high antibody reactivity of the patient's serum, which is indicative of an infection with E multilocularis. Diagnosis was finally confirmed by molecular and immunologic analyses of the cytologic material by polymerase chain reaction and direct immunofluorescence. CONCLUSION: This case illustrates the value of cytology in the identification of echinococcosis, particularly when it involves extrahepatic sites, where the risk of misdiagnosis may be related to its extremely rare occurrence. Precise parasitologic tying of E multilocularis in endemic areas is important.

Undifferentiated carcinoma of the gallbladder. Report of a case with immunohistochemical findings.

One case of undifferentiated carcinoma of the gallbladder was studied using an extensive immunohistochemical panel of antibodies. The biphasic differentiation of the tumor was highlighted by different immunoreactivity to antibodies against cytokeratins, vimentin, epithelial membrane antigen, and carcinoembryonic antigen of the adenocarcinomatous and mesenchymallike components, although the latter showed a faint positivity for CAM5.2 antibody, probably indicating an epithelial origin. Furthermore, the higher levels of expression of p53 protein and the faster growth rate in the pseudosarcomatous component suggest its more malignant phenotype. The relationship with "true" carcinosarcomas of the gallbladder and the histogenetic theories concerning these tumors are also discussed.

Transfusion-associated graft-versus-host disease in a patient treated with Cladribine (2-chlorodeoxyadenosine): demonstration of exogenous DNA in various tissue extracts by PCR analysis.

Transfusion-associated graft-versus-host disease can occur in both immunocompetent and immunocompromised hosts. Cladribine is a synthetic analogue of adenine used in the treatment of lymphoid malignancies, commonly associated with a decrease in T lymphocytes. Cladribine was given for a low-grade non-Hodgkin's lymphoma with thrombocytopenia as the main side-effect. Six units of pooled non-irradiated platelets were transfused from six unrelated donors; 10 d later a clinical picture typical of graft-versus-host disease resulted. Polymerase chain reaction of the highly polymorphic DNA minisatellites and HLA-DR oligotyping were used to demonstrate the exogenous DNA. In the patient's blood and tissues, only the pattern of donor 5 was found. The patient (DRB1*0301/1101; DRB3*0101/02) and this donor (DRB1*0301/1104; DRB3*02) by chance shared a partial common haplotype. This complication highlights the sensitivity of DNA minisatellite analysis. It further raises the question of transfusion and of prophylactic irradiation of all blood products in immunosuppressed patients and those treated with cladribine. This case represents a previously unreported situation where an immunosuppressed patient was able to eliminate cells from five totally HLA-DR dissimilar donors but not from one heterozygous donor with strong HLA-DR similarity.